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1 Italian Journal of Gynaecol og y & Obstetrics The Official Journal of the Società Italiana di Ginecologia e Ostetricia (SIGO) March Vol N. 1 - Quarterly - ISSN Quarterly Partner-Graf 1

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3 Italian Journal of Gynae col og y & Obstetrics The Official Journal of the Società Italiana di Ginecologia e Ostetricia (SIGO) Quarterly Partner-Graf

4 Editor in Chief Paolo Scollo, Catania Editors Herbert Valensise, Roma Enrico Vizza, Roma Editoral Board Cervigni Mauro, Roma Chiantera Vito, Napoli Costa Mauro, Genova De Stefano Cristofaro, Avellino De Vita Davide, Salerno La Sala Giovanni Battista, Reggio Emilia Locci Maria Vittoria, Napoli Marci Roberto, Roma Monni Giovanni, Cagliari Ragusa Antonio Franco, Milano Sirimarco Fabio, Napoli Trojano Vito, Bari Viora Elsa, Torino Editoral Staff Roberto Zerbinati Serena Zerbinati Management, Administrative office Partner-Graf Srl - Via F. Ferrucci, Prato Tel Fax The Italian Journal of Gynaecology & Obstetrics is a digital magazine. You can download it freely from or

5 It. J. Gynaecol. Obstet. 2014, 26: N.4 Table of contents Editorial. The two genes and the Jolie s Sindrome Paolo Scollo Laparoscopic radical hysterectomy with the use of SNAIL Tenaculum. A simplified uterine manipulator for the management of early cervical cancer Francesco Barletta, Giacomo Corrado, Enrico Vizza 6 9 Vaginal Erbium Laser: the Second Generation Thermotherapy for the Genitourinary Syndrome of Menopause (GSM) in Breast Cancer Survivors. A preliminary report of a pilot study Marco Gambacciani, Marco Levancini New therapeutic strategies in short cervical length: Arabin pessaries Lucio Juliano, Fabiana De Benedictis, Teresa Guarino, Maria Giovanna Schiattarella Studio Aldati Napoli Serum C-reactive protein as potential independent prognostic factor for breast cancer Adela Stoenescu, Christoph Gerlinger, Erich Franz Solomayer, Christoph Scholz, Ingolf Juhasz- Böss, Julia Radosa

6 It. J. Gynaecol. Obstet. 2015, 27: N.1 Editorial The two genes and the "Jolie's Sindrome" Paolo Scollo The recent decision of Angeline Jolie to undergo to a prophylactic BSO and, the following worldwide media debate focused again the attention of millions of women on this topic. Not always in the right way. BRCA1 and BRCA2 are human genes that produce tumour suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cell s genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer. A harmful BRCA1 or BRCA2 mutation can be inherited from a person s mother or father. Each child of a parent who carries a mutation in one of these genes has a 50 percent chance of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a person s second copy of the gene is normal. Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall. Breast cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than sporadic breast cancers. Moreover, harmful mutations in BRCA1 and BRCA2 increase the risk of several cancers in addition to breast and ovarian cancer. BRCA1 mutations may increase a woman s risk of developing fallopian tube cancer and peritoneal cancer. Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are also at increased risk of breast cancer. Men with harmful BRCA1 or BRCA2 mutations have a higher risk of prostate cancer. Men and women with BRCA1 or BRCA2 mutations may be at increased risk of pancreatic cancer. Several options are available for managing cancer risk in individuals who have a known harmful BRCA1 or BRCA2 mutation. These include enhanced screening, prophylactic (risk-reducing) and surgery. Enhanced Screening. Some women who test positive for BRCA1 and BRCA2 mutations may choose to start screening at younger ages than the general population or have more frequent screening. For example, some experts recommend that women who carry a harmful BRCA1 or BRCA2 mutation undergo clinical breast examinations beginning at age 25 to 35 years. And some expert groups recommend that women who carry such a mutation have a mammogram every year, beginning at age 25 to 35 years. Unfortunately, no effective methods of ovarian cancer screening currently exist. Some groups recommend transvaginal ultrasound examinations, blood tests for the antigen CA-125, and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 mutations, but none of these methods appears to detect ovarian tumours at an early enough stage to reduce the risk of dying from ovarian cancer. The benefits of screening for breast and other cancers in men who carry harmful mutations in BRCA1 or BRCA2 is also not known, but some expert groups recommend that men who are known to carry a harmful mutation undergo regular mammography as well as testing for prostate cancer. 6 Prophylactic (Risk-reducing) Surgery. Prophylactic surgery involves removing as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed (bilateral prophylactic mastectomy) to reduce their risk of breast cancer. Surgery to remove a woman's ovaries and fallopian tubes (bilateral prophylactic salpingo-oophorectomy) can help reduce her risk of ovarian cancer. Removing the ovaries also reduces the risk of breast cancer in premenopausal women by eliminating a source of hormones that can fuel the growth of some types of breast cancer. Prophylactic surgery does not completely guarantee that cancer will not develop because not all at-risk tissue can be removed by these procedures. Some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. Nevertheless,

7 Editorial the mortality reduction associated with this surgery is substantial: one study showed that women who underwent bilateral prophylactic salpingo-oophorectomy had a nearly 80 percent reduction in risk of dying from ovarian cancer and a more than 50 percent reduction in risk of dying from breast cancer. No evidence is available regarding the effectiveness of bilateral prophylactic mastectomy in reducing breast cancer risk in men with a harmful BRCA1 or BRCA2 mutation or a family history of breast cancer. Therefore, bilateral prophylactic mastectomy for men at high risk of breast cancer is considered an experimental procedure, and insurance companies will not normally cover it. World Health Organization criteria for population screening for genetic predisposition to disease are that the disease is an important public health burden in the target population; that the risk of disease due to mutations in the screened genes is known; and that effective intervention exist to reduce morbidity and mortality among genetically susceptible individuals. At present, the US Preventive Services Task Force (USPSTF) supports BRCA1 and BRCA2 testing based on family history and ancestry, but not for the entire female population, given the lack of data on risks for mutation carriers ascertained from the general population, rather than through a personal or family history of cancer. This position was correct based on the data then available. However, a just-completed study now provides evidence that supports offering BRCA1 and BRCA2 sequencing to all women. Population-based screening enables mutation carriers to be identified independent of physician referral or family involvement. This is important, because at present, there is marked variability in practice in following the USPSTF guidelines. A recent survey revealed that only 19% of US primary care physicians accurately assessed family history for BRCA1/BRCA2 testing. Population-wide screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that protect them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2. Therefore, the role of both gynecologists and oncologists to educate the population is cucial if we want to avoid that this process will be emotionally influenced by the media generating a new collective syndrome. Prof. Paolo Scollo S.I.G.O. President 7

8 FARMACEUTICAMEV IN GINECOLOGIA LA NATURA CHE AIUTA ClimaMEV IncontinenzaMEV VenaMEV FARMACEUTICA MEV - Strada Cassia Sud, Siena (SI) Tel / Fax

9 Laparoscopic radical hysterectomy with the use of SNAIL Tenaculum. A simplified uterine manipulator for the management of early cervical cancer Francesco Barletta 1, Giacomo Corrado 2, Enrico Vizza 2 1 Gynecology and Obstetrics Unit, San Giovanni-Addolorata Hospital, Rome, Italy 2 Gynecologic Oncology Unit, Regina Elena National Cancer Institute, Rome, Italy ABSTRACT Objective: To evaluate safety and efficacy of the SNAIL Tenaculum uterine manipulator (Simple Nebs Arising Incision Landmark) for total laparoscopic radical hysterectomy in early cervical cancer. Material and Methods: SNAIL Tenaculum uterine manipulator origin by a surgical reusable instrument named Uterine Tenaculum Forceps, model Schroder (code of Martin catalogue). It is modified adding two or four nebs 1-2 cm of distance from the tips of the instrument. We grasped the cervix with SNAIL Tenaculum and n order to preserve an adequate pneumoperitoneum during colpotomy surgical gloves are placed in vagina. Results: Twenty patients with early cervical cancer underwent total laparoscopic radical hysterectomy used SNAIL Tenaculum uterine manipulator. During surgery the nebs were always under vision and the median length of vagina removed was 21 mm. (range 10-40mm). None intra-operative complications were registered. Conclusion: We found SNAIL Tenaculum to be a safe and efficient tool with lowest cost so far recorded. It eliminated risks of perforation and LVS involvement, maintaining good uterine mobility. Also the nebs allow surgeon to choose the length of vaginal wall to be removed. Keywords: Simple Nebs Arising Incision Landmark; SNAIL Tenaculum uterine manipulator; laparoscopic radical hysterectomy; early cervical cancer SOMMARIO Obiettivi: Valutare la sicurezza e l efficacia della pinza da presa SNAIL Tenaculum come manipolatore uterino per l isterectomia radicale laparoscopica nel trattamento del cancro cervicale iniziale. Materiali e metodi: Lo SNAIL Tenaculum origina da uno strumento chirurgico riutilizzabile denominato Uterine Tenaculum Forceps, modello Schroder (codice del catalogo Martin degli strumenti chirurgici). Questa pinza fu modificata aggiungendo due o quattro rebbi, di 0.8-1cm di lungezza, a 1 o 2 cm di distanza dall estremità dello strumento. Prima dell intervento chirurgico, la cervice fu pinzata e chiusa con lo SNAIL Tenaculum e il pneumoperitoneo, durante la colpotomia circolare, fu mantenuto inserendo alcuni guanti chirurgici nella vagina. Risultati: 20 pazienti furono sottoposte a isterectomia radicale laparoscopica con l utilizzo dello SNAIL Tenaculum. Durante l intervento chirurgico i rebbi furono sempre evidenziati attraverso la parete vaginale anche nelle pazienti obese. La vagina rimossa fu mediamente di 21 mm (range, tra 10 e 40 cm) e nessuna complicazione intraoperatoria si verificò. Conclusioni: Lo SNAIL Tenaculum si rilevò un manipolatore uterino sicuro, valido e di basso costo eliminando i rischi di perforazione uterina e di coinvolgimento neoplastico degli spazi linfovascolari, mantenendo una buona mobilità uterina e permettendo al chirurgo di scegliere la lunghezza di vagina da asportare. INTRODUCTION The advantages of minimally invasive gynecologic surgery have been described more recently even for oncologic cases such endometrial and cervical cancer (1,4). In a review by the SGO Clinical Practice Endometrial Cancer Working Group for the Society of Gynecologic Oncology Clinical Practice Committee (5) it refers in recommendations : laparoscopy should be embraced as the standard surgical approach for comprehensive surgical staging in women with endometrial cancer (level of evidence: A). Also in cervical cancer FIGO stage IB1,IB2,IIB, multiple studies and trials support the advantages of laparoscopic approach (6,8). The procedure of Total Laparoscopic Radical Hysterectomy (TLRH) performed in these cases assume using of uterine manipulator. Correspondence to: Copyright 2014, Partner-Graf srl, Prato At present there is no standard recommendation for use of manipulators in the surgical treatment of endometrial and cervical cancer. Risk of perforation, LVS involvement and positive peritoneal cytology by uterine manipulation is still debated. Should also be considered the costs of uterine manipulators both reusable and disposable. We evaluate safety and efficacy of a modified tenaculum called SNAIL Tenaculum (Simple Nebs Arising Incision Landmark ) for laparoscopic radical hysterectomy in early cervical cancer. MATERIAL AND METHODS We prospectively collected data from patients with cancer of the uterine cervix in FIGO stage IB1. All patients underwent a type C1 laparoscopic radical hysterectomy plus pelvic 9

10 It. J. Gynaecol. Obstet. 2015, 27: N.1 lymphadenectomy, with the use of SNAIL Tenaculum like uterine manipulator. This invention origin by a surgical reusable instrument named Uterine Tenaculum Forceps, model Schroder, code of Martin catalogue. This tenaculum is modified adding two or four nebs 1-2 cm of distance from the tips of the instrument. The nebs are 0,8-1 cm each and widen with a 90 degrees angle between them. They can be perpendicular to main axis of instrument or forming with latter degrees angle bent forward (Figure 1). In order to preserve an adequate pneumoperitoneum during colpotomy surgical gloves are placed in vagina. Surgical technique No uterus manipulator devices were used, but the cervix were grasped with a SNAIL (Figure 2) and a iodine gauze with some gloves, depending by width of the vagina, were emplaced in vagina in order to preserve an adequate pneumoperitoneum during colpotomy. Figure 2: Cervix is grasped with a SNAIL Tenaculum 10 Figure 1: Simple Nebs Arising Incision Landmark (SNAIL) uterine manipulator Inclusion criteria were: good general condition, tumor size < 3 cm, no evidence of lymph node metastases in imaging study (MRI and/or CT and/or PET). BMI was not a considered an exclusion criterion. All patients were staged according the most recent FIGO clinical staging system (9). All patients received a bowel preparation preoperatively, and antithrombotic prophylaxis with subcutaneous low-molecular weight heparin. Approval to conduct the study was obtained independently from an internal review board at each participating institution. Clinical patient characteristics included age, body mass index (BMI), histopathological subtype, and tumour grade. Intraoperative parameters evaluation included operative time, complications, and blood loss. Blood transfusions were administrated if Hb value was 7 g/l. Postoperative parameters included short-term (within 30 days of the procedure), and longterm complications (more than 30 days after the procedure); moreover, status of the surgical margins, status and number of pelvic lymph nodes removed, length of dissected vagina, width of bilateral parametrium were evaluated, along with length of hospitalization, time to recovery of normal bladder function. The first step of our technique consist of open the all retroperitoneal spaces according to the following sequence: paravescical space, pararectal lateral space (Latzko), pararectal medial space (Okabayashi), rectovaginal space and vescicovaginal space. The second step is the en bloc level 1 and level 2 pelvic lymphadenectomy according to Queleu and Morrow classification (10). Para-aortic lymphadenectomy is not routinely performed unless suspicious pelvic lymph nodes are confirmed to have metastatic disease on frozen section evaluation in order to determine the field of postoperative radiation. Afterwards, type C1 radical hysterectomy was performed as described by Querleu and Morrow. During surgery, we used an advanced multifunctional ultrasounds instrument (Ethicon Harmonic Ace curved shears ) to dissect, cut and coagulate. In young patients whose ovarian function needs to be preserved, the ovaries are transposed laterally to the para-colic gutters and fixed securely to the abdominal wall, or else the ovaries are moved from the infundibulopelvic vessels with a caution of the ureter. After a careful control of blood loss, to minimize the risk of port site metastases, the vagina prior to removal of the ports and all the ports sites are irrigated with 5% povidine iodine solution prior to completion of the surgery. In all patients the urine catheter is removed 3 days after

11 F. Barletta et al. operation and an intermittent self catheter is used for voiding until the residual urine volume is less than 100 ml. RESULTS From Jannuary 2013 to December 2014, twenty patients were included into the study. The median age was 46 years (range, 25 65), median BMI was 24 kg/m2 (range, kg/m2). There were not conversion to abdominal surgery and all patients underwent total laparoscopic radical hysterectomy (type C1) and pelvic lymphadenectomy (Table I). Table I: Clinical characteristics of the 20 women with early cervical cancer underwent TLRH with pelvic lymphadenectomy with use of SNAIL manipulator Characteristics Patients Median Age (years) 44 (19-72) Median BMI (kg/m 2 ) 24 (16-34) Median tumour size (mm) 15 (10-30) Previous abdominal surgery 10 (50%) Histology Squamous Adenocarcinoma Grading G1 G2 G3 13 (65%) 7 (35%) 1 (5%) 8 (10%) 11 (55%) The surgical outcomes are summarized in Table II. The median operating time was 188 minutes (range, minutes) with no limitation of BMI. The median blood loss was 240 ml (range, ml); none of the patients required intraoperative blood transfusion, while two patients had a postoperative blood transfusion. The median number of removed pelvic lymph nodes was 21 (range, 10 37). Five squamous cell carcinoma and one adenocarcinoma patients had a total of 9 positive pelvic nodes at frozen section. In these patients, lymphadenectomy was extended to the para-aortic nodes, with negative specimens. The superior border of the dissection in the para-aortic lymphadenectomy was the inferior mesenteric artery and the median number of removed para-aortic lymph nodes was 7 (range, 5 11). The median length of dissected vagina was 21 mm (range, mm). The median width of parametrium was 24 mm on the right side (range, mm) and 25 mm on the left side (range, 15 50). The surgical margins were free of disease in all cases. Table II: Surgical outcome of the 20 patients with early cervical cancer operated by TLRH with pelvic lymphadenectomy with use of SNAIL manipulator Characteristics TRRH Median operative time (min) 188 ( ) Median blood loss (ml) 240 (30 480) Median pelvic lymph nodes 21 (10 37) Median width right parametrium (mm) Median width left parametrium (mm) 24 (10 50) 25 (15 50) Median length vaginal cuff (mm) 21 (15 45) Major intraoperative complications Major early postoperative complications Major late postoperative complications 1 (5%) 2 (10%) 9 (25%) Blood transfusion 2 (10%) Conversion to laparotomy 0 Reoperation 0 Median hospital stay (days) 4 (2 10) There was one intra-operative complication: one patient had injury of the left hypogastric vein and promptly repaired during the same laparoscopic surgery with a total blood loss of 480 ml. She needed a post operative of blood transfusion. There were two postoperative short term complications: in one case postoperative pelvic bleeding was successfully recovered by drainage; the other woman suffered from lymphocyst on the 10th day post-operation. The median hospital stay was 4 days (range, 3 10 days). The self catheter commenced postoperatively from day 3. The time to resumption of normal bladder function ranged from 10 days to 3 months. Four patients treated with radiation therapy and three with chemoradiation plus brachytherapy showed a worsening in condition. Long term complications were: 2 patients suffered urinary incontinence; 2 patients had constipation, while other 1 patient had dyspareunia. Of these 5 patients, 3 patients had undergone further radiotherapy. Adjuvant therapy was administrated in 10 patients. Six patients, with pelvic lymph nodes metastasis, underwent adjuvant radiochemotherapy. Four patients underwent adjuvant radiotherapy for lymph-vascular space invasion (LVSI) and high grade lesion. 11

12 It. J. Gynaecol. Obstet. 2015, 27: N.1 12 The median follow-up was 12 months (range, 3 27) and although our median follow-up is still less than 3 years of survival, all patients are alive without disease. DISCUSSION Most gynecologic surgeons appreciate the advantages of uterine manipulation during hysterectomy procedures because of the improved visualization of key anatomic structures throughout the dissection. However there have been concerns that uterine cancer pathology may be altered (increased LVSI) from uterine manipulators (11,13) and some investigators choose not to use manipulators in cervical cancer (14,16) without mentioning the risk of perforation and positive peritoneal cytology. In a prospective randomized clinical trial about effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer (17) the authors did not find an increase rate of positive peritoneal cytology or lymphovascular space invasion after using of a uterine manipulator. Subsequently on International Journal of Gynecological Cancer appeared a comment (18) on Lee paper showing some limitations of the study. Between them the uterine manipulator was inserted after ligation of both the fallopian tubes so one would not expect to find endometrial cancer cell spillage. Moreover the risk of perforation when using a uterine manipulator in endometrial cancer patients was not mentioned. This may reflect publication bias of relatively rare complications. In patients with deep myometrial invasion this may be important. Since that over 70% of the included patients have less than 50% myometrial invasion, this study may be underpowered to detect differences in recurrence. Larger series are necessary to confirm the findings as well as the risks of perforation on outcome. At present there is no standard recommendation for use of uterine manipulators in the surgical treatment of endometrial and cervical cancer. The influence on both surgical and oncological outcome using the already known uterine devices is unclear. The risk of perforation, lympho-vascular spaces (LVS) involvement and positive peritoneal cytology by uterine manipulation is still debated. A uterine manipulator performs the following functions: manipulates the uterus stretching the side being operated upon and brings the uterus closer to the surgical laparoscopic instruments facilitating the procedure; increases the distance between the uterus and bladder, ureters, rectum thus reducing the chance of injury; facilitates identification of the vaginal cuff just below the cervical attachment; pulls the uterus vaginally after its complete detachment and maintains the pneumoperitoneum following colpotomy. An ideal uterine manipulator to perform TLRH in endometrial or cervical cancer should have the following characteristics: easy to assemble, inexpensive, does not fragment or break down into pieces during the procedure, none risk of perforation, has a good range of mobility and mobilizes the uterus in anteversion, retroversion and lateral movements, should close external uterine orifice to avoid endometrial cells leakage in vagina, facilitates identification of the vaginal cuff choose the length of vaginal wall to be removed modulating, proximally or distally, the incision line. There are many uterine manipulators available; some manipulators are reusable (ideal), some are disposable and some are partially disposable and partially reusable such that the tips are disposable but the handle is reusable. Complications attributable to the use of uterine manipulators include cervical lacerations, uterine perforation, laceration of the uterine vessels, retroperitoneal or intraperitoneal bleeding, perforation of the bowel, rectum or bladder, ascending infection, interruption of unsuspected intrauterine pregnancy and retention of part of the manipulator as a foreign body. In oncologic cases we were looking for something which doesn t stress the inner surface of the uterus, without any pushing or squeezing the endometrium and the cervical canal, which are the sites of neoplasm, and without any possible leakage of neoplastic cells in vagina. So the solution for our needs was close our eyes. We did a simple modification of an instrument very familiar and used by gynecologists worldwide: a surgical reusable instrument named Uterine Tenaculum Forceps, model Schroder, code of Martin catalogue. This tenaculum is modified adding two or four nebs 1-2 cm of distance from the tips of the instrument. The nebs are 0,8-1 cm each and widen with a 90 degrees angle between them. They can be perpendicular to main axis of instrument or forming with latter degrees angle bent forward in order to respect the different angle of the posterior fornix, despite the anterior, with the vagina. The nebs expose very clearly the vagina for colpotomy and allow surgeon to choose the length of vaginal wall to be removed modulating, proximally or distally

13 F. Barletta et al. to them, the incision line. In some patients, not included in the study, the SNAIL Tenaculum has poor chances to fix the uterus since the disappearance of the cervix after amputation or radiochemotherapy (RTCT). We found SNAIL Tenaculum to be a safe and efficient tool for patients who undergoing TLRH since it eliminates risks of perforation, LVS involvement and positivization of peritoneal cytology, maintaining good chances of uterine mobility. Also the nebs allow surgeon to choose the length of vaginal wall to be removed. Last, but not least, must be said SNAIL Tenaculum combines the ease of use of a very familiar instrument to gynecologists, widespread at all latitudes, with the lowest cost so far recorded. COMPETING INTERESTS The authors report no conflicts of interest. The authors are responsible for the content and writing of the paper. REFERENCES 1) Palomba S, Falbo A, Mocciaro R, Russo T, Zullo F. Laparoscopic treatment for endometrial cancer: a meta-analysis of randomized controlled trials (RCTs). Gynecol Oncol.2009;112: ) Gaia G, Holloway RW, Santoro L, Ahmad S, Di Silverio E, Spinillo A. Robotic-assisted hysterectomy for endometrial cancer compared with traditional laparoscopic and laparotomy approaches: a systematic review. Obstet Gynecol 2010; 116: ) Lu D, Liu Z, Shi G, Zhou X. Robotic assisted surgery for gynaecological cancer. Cochrane Database Syst Rev 2012;18:1 4) Ramirez PT, Adams S, Boggess JF, Burke WM, Frumovitz MM, Gardner GJ, Havrilesky LJ, Holloway R, Lowe MP, Magrina JF, Moore DH, Soliman PT, Yap S. Robotic-assisted surgery in gynaecologic oncology: a Society of Gynecologic Oncology Consensus Statement Developed by the Society of Gynecologic Oncology s clinical Practice Robotics Task Force. Gynecol Oncol 2012;124: ) SGO Clinical Practice Endometrial Cancer Working Group. Endometrial cancer: a review and current management strategies: Part I. Gynecol Oncol 2014;134, ) Ghezzi F, Cromi A, Ditto A, Vizza E, Malzoni M, Raspagliesi F, Uccella S, Corrado G, Cosentino F, Gotsch F, Martinelli F, Franchi M Laparoscopic Versus Open Radical Hysterectomy for Stage IB2-IIB Cervical Cancer in the Setting of Neoadjuvant Chemotherapy: A Multi-institutional Cohort Study. Ann Surg Oncol. 2013; 20(6): ) Pellegrino A, Vizza E, Fruscio R, Villa A, Corrado G, Villa M, Dell'anna T, Vitobello D. Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in patients with Ib1 stage cervical cancer: Analysis of surgical and oncological outcome. Eur J Surg Oncol. 2009; 35(1): ) Vizza E, Pellegrino A, Milani R, Fruscio R, Baiocco E, Cognetti F, Savarese A, Tomao F, Chen C, Corrado G. Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in locally advanced stage IB2-IIB cervical cancer patients after neoadjuvant chemotherapy. Eur J Surg Oncol. 2011;37(4): ) Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix and endometrium. Int J Gynaecol Obstet 2009;105(2): ) Querleu D,Morrow CP. Classification of radical hysterectomy. Lancet Oncol.2008; 9(3): ) Kitahara S, Walsh C, Frumovitz M, Malpica A, Silva EG. Vascular pseudo-invasion in laparoscopic hysterectomy specimens for endometrial carcinoma: a grossing artifact? Am J Sur Pathol 2009;33: ) Logani S, Herdman AV, Little JV, Moller KA. Vascular Pseudo-invasion in laparoscopic hysterectomy specimens: a diagnostic pitfall. Am J Sur Pathol 2008; 32: ) Krizova A, Clarke BA, Bernardini MQ, James S, Kalloger SE, Boerner SL, Mulligan AM. Histologic artefacts in abdominal, vaginal, laparoscopic, and robotic hysterectomy specimens : a blinded, retrospective review. Am J Surg Pathol 2001; 35: ) Shafer A, Boggess JF. Robotic-assisted endometrial cancer staging and radical hysterectomy with the Da Vinci surgical System. Gynecol Oncol 2008; 111(Suppl.2): ) Estape R, Lambrou N, Diaz R, Estape E, Dunkin N, Rivera A. A case matched analysis of robotic radical hysterectomy with lymphadenectomy compared with laparoscopy and laparotomy. Gynecol Oncol 2009; 113: ) Magrina J, Kho R, Magtibay PM. Robotic radical hysterectomy: technical aspects. Gynecol Oncol 2009; 113: ) Lee M, Kim YT, Kim SW, Kim S, Kim JH, Nam EJ. Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective randomized clinical trial. Int J Gynecol Cancer. 2013;23(2): ) Smid AT, Piek JM, Pijnenborg JM. Comments on "Effects of uterine manipulation on surgical outcomes in laparoscopic management of endometrial cancer: a prospective randomized clinical trial". Int J Gynecol Cancer. 2013;23(6):980 13

14 14 It. J. Gynaecol. Obstet. 2015, 27: N.1

15 Vaginal Erbium Laser: the Second Generation Thermotherapy for the Genitourinary Syndrome of Menopause (GSM) in Breast Cancer Survivors. A preliminary report of a pilot study Marco Gambacciani 1, Marco Levancini 1, 2 1 Department of Obstetrics and Gynecology, Pisa University Hospital 2 Department of Obstetrics and Gynecology, Clinica Alemana, Universidad Del Desarrollo, Santiago. Chile ABSTRACT This is a preliminary report of a pilot study aimed to assess the effectiveness and safety of vaginal erbium laser in the treatment of Genitourinary Syndrome of Menopause (GSM) in postmenopausal breast cancer survivors. GSM symptoms were assessed before and after three applications of erbium laser in 13 women, using subjective (visual analog scale) and objective (Vaginal Health Index Score, VHIS) measures. Vaginal Erbium laser treatment was effective to improve GSM symptoms. Both subjective and objective scores significantly improved in comparison with baseline values ( p <0.01). No adverse events were recorded during the study period. This preliminary results suggest that Vaginal Erbium Laser is effective and safe for the treatment of GSM in postmenopausal Breast Cancer Survivors. SOMMARIO Il lavoro riporta una analisi preliminare di uno studio pilota condotto per valutare efficacia e sicurezza del trattamento con laser Erbium vaginale della sindrome genitourinaria della menopausa (Genitourinary Syndrome of Menopause, GSM) in donne in postmenopausa dopo trattamento per una carcinoma della mammella. I sintomi sono stati valutati in 13 donne, usando scale per la valutazione soggettiva (VAS, visual analog scale) e oggettiva (Vaginal Health Index Score, VHIS). Il trattamento con laser Erbium vaginale è risultato capace di ridurre la sintomatologia della GSM. Sia gli score soggettivi che quelli oggettivi hanno mostrato un significativo miglioramento rispetto ai valori basali ( p <0.01). Non sono stati riscontrati eventi avversi durante lo studio. In conclusione, questi risultati preliminari suggeriscono che il con laser erbium possa rappresentare una alternative efficace e sicura per il trattamento della GSM in donne in postmenopausa dopo Carcinoma della Mammella. Keywords: Menopause, Estrogen, Erbium Laser, Genitourinary Syndrome of Menopause, Breast Cancer Survivors INTRODUCTION The genitourinary syndrome of menopause (GSM) may affect up to 50% of postmenopausal women and their symptoms tend to be progressive, jeopardizing the quality of life and sexual relationships (1-3). Local hormone replacement therapy (HRT) is the treatment of choice (2-5). However, many women have contraindications, such as a history of estrogen-dependent tumors, particularly endometrial cancer and breast cancer (2-5). No single agent can globally ameliorate the quality of life of breast cancer survivors, coping with menopausal symptoms. Particularly, specific studies on GSM treatment in breast cancer survivors are scarce. Laser technology is currently widely used with positive effects demonstrated on basic and clinical studies on tissue remodeling, collagenogenesis and angiogenesis (6-8). The different types of lasers have different physical Correspondence to: Copyright 2014, Partner-Graf srl, Prato characteristics that determine specific effects on tissues. Recently in a pilot study, Salvatore et al. (9) demonstrated that treatment with fractionated CO2 laser induced a significant improvement of the GSM in postmenopausal women. The aim of this study is to evaluate the short-term efficacy and acceptability of a second generation of vaginal laser treatment, using an erbium laser crystal yttrium-aluminum-garnet (Er: YAG) as a non-ablative photothermal therapy for the management of GSM in breast cancer survivors. MATERIAL AND METHODS This is a pilot study, conducted in women attending menopause clinic of Pisa University Hospital with an history of treated breast cancer and suffering from GSM. All patients gave written informed consent. The protocol was revised by an National Independent Advisory Board and approved by the Ethics Committee of the Department of Obstetrics and Gynecology. The 15

16 It. J. Gynaecol. Obstet. 2015, 27: N.1 16 procedures followed were in accordance with the ethical standards of the Committee on Institutional human experimentation, and with the Helsinky Declaration of 1975, as revised in Inclusion criteria were the presence of GSM in women with plasma levels of gonadotropin and estradiol in postmenopausal range (FSH> 40 U/L; estradiol <25 pg/ml) and negative PAP smear. Exclusion criteria were: lesions, scars or infection active or recents (30 days) of the genitourinary tract; abnormal uterine bleeding; use of lubricants or any other local preparation within 30 days prior inclusion to study; history of photosensitivity disorder or use of photosensitizing drugs; genital prolapse (grade II-III classification POP-Q); serious or chronic illness that could interfere with the fulfillment of the study; and have been treated with hormones or other medications to relieve menopausal symptoms in the previous 3 months. In this preliminary report, we show the results of patients suffering from severe GSM after a successful treatment for breast cancer. All patients women were treated with Erbium laser (XS Fotona Smooth, Fotona, Ljubljana, Slovenia) with a wavelength of 2940 nm. The diameter of the laser spot size was 7 mm, with a pulse according to the SMOOTH mode at a frequency of 1.6 Hz, and fluence (laser energy emitted per unit area) of 6.0 J/cm 2. The procedures were performed on an outpatient basis without anesthesia or drug use before or after the intervention. The treatment protocol consists of 3 laser applications every 30 days (L1, L2, L3) with a visit 2-4 weeks before treatment (V0) and a follow-up visit 4 and 12 weeks after the last application. After treatment, patients are recommended to have sexual abstinence for one week. Subjective symptoms (vaginal dryness and dyspareunia) were assessed using a visual analogue scale (VAS) at each visit (range 0-10, 0 = total absence of symptom and 10 cm = worst symptom) and the Vaginal Health Index Score (VHIS) was calculated. VHIS evaluates the aspect of the vaginal mucosa (elasticity, ph, vaginal discharge, mucosal integrity and moisture). These parameter were evaluated at baseline (T0), after the first (L1), second (L2) and third (T3) laser treatments, as well as after 4 (T+4) and 12 (T+12) weeks after the last laser treatment. Each parameter is graded from 1 to 5 being atrophic a total score 15 (10). In the post-treatment control, acceptability of therapy was asked, describing it as: excellent, good, fair, bad or unacceptable. Patients who leave the study before the deadline were considered dropouts. This is an interim report, of an ongoing study the sample size was not based on a statistical rationale. Data are presented as mean and standard deviation. Continuous variables were analyzed using the ANOVA for repeated measures and the Wilcoxon sign-rank test. Data were analyzed using StatView version 2.5 software (SAS Science, Chicago, IL, USA). RESULTS Table I show demographic characteristics of patients included in the study. Table I. Baseline characteristics of the breast cancer survivors (n=13) included in the study. Mean DS Min-Max Age Age at menopause Years since menopause Vaginal dryness and dyspareunia scores showed a progressive decrease after 1st, 2nd and 3rd treatment (p<0.01, Figure 1).. The results were maintained during the follow up, after 4 and 12 weeks from the last laser treatment (p<0.01, Figure 1). Figure 1. Effect of second generation laser thermotherapy on Dryness and Dyspareunia scales (10-point scale, cm) in 13 postmenopausal breast cancer survivors (* p< 0.01 vs basal values). See text for details. Conversely, VHIS values showed a significant increase during the treatment, and the results were maintained after 4 and 12 weeks from the last laser treatment (p<0.01, Figure 2). No adverse events related to the procedure were recorded throughout the study period. No patients dropped out from the study.

17 M. Gambacciani et al. Figure 2. Effect of second generation laser thermotherapy on Vaginal Health Index Score (VHIS) in 13 postmenopausal breast cancer survivors (* p< 0.01 vs basal values). See text for details. DISCUSSION The analysis of this preliminary study indicates that the second generation vaginal thermotherapy using Erbium laser is effective and safe for the treatment of GSM in postmenopausal breast cancer survivors. The results obtained in this small series of patients indicate that this method is practical, seems to be well accepted and not related to adverse events. In these particular set of patients the vaginal erbium laser improved the most bothersome symptoms, just after the first application of laser. Similar results were previously reported in normal postmenopausal women using either the Erbium laser (11), and the CO2 laser (9). These preliminary, short term results show that treatment with vaginal Erbium laser in breast cancer survivors suffering from severe GSM is feasible, effective and safe in the short term. Further studies are needed to evaluate the effectiveness and the safety of vaginal erbium laser treatment. If these results will be confirmed in properly sized and long-term studies, we will have a safe and effective option to treat GSM in women presenting contraindication to postmenopausal hormone use. AKNOWDLEGMENTS The AA express their thanks to the Members of National Independent Advisory Board, Prof Nicoletta Biglia, Torino; Prof. Rossella Nappi, Pavia; Prof. Anna Maria Paoletti, Cagliari, for their excellent work in revising the protocol. REFERENCES 1) Portman D. J. and Gass M. L. S. on behalf of the Vulvovaginal Atrophy Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women s Sexual Health and The North American Menopause Society. Climateric 2014; 17 (5): ) Sturdee D W, Panay N. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 2010; 13 (6): )Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013; 20: )Santen RJ, Allred DC, Ardoin SP, et al. Executive summary: Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010 ; 95 (Suppl 1) : s1 66 5) De Villiers T. J., A. Pines, N. Panay, M. Gambacciani, D. F. Archer, R. J. Baber, et al., on behalf of the International Menopause Society. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climateric 2013; 16: ) Kaufmann R, Hibst R. Pulsed Erbium:YAG laser ablation in cutaneous surgery. Lasers Surg Med. 1996;19(3): ) Levy JL, Trelles MA. New operative technique for treatment of xanthelasma palpebrarum: laser inverted resurfacing: preliminary report. Ann Plast Surg Apr; 50(4): ) Vizitin Z., Novel Minimally Invasive VSPEr:YAG Laser Treatments in Gynecology, J. LAHA, Vol. 2012, No.1; pp ) Salvatore S, Nappi R E, Zerbinati N, Calligaro A, Ferrero S, Origoni M, et al. A 12-week treatment with fractional CO 2 laser for vulvovaginal atrophy: a pilot study. Climacteric 2014;17:1 7 10)Bachmann GA, Notelovitz M, Kelly SJ, et al. Longterm nonhormonal treatment of vaginal dryness. Clin Pract Sexuality 1992 ; 8 : ) Gaspar A. Comparison of New Minimally Invasive Er:YAG Laser Treatment and Hormonal Replacement Therapy in the treatment of Vaginal Climacteric 2014;17(Suppl 1):48 108, P

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19 New therapeutic strategies in short cervical length: Arabin pessaries Lucio Juliano 1, Fabiana De Benedictis 2, Teresa Guarino 1, Maria Giovanna Schiattarella 3 Studio Aldati Napoli 1 A.O. A. Cardarelli Napoli (ITA) 2 A.O. S. Jacopo Pistoia (ITA) 3 A.O. M. Bufalini Cesena (ITA) ABSTRACT The progress made in the field of ultrasound in the diagnosis of threatened preterm delivery in the case of short cervical length (SCL) are unfortunately not paid advances in therapy, since actual treatment options are confined to the use of progesterone, micronized vaginally or orally, of antibiotics and indomethacin, which are also used vaginally or orally, of nifedipine, used orally, until reaching to promising use of lactoferrin or lactoglobulin, vaginally, or to the packaging of a surgical cerclage procedure now almost obsolete in most European countries because of the many complications that occurred. New perspectives seems to offer the application of silicone vaginal devices specifically designed to modify the cervical plasticity and reduce, with very striking mechanism as will be seen, the possibility of occurrence of segmental uterine contractions; for such features to cervical support such devices are called pessaries, whose function is mistakenly equated with classic surgical cerclage, invasive method, bloody, costly and much less effective in preventing preterm birth. Our experience is based on the application of 32 vaginal devices in the period October May 2014; of these 28 (p=87.5%) were placed in singleton pregnancies and 4 (12.5%) in twin pregnancies (3 bigemine pregnancies 1 and triplets). In 22/32 pregnant women (p=69%) the application of the pessary has been associated with the use of a medicament, as we shall see later in the specification, while in 10/32 (p=31%) was not associated with any medication. Surprisingly, the outcome of these 2 latter groups did not show substantial changes, so as to lead us to believe that the action of vaginal device is the real creator in obtained benefits. Last notation must be made on gestational period of positioning pessary that in the vast majority of cases occurred between 22 and 28 weeks (n=29, p=90%), while in only 3 cases (p=10%) the time of insertion was greater than 28 weeks. Almost all pregnant women had when inserting a BMI> 25 (n=30, p=94%), while only 2 were 25. Keywords: Arabin pessary, Flabby Cervix, Short Cervix, Preterm Delivery, Premature Rupture Of Membranes, Non-invasive cerclage SOMMARIO Ai progressi compiuti in campo ecografico nella diagnosi di minaccia di parto pretermine (MPP) nei casi di short cervical lenght (SCL) non sono purtroppo corrisposti progressi in campo terapeutico, dal momento che le opzioni terapeutiche ad oggi applicate sono confinate all utilizzo di progesterone, micronizzato per via vaginale o per via orale, di antibiotici e di indometacina, anch essi utilizzati per via vaginale o per via orale, alla nifedipina, utilizzata per via orale, al promettente utilizzo di lattoferrina o lattoglobulina, per via vaginale, e/o al confezionamento di un cerchiaggio chirurgico, procedura ormai quasi in disuso nella stragrande maggioranza dei Paesi Europei a causa delle numerose complicanze riportate. Nuove prospettive in tal senso sembra offrire l applicazione di dispositivi vaginali in silicone specificamente progettati per modificare la plasticità cervicale e ridurre, con meccanismo molto suggestivo come si vedrà, la possibilità di insorgenza di contrazioni segmentarie uterine; per tali funzioni di supporto cervicale tali dispositivi sono denominati pessari, la cui funzione è erroneamente assimilata al classico cerchiaggio chirurgico, metodica invasiva, cruenta, costosa e molto meno efficace nel prevenire il parto pretermine. La nostra esperienza personale si basa sull applicazione di 32 dispositivi vaginali nel periodo ottobre maggio 2014; di questi 28 (p=87.5%) sono stati posizionati in gravidanze singole e 4 (12.5%) in gravidanze gemellari (3 gravidanze bigemine e 1 trigemina). In 22/32 gravide (p=69%) l applicazione del pessario è stato associato all utilizzo di un medicamento, come poi vedremo nella specifica, mentre in 10/32 (p=31%) non è stato associato alcun farmaco. Sorprendentemente l outcome tra questi 2 ultimi gruppi non ha mostrato sostanziali variazioni, tanto da indurci a ritenere che l esclusiva azione del dispositivo vaginale sia il reale artefice dei benefici ottenuti. Ultima notazione va fatta sull epoca gravidica di posizionamento del pessario che nella stragrande maggioranza di casi è avvenuto tra la 22 a e la 28 a settimana (n=29 p=90%), mentre in soli 3 casi (p=10%) l epoca di inserimento è stata maggiore delle 28 settimane. Quasi tutte le gravide presentavano all atto dell inserimento un BMI>25 (n=30 p=94%), mentre solo 2 erano 25. INTRODUCTION The threatened preterm delivery, or SPB (Spontaneous Preterm Birth), is a syndromic disease that recognizes a variety of causes. Almost 100 years the pessaries have been successfully used in genital prolapse treatment (4,6,8,42). Different types of pessary have succeeded over the years, from the classic ring pessaries (Figure 1) to Donut Correspondence to: pessaries (Figure 2), by Hodge pessary (Figure 3) to Jorde-Hamann pessaries (Figure 4 ), all used in the symptomatic treatment of genital prolapse and therefore not very considered by gynecologists with higher surgical inclinations that saw, and in some cases can still be seen today, in the packaging of surgical cervical cerclage the only successful attempt to oppose the SPB, regardless of the many failures and multiple complications obtained. Copyright 2014, Partner-Graf srl, Prato 19

20 It. J. Gynaecol. Obstet. 2015, 27: N.1 Figure 1. Ring Pessary. Figure 2. Donut Pessary Figure 3. Hodge Pessary Figure 4. Jorde-Hamann Pessary 20 In 1979 the german gynecologist Hans Arabin devised a flexible silicon device which is well suited to the natural shape of the vaginal fornices, with a circular central space to permit the entire cervix to be included and therefore supported and angulated in a position more suited to the physiological hereinafter of pregnancy. Just this latter point has been to intuition of dr. Arabin, which assumed that he must not forcibly close the cervical canal, the principle on which is based the surgical cerclage, but restore to the cervix the natural angle with the uterine body to ensure that it interrupted the inevitable evolution towards the onset of contractions that ultimately led to preterm delivery. As indeed it himself wrote in his publication Pessartherapie (Gynäkologie ed. Thieme 1991, ),..the body of the uterus and cervix are 2 entities histologically and functionally different, so different that they can be considered as two bodies which form part of the same apparatus; must be maintained an angulation between 30 and 45 degrees, a prerequisite to the physiological continuation of the pregnancy. In the moment in which this angle is lost, resulting in straightening of the cervix with respect to the body, it triggers a process that ultimately leads to the onset of uterine contractions, almost like a trigger of a mine that is activated when fit together 2 ends normally separate [..].Therefore the Arabin pessary was designed with the intent not only to hold and squeeze the cervix, but especially to tilt the cervix and rotate it slightly toward the sacred (Figure 5). Only with the advent of transvaginal sonography has been documented effectively reducing or at least stabilizing the cervical funneling after placement of Arabin pessary in selected patients (2,10,25,26,27,29,30,33,37,39,42) (Figure 6). There are several hypotheses regarding Arabin pessary purpose in the prevention of premature rupture of membranes (PROM) and then ultimately prevent the spontaneous preterm birth (SPB) (4,7,8,9,11,12,13,14,20,25,28,40). The evidence which is the starting, documented by studies performed with transvaginal ultrasound (TVS) and with magnetic resonance (RMI), is that the Arabin pessary restores the normal utero-cervical angle, which so it remains until the device stand in place. Figure 5. Arabin pessary and its positioning. The first consequence of this modification is that it removes the direct pressure of amniotic fluid on the membranes covering the internal uterine orifice (IUO), preventing further cervical dilation triggered by the dissociation between amnion and chorion especially when pregnant is in the upright position (2,3,4,7,8,9,11,12,13,14,16). It 'also been postulated that genetically determined factors make the amniotic membranes more susceptible to mechanical stress or infection, for which the effect of the device would suffer from subjective factors not quantifiable. Another interesting hypothesis, advanced by N. Becher in 2009 and taken up by DC Lee in 2011 (18,19), is that the device prevents the mobilization of so-called "mucous plug", much studied issue actually, which seems play a very important role in the maintenance of pregnancy because, due to its unique protein structure and

21 L. Juliano et al. Figure 6. Large cervical funneling (U-shaped) reduced by positioning of Arabin pessary immunological capacity would responsible for protecting the uterine cavity by inflammatory and ascending infectious liables for initiation of preterm labor or PROM; it is well known that expulsion of the mucous plug a few hours preceding the onset of spontaneous labor in pregnant women at term. In a study of 2013, Cannie MM demonstrated with MRI aid that more time stationing the pessary and more greater the chances that the cervix will generates focal thickening and edema phenomena, which could complicate the dynamic changes of the cervix during labor (15). For those headings it is advisable to establish the cut-off tolerance average is 15 weeks, reserving to periodic checks of local conditions any greater permanence. In February of 2013 A. Baschat (pers. com.) has suggested that the pessary may decrease so-called Ferguson reflection, positive feedback that triggers when the cervix or vaginal walls pressure increases inducing production of oxytocin by the hypothalamicpituitary axle (41). Whatever the actual mechanism of pessary action, it is very important to evaluated the correct size to be placed. There are several sizes of Arabin pessary, and it s important to stick to pragmatic criteria in the choice of device that may be specifically adapted to peculiar characteristics of each specific patient. The latest generation devices are made in soft silicone with multiple circumferential perforations that allow secretions outflow that accumulates in the fornices, but the factor that distinguishes them is exclusively the size. The proximal hole diameter varies from 32 to 35 mm, while distal hole diameter goes from 65 to 70 mm; the height can be of and 30 mm. In general a size of 32 mm is used when the pessary is applied during the first trimester of singleton pregnancy or after surgical conization or even in the second and third trimesters without significant cervical funneling (Y-shaped) (9,16,25,42). In pregnants with large and edematous cervix or wide cervical funneling (U-shaped or V-shaped) is preferred devices with inner hole of 35 mm in order to avoid increases in focal pressure on the membranes and the release of prostaglandins during placement. Moreover, in physically smaller woman or nulliparous is advisable an outer diameter of 65 mm, to reserving 70 mm in constitutionally large patients or in multiparous. About the height of the Arabin pessary is advisable to use the small sizes of mm in singleton pregnancies, the 25 mm in pregnants with uterine distension (multiple pregnancies and/or polyhydramnios), and finally the 30 mm in patients with uterine prolapse during pregnancy (Table I). It s guessed that greater is device diameter and the more frequently the pregnant may complain of discomfort, due to distension of fornices operated from normal secretions which inevitably accumulate behind the pessary; this problem has been largely overcome to use of drilled devices (1,7,11,12,13,14,20,25,28,30,31,32,34,42). 21

22 It. J. Gynaecol. Obstet. 2015, 27: N.1 Table I. Sizes of Arabin pessaries Proximal hole diameter Distal hole diameter Height (mm) Clinical state 32 mm 35 mm 65 mm 70 mm Short or Flabby cervix at II trimester 25 mm Singleton Pregnancy o With or without Y-shaped funneling Nulliparous o o o Pluriparous o o o o With V- or U-shaped funneling (Flabby cervix) Nulliparous o o o Pluriparous o o o Twins o Without funneling Nulliparous o o o Pluriparous o o o o With V- or U-shaped funneling (Flabby cervix) Nulliparous o o o Pluriparous o o o Short or Flabby cervix at I trimester or after surgical conization o Singleton Pregnancy Nulliparous o o o Pluriparous o o o o Twins Nulliparous o o o Pluriparous o o o o With genital prolapse Nulliparous o o o Pluriparous o o o 22 Some considerations should be taken prior to placement of vaginal device, regardless of type and size used. We have to carefully evaluate the cervical characteristics by transvaginal ultrasonography (TVS). (10,14,16,22,23,26,29,30,37,39,42) The cut-off of 25 mm so far considered in the definition of short cervix should not be the only discriminating; this parameter might not be to treatment if just isolated finding in gestational age 32 weeks in nulliparous with singleton pregnancy, while it might be an adequate criterion when combined with funnelling cervix and/or cervical hypoechoic pattern. In our experience, lowest is cervical echogenicity and worst is the prognosis in terms of progression to generalized cervical incompetence that led to the triggering of preterm labor for activation of Ferguson reflection. The reasons should be sought in the histological characteristics of the cervix, very poor in muscle fibers which, due to prostaglandins release secondly oxytocic effect of Ferguson reflection, loosen increasing distance between them and making the ultrasound cervical pattern objectively less compact, just hypoechoic. So rather than using short cervix as a marker, we propose to introduce the term of flabby cervix to define by ultrasound (TVS) a cervical length 25 mm with hypoechoic parenchymal pattern and funneling (Y, U or V-shaped). Essential aspect to consider prior to placement of the pessary is the lack of previous vaginal infections by performing a vaginal swab, which excludes the presence of Chlamydia, β-hemolytic Streptococcus, Mycoplasma spp and Candida albicans, Gardnerella and Trichomonas. The secretions which inevitably accumulates in fornices where is placed the Arabin pessary, if copious may creates focal increases of pressure responsible for the Ferguson reflection, with increased risk of amnionitis and PROM (1,2,3,7,14,17,24,25,34,38). To complete prevention against vaginal infections, the pessary should be covered with antibacterial

23 L. Juliano et al. cream before insertion, also for lubricant effects that facilitates the positioning and minimizes the discomfort complained of by pregnant. There is no need to use anesthetics or analgesics (42), partly because the sensations reported by all patients at approximately 30 minutes from the introduction of the device was a subjective sense of relief. In any case it was decided to recommend the resting after the introduction of Arabin pessary, even in cases of marked flabby cervix. MATERIALS AND METHODS Our experience is based on the application of 32 Arabin pessary of ASQ type in the period October May In 28/32 cases (p=87.5%) they were singleton pregnancies and in 4/32 cases (p=12.5%) were twins pregnancies (3 bigemine pregnancies and 1 triplets). Only in 3 patients (p=90.6%) was the first pregnancy (1 triplets, 1 twins and 1 singleton pregnancy), while the others were all multiparous. Regardless the number of fetuses, in all pregnancies the pessary has been positioned between the 22nd and 23rd week due to an apparent shortening of the cervix measured with TVS (average length 23 mm); in 3 cases the shortening was an isolated finding (short cervix) while in the remaining cases were associated sonographic signs of flabby cervix (funnelling and hypoechoic stromal). In the remaining singleton pregnancies (28/32 cases, p=87.5%) the device was inserted between the 22nd and 28th weeks on the basis of ultrasound flabby cervix (short cervix, funnelling and hypoechoic stromal); only in 4/28 cases (p=14.3%) was considered discriminating the presence of only short cervix. In 26/32 cases (p=81%) the pessary was removed between 36th and 37th weeks with spontaneous delivery at 38 weeks (7/26 cases, p=27%), at 39th weeks (12/26 cases p=46%) and at 40th weeks or over (7/26 cases, p=27%); in 2/7 patients who delivered spontaneously were twins pregnancies. In remaining 5/32 cases (p=16%) the device was removed at 34 weeks with cesarean delivery for the 36th to 37th weeks in twins pregnancies in previous cesarean sections (2/5 cases, p =40%) or multiple previous cesarean sections in 3/5 cases (p=60%); in 1/32 case (p=3%) the pessary was removed after cesarean section for forgetfulness. In 2/26 cases (p=7,6%) the pessary was not removed despite premature rupture of membranes at 28 and 31 weeks, but until the complete removal at the term (37 and 38 weeks), we performed weekly vaginal swab, blood count and serum PCR to 23

24 It. J. Gynaecol. Obstet. 2015, 27: N.1 24 exclude corionamnionitis onset. In 22/32 pregnant women (p=69%) application of pessary has been associated with the use of (GROUP A): Progesterone (21,22,23,24,34,40), micronized vaginally or orally, 400 mg bid in 18/22 patients (p=82%); Magnesium [24,40], orally 400 mg m.i.d. in 18/22 patients (p=82%); Nifedipine (21,23), orally 20 mg b.i.d. in 4/22 patients (p=18%); Lactoferrine o Lactoglobuline (40,42), vaginally 300 mg m.i.d. in 4/22 patients (p=18%). In 10/32 cases (p=31%) was not associated any medications (GROUP B). So let s see how to insert and remove the Arabin pessary. The Arabin pessary, covered with antibacterial cream on the surface that will contact with fornices, is squeezed between thumb and forefinger with the larger hole facing up and plugged intake vagina with the major axis parallel to the major axis of the vagina. Within the vagina the device opens and with 2 fingers gently pushing towards fornices and place it so that cervix is completely included in the smaller hole. Once obtained the positioning, remains the most important act, or give the right angle to the cervix in order to maintain the cervixuterine angle at a value comprised between 30 and 45 (16,42). To achieve this objective to push with the index finger on the front edge of the rear toward the sacral bone. Immediately after insertion, the patient is asked to walk for a few minutes and to report any unpleasant sensations; the presence of a prolonged and worsening sense of discomfort should make us reconsider the size or type of device placed (9,16,42). Usually the device has been removed around the 37th week, except the onset of contractions or PROM before that period; in our series in 2 cases the pessary was not removed despite premature rupture of membranes at 28 and 31 weeks, but until the complete removal at the term (37 and 38 weeks), we performed weekly vaginal swab, blood count and serum PCR to exclude corionamnionitis onset. Of course the use of the pessary should not be extended to all women with flabby cervix, but there are some conditions that contraindicate the use of the pessary. Should be considered absolute contraindications (9,14,36,42) : presence of major fetal malformations incompatible with life; corionamnionitis known or suspected; protrusion of the amniotic membranes over an external uterine gaping orifice; valid and rhythmic uterine contractions; bleeding of uterine origin; placenta praevia major; previous cervical conization with the remaining cervix of <30%; premature rupture of membranes; gestational age <22 or> 30 weeks. Instead should be considered relative contraindications (9,14,36,42) : marginal or partial placenta praevia; rupture of the membranes with small eccentric outflow of amniotic fluid and no sign of amnionitis; further uterine malformations, such as a uterus bicolle in which the positioning of the pessary may be very problematic; previous cervical conization with residual cervix of 50%; gestational age between 30 and 32 week. RESULTS We ve applicated 32 Arabin pessary of ASQ type in the period October 2012-May In 28/32 cases (p=87.5%) they were singleton pregnancies and in 4/32 cases (p=12.5%) were twins pregnancies (3 bigemine pregnancies and 1 triplets). Only in 3 patients (p=90.6%) was the first pregnancy (1 triplets, 1 twins and 1 singleton pregnancy), while the others were all multiparous. All patients showed flabby cervix or simply short cervix, but all of them have reached the end of pregnancy despite initial expectations. In 26/32 cases (p=81%) the pessary was removed between 36th and 37th weeks with spontaneous delivery at 38 weeks (7/26 cases, p=27%), at 39th weeks (12/26 cases p=46%) and at 40th weeks or over (7/26 cases, p=27%); in 2/7 patients who delivered spontaneously were twins pregnancies. In remaining 5/32 cases (p=16%) the device was removed at 34 weeks with cesarean delivery for the 36th to 37th weeks in twins pregnancies in previous cesarean sections (2/5 cases, p =40%) or multiple previous cesarean sections in 3/5 cases (p=60%); in 1/32 case (p=3%) the pessary was removed after cesarean section for forgetfulness. In 2/26 cases (p=7,6%) the pessary was not removed despite premature rupture of membranes at 28 and 31 weeks, but until the complete removal at the term (37 and 38 weeks), we performed weekly vaginal swab, blood count and serum PCR to exclude corionamnionitis onset.

25 L. Juliano et al. We already said that in 22/32 pregnant women (p=69%) application of pessary has been associated with a medication (GROUP A), while in 10/32 cases (p=31%) was associated anything (GROUP B). Surprisingly, the outcome of these 2 latter groups did not show substantial changes, so as to lead us to believe that the exclusive action of the vaginal device is the real creator of obtained benefits. Last notation should be made on the weight of pregnant women at insertion; the majority of pregnant women showed when inserting a BMI> 25 (n =30, p =94%) while only 2 were 25, which account for the increased risk of preterm delivery in pregnant women are overweight. All the foregoing is however a speech in constant evolution; thus, for example, as squeezing and angling the cervix prevents the mobilization of the cervical mucus, whose key role in the stabilization of collagen tissue and extracellular matrix by the hydration of the fibers is still today under study, both through the new techniques of PCR molecular biology both by promising transvaginal sonoelastography. DISCUSSION While as claimed by anglosaxon authors to do nothing is not an option any longer [42], the American College of Obstetricians and Gynecologists (ACOG) underlines the risk of unnecessary interventions in single pregnancies without a history of childbirth spontaneous preterm. In one of the most important study published by Goya in Lancet on 2012 (14), a multicenter study on the use of the pessary in women with short cervical length selected (<25mm) aged between 18 and 22 weeks showed that the use of the pessary increases the pregnancy rate come to term with respect to control. In this study, 385 women were recruited: 192 was placed an Arabin pessary, while 193 were adopted alternative therapeutic measures. Were excluded women with a higher fetal malformation, those with actual uterine contractions, vaginal bleeding, and premature rupture of membranes, placenta previa, or a history of conization or cerclage in situ. In the group with pessary has had the lowest rate of births before 34 weeks (6% vs27%), before the 37th week (22% vs 59%) and before the 28th week (2% vs 8%). Of course the use of the pessary should not be extended to all women with flabby cervix, but there are some conditions that contraindicate the use of the pessary, conditions, as already mentioned, unanimously shared by the various authors consulted in indexed publications. As mentioned in our experience the sensation reported by all patients at approximately 30 minutes from the introduction of the Arabin pessary has been enjoyable and a subjective sense of relief. The Arabin pessary is officially indicated in all cases of preterm delivery threatened, certified registered with the Ministries of Health in all countries of the European Union (Identification number: MED/ CERT0482 EN ISO13485 Council directive 93/42/EEC reg. medical devices), in Scandinavia, the Russian Federation, Indonesia and the United Arab Emirates (9,14,36,42). It s necessary to confirm the correct positioning of the pessary after insertion through a clinical and sonographic examination. In all cases of expulsion of device, operator independent, the pessary can be repositioned; a further expulsion should lead one to consider a change of measure or type of pessary. In general, the pessary should be kept in place for up to 37 weeks if there are no indications for early removal. The patient will be asked to notify the obstetrician in case of discomfort, contractions or vaginal bleeding. The pessary should always be considered a foreign body in the vagina, so it is important to carefully observe periodic prophylactic hygienic washes and ovules antiseptic of chlorhexidine. As regards the combination of tocolitic and/ or colpotonic therapies, has already been said that in our report 69% of cases has been associated with use of progesterone, magnesium, nifedipine and lactoferrin, while in 31% of cases was not associated with any medications. In case of hospitalization prior to the planned removal of the pessary, you should always inform the staff of the structure in order to allow the inevitable premature removal if deemed necessary (9,14,36,42). All the foregoing is however a speech in constant evolution; new techniques of PCR molecular biology and promising transvaginal sonoelastography will certainly contribute to the development and refinement of new knowledges for the prevention of preterm birth. 25

26 It. J. Gynaecol. Obstet. 2015, 27: N.1 26 REFERENCES 1) GoldenbergRL, Gravett MG, Iams J, Papageorghiou AT, Waller SA, Kramer M, Culhane J, Barros F, Conde- Agudelo A, Bhutta ZA, Knight HE, Villar J. The preterm birth syndrome: issues to consider in creating a classification system. Am J Obstet Gynecol 2012; 206: ) Romero R, Mazor M, Munoz H, Gomez R, Galasso M, Sherer DM. The preterm labor syndrome. Ann N Y Acad Sci 1994; 734: ) Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, Rudan I, Campbell H, Cibulskis R, Li M, Mathers C, Black RE. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since Lancet 2012; 379: ) Culligan PJ. Nonsurgical management of pelvic organ prolapse. Obstet Gynecol 2012; 119: ) Cross R. Treatment of habitual abortion due to cervical incompetence. Lancet 1959; 274: ) Oster S, Javert CT. Treatment of the incompetent cervix with the Hodge pessary. 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28 Serum C-reactive protein as potential independent prognostic factor for breast cancer Adela Stoenescu* 2, Christoph Gerlinger 1, Erich Franz Solomayer 1, Christoph Scholz 2, Ingolf Juhasz-Böss 1, Julia Radosa 1 1 Department of Obstetrics and Gynaecology, University of Saarland, Homburg / Saar, Germany 2 Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany ABSTRACT BACKGROUND: The possible involvement of inflammation in breast carcinogenesis has potential prognostic and therapeutic consequences. We investigated whether C-reactive protein is expressed in breast cancer and evaluated its correlation with clinicopathological findings. METHODS: We analyzed CRP in plasma samples of 219 cases of metastatic and nonmetastatic invasive cancer and carcinoma in situ, selected among participants in a retrospective study. Circulating plasma CRP measurements were performed at the time of primary diagnosis. RESULTS: We observed higher levels of CRP in patients with cancer compared with patients with non-invasive tumors (p=0.0037) and a significant association between elevated CRP levels and advanced tumor stage only in patients with nonmetastatic breast cancer. The CRP level significantly increases with the size of the breast cancer in patients with non-metastatic disease: Tis 1.58 mg/l, T mg/l, T mg/l, T mg/l, T mg/l; p= CONCLUSION: Our data suggest that elevated plasma CRP levels are associated with advanced stages of breast cancer and bad prognosis. CRP levels might be an independent and potential long-term prognostic factor for breast cancer and could be probable used as tumor marker in patients without inflammatory diseases. Non-steroidal anti-inflammatory drugs could be used in the treatment of malignancy. Several trials are being conducted to study the use of COX (enzyme cyclo-oxygenase) inhibitors in the treatment of breast cancer. Keywords: Breast cancer, prognosis, inflammation, tumor maker. SOMMARIO BACKGROUND: Il possibile coinvolgimento dell infiammazione nella carcinogenesi ha un potenziale prognostico e delle conseguenze terapeutiche. Abbiamo investigato sull eventualità che la proteina C-reattiva sia coinvolta nel cancro al seno e abbiamo valutato la sua correlazione con i riscontri clinicopatologici. METODOLOGIA: abbiamo analizzato il CRP nei campioni di sangue di 219 casi di cancro invasivo metastatico e non, e nel carcinoma in situ, selezionati tra I partecipanti agli studi retrospettivi. I valori di CRP nel plasma sono stati misurati al momento della diagnosi primaria. RISULTATI: Abbiamo osservato un maggiore livello di CRP in pazienti con il cancro rispetto a pazienti con tumori non invasivi (p = ) e una significativa correlazione tra i livelli di CRP elevati e il tumore in uno stadio avanzato presente nei pazienti con cancro al seno non metastatico. Il livello di CRP aumenta significatamente con l ingrandirsi del cancro al seno non metastatico: Tis 1.58 mg/l, T mg/l, T mg/l, T mg/l, T mg/l; p= CONCLUSIONI: I nostri dati suggeriscono che elevati livelli di CRP nel sangue sono associabili con stadi avanzati di cancro al seno e prognosi maligne. I livelli di CRP potrebbero essere un potenziale fattore di prognosi a lungo termine del cancro al seno e probabilmente potrebbe venir usato come marcatore tumorale nei pazienti senza malattie infiammatorie. Farmaci anti-infiammatori non steroidei possono essere usati nel trattamento delle neoplasie maligne. Sono stati condotti numerosi trials sullo studio dell utilizzo dei COX (enzima ciclo-ossignasi) inibitori nel trattamento del cancro al seno. INTRODUCTION Chronic inflammation has been hypothesized for many years to be associated with cancer development and progression and has been studied for a long time (1-3). Serum C-reactive protein (CRP), an acute phase protein and a sensitive nonspecific marker of systemic inflammation, has been reported to be associated with a number of cancers, including breast cancer. Its expression is induced by proinflammatory cytokines and is produced mainly in hepatocytes (17). However, results in the literature Correspondence to: Copyright 2014, Partner-Graf srl, Prato are inconsistent and remain controversial. There are two hypotheses that might explain the correlation between CRP and cancer: 1) high CRP levels are a result of cancer or a premalignant state; 2) chronic inflammation with elevated CRP concentrations promotes cancer growth (6). The production of cytokines and growth factors, the induction of cyclooxygenase-2 in macrophages and epithelial cells, the generation of mutagenic reactive oxygen, and nitrogen species are possible mechanisms for carcinogenesis (18). Cytokines (interleukin-1, interleukin-6, tumour necrosis factor) regulate the synthesis of CRP. The role of elevated CRP levels in patients with carcinoma is not yet clear. Nozoe et al. first described an association between CRP and carcinogenesis in patients with oesophageal 28

29 A. Stoenescu et al. squamous carcinoma (19). They demonstrated an increased incidence of peritoneal, lymph node and liver metastases, intravascular invasion and poor prognosis in patients with preoperatively increased CRP levels. It has been reported that serum CRP expression has a prognostic value for gastric, colorectal, esophageal carcinoma, multiple myeloma and malignant fibrous histiocytoma (19-23). It has not been clarified, however, whether the serum CRP expression is a prognostic indicator in patients with breast cancer. Some previous studies have reported that breast cancer patients have elevated levels of CRP before surgery, especially in women with advanced disease (16). The results showed that the higher the CRP level at diagnosis, the worse the prognosis was. Elevated levels have been associated with poor prognosis in patients with breast cancer (6,12). Therefore, the aim of our retrospective study was to investigate the association between serum CRP levels before treatment and the pathological stages of breast cancer. PATIENTS AND METHODS We analyzed CRP in plasma samples of 532 cases of invasive cancer and 49 cases of carcinoma in situ, selected among participants in a retrospective study. The study population included participants who were diagnosed and treated at the Department of Gynaecology at the Saarland University Hospital between January 2010 and December Patients with documented bacterial infections and high CRP levels were excluded from the study. Information concerning age, menopausal status, diagnosis, and clinical pathology were collected for each patient and are summarized in Table I. The breast cancer patients were staged according to TNM-UICC classification. 532 patients were diagnosed histologically with ductal infiltrating carcinoma, along with 49 of carcinoma in situ. Tumor size was classified as T1 (less than or equal to 2 cm) in 297 (50.77 %), T2 (tumor size between 2 and 5 cm) in 157 (26.84 %), T3 (tumor size more than 5 cm) in 27 (4.62 %) and T4 (tumor extends to chest wall) in 29 (4.96 %) of the cases. Table I: Main clinical-pathological tumor characteristics of 586 breast cancer patients Characteristic Patients Percent Characteristic Patients Percent Age < 50 years years > 70 years % % % Menopausal status Premenopausal Perimenopausal Postmenopausal % 5.97 % % Histological diagnosis Grading Infiltrating carcinoma In situ carcinoma % 8.43 % G1 G2 G % % % Tumor size Nodal involvement T % N % T % N % T % N % T % N % Metastatic site HER2/neu status M % Negative % M % Positive % ER status % PgR status Negative % Negative % Positive Positive % Local relapse Death No % No % Yes % Yes % 29

30 It. J. Gynaecol. Obstet. 2015, 27: N.1 There were 400 patients with negative lymph nodes and 162 patients with positive lymph nodes. Main tumor characteristics are shown in Table I. Circulating plasma CRP measurements were performed at the time of primary diagnosis in 219 participants. The cut-off level for serum CRP was established at 5 mg/l. We determined the plasma CRP levels in fresh plasma samples in our laboratories at the Department of Clinical Biochemistry, Saarland University Hospital. The statistical analyses were carried out using SAS version 9.2 statistics software. The Kruskal-Wallis test was used for relating CRP levels to clinicopathological parameters. A p-value of less than 0.05 was considered to be significant. Serum levels of CRP in patients with nonmetastatic and low-grade malignancy cancers (G1) did not differ significantly as compared with patients with medium (G2), respectively high-grade malignancy cancers (G3): 2.84 mg/l vs mg/l, respectively 4.84 mg/l, p>>0.05 (Figure 2). RESULTS High circulating plasma levels (> 5 mg/l) of CRP were associated with advanced-stage breast cancer and metastasis. Of the 219 patients with data, 43 (19.63%) showed an abnormal CRP level at the time of primary diagnosis. Patients diagnosed with invasive cancers had significantly higher levels of CRP than patients with carcinoma in situ; p= A mean CRP concentration of 5.91 mg/l was found, while patients with noninvasive cancers had a mean CRP level of 1.25 mg/l. Relationship between CRP and tumor characteristics in adjuvant patients We noted that CRP levels did differ significantly with tumor size. The CRP level significantly increases with the size of the breast cancer in patients with nonmetastatic disease: Tis 1.58 mg/l, T mg/l, T mg/l, T mg/l, T mg/l; p= (Figure 1). Figure 2: CRP and grading We evaluated correlation of CRP level at the time of primary diagnosis with nodal burden. CRP concentrations were higher in patients with positive nodal status. Patients with no lymph node involvement (N0) had a mean CRP level of 4.07 mg/l, while patients with positive axillary lymph nodes as follows: N mg/l, N mg/l. There was only one patient with N3 breast cancer, who had a CRP level at the time of primary diagnosis of 1.80 mg/l. However, the observed differences of CRP levels are not significant (Figure 3). Figure 3: CRP and nodal status 30 Figure 1: CRP and tumor stage Relationship between CRP and tumor characteristics in patients with metastatic disease 26 patients with data had distant metastasis at time of their initial breast cancer diagnosis as follows: 5 patients had lung metastases, 8 bone metastases, 2 liver metastases and the others had more than one

31 A. Stoenescu et al. location of distant metastasis. Patients with metastatic disease had a mean CRP level of 3.43 mg/l, almost equal to patients with non-metastatic disease (Figure 4). Figure 6: CRP and nodal status Figure 4: Relationship between CRP and distant metastases in patients with non-metastatic vs. metastatic disease Non-significant elevations of CRP levels were observed in patients with T2, respectively T4 breast cancer and distant metastases (4.44 mg/l, respectively 4.10 mg/l). A CRP level of 3.70 mg/l was observed in patients with T1 breast cancer. There was only one patient with T3 breast cancer and distant metastases with a CRP level of 1.40 mg/l (Figure 5). Figure 7: CRP and grading Figure 5: CRP and tumor stage CRP serum levels increase with nodal status of breast cancer. This difference again did not reach statistical significance. A level of 3.15 mg/l was observed in nodal negative patients. Patients with N1 and N2 breast cancer had a CRP level of 3.85 mg/l and 3.80 mg/l, respectively, while a level of 4.00 mg/l was observed in patients with N3 breast cancer (Figure 6). The CRP concentrations were independent of grading in patients with distant metastases (Figure 7). Correlation of CRP level at the time of primary diagnosis with ER, PgR and HER2-expressions We didn t notice any significant correlations of CRP levels with receptor status in our study. A detailed breakdown of distribution is shown in Figures No difference was observed in patients with nonmetastatic compared to metastatic hormone receptor positive, HER2-negative breast cancer (Figure 8). Patients with metastatic hormone receptor positive, HER2-positive breast cancer had non-significant lower CRP levels than patients with non-metastatic disease, 2.75 mg/l compared to 4.37 mg/l (Figure 9). Slightly higher CRP levels were observed in patients with non-metastatic triple negative breast cancer (3.52 mg/l) compared to patients with metastatic triple negative breast cancer (2.30 mg/l) (Figure 11). Similarly, patients with non-metastatic hormone receptor negative, HER2-positive disease had a non-significant higher CRP level than patients with metastases, 7.72 mg/l vs mg/l (Figure 10). 31

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