Patients triaged to neoadjuvant chemotherapy have higher rates of sarcopenia: An opportunity for prehabilitation.

OBJECTIVE: To compare baseline body composition measures (BCM), including sarcopenia, between patients with advanced epithelial ovarian cancer (EOC) undergoing primary cytoreductive surgery (PCS) versus neoadjuvant chemotherapy/interval cytoreductive surgery (NACT/ICS) and evaluate changes in BCM pre-NACT versus pre-ICS. METHODS: Patients with stage IIIC/IV EOC who underwent PCS or NACT with curative intent between 1/1/2012 and 7/31/2016 were included. Computed tomography scans were evaluated via a semi-automated program to determine BCM. Measures evaluated include skeletal muscle area (SMA), skeletal muscle density (SMD), skeletal muscle index (SMI), and skeletal muscle gauge (SMG). Sarcopenia was defined as SMI <39.0 cm2/m2. RESULTS: The study included 200 PCS patients and 85 NACT/ICS patients, of which 76 had both pre-NACT and pre-ICS scans. NACT patients were significantly more likely to be sarcopenic compared to PCS patients (40.0% vs 27.5%, p = 0.04). Mean SMA (107.3 vs 113.4 cm2, p = 0.004) and mean SMG (1344.6 vs. 1456.9 (cm2 x HU)/m2, p = 0.06) were lower in NACT patients. Among NACT/ICS patients, mean SMI significantly decreased -1.4 cm2/m2 (p = 0.005) at the time of surgery, resulting in a non-statistically significant increase in the percentage of sarcopenic patients from baseline (40.8% vs. 50.0%, p = 0.09). CONCLUSIONS: Sarcopenia is more common in patients with advanced EOC undergoing NACT compared to PCS when using an evidence-based triage system for triage decisions. Body composition changes significantly over the course of NACT. Sarcopenia may be an indicator of debility and another factor for consideration in treatment planning. Further research into body composition's effects on prognosis and altering sarcopenia is necessary.

Evidence-based wound classification for vulvar surgery: Implications for risk adjustment.

OBJECTIVES: The correct wound classification for vulvar procedures (VP) is ambiguous according to current definitions, and infection rates are poorly described. We aimed to analyze rates of surgical site infection (SSI) in women who underwent VP to correctly categorize wound classification. METHODS: Patients who underwent VP for dysplasia or carcinoma were collected from the National Surgical Quality Improvement Program database (NSQIP). SSI rates of vulvar cases were compared to patients who underwent abdominal hysterectomy via laparotomy, stratified by the National Academy of Sciences wound classification. Descriptive analyses and trend tests of categorical variables were performed. RESULTS: Between 2008 and 2016, 2116 and 31,506 patients underwent a VP or TAH, respectively. Among VP, 1345 (63.6%), 364 (17.2%), and 407 (19.2%) women underwent simple vulvectomy, radical vulvectomy, or radical vulvectomy with lymphadenectomy, respectively. The overall rate of SSI for VP was higher than that observed for TAH (5.6% vs. 3.8%; p < 0.0001). While patients undergoing TAH displayed a corresponding increase in the rate of SSI with wound type (type I: 3.4%; type II: 3.8%, type III: 6.8%; type IV 10.6%; p < 0.001), no such correlation was observed for simple VP (type I: 3.3%, type II: 3.0%; type III: 3.2%; type IV: 0%; p = 0.40). On the other hand, a non-significant correlation was observed for radical VP (type I: 4.0%, type II: 10.1%; type III: 14.3%; type IV: 20.0%; p = 0.08). The overall rate of SSI in patients undergoing any radical VP was similar to patients undergoing hysterectomy with a type IV wound (10.1% vs 10.6%, p = 0.87). CONCLUSION: Patients undergoing VP are at high risk of infection. Simple vulvectomy should be classified as a type II and radical vulvectomy as a type III wound. These recommendations are important for proper risk adjustment.

Prediction of short-term surgical complications in women undergoing pelvic exenteration for gynecological malignancies.

OBJECTIVE: Pelvic exenteration (PE) is an extensive surgery associated with high rates of postoperative morbidity and mortality. The absence of well-defined preoperative selection criteria to identify patients eligible for PE prompted the assessment of pre-operative predictors of 30-day major surgical complications. METHODS: Demographics and surgical characteristics of patients undergoing PE for gynecologic cancer in a single institution between 01/2004-12/2016 were reviewed. Postoperative complications within 30 days following surgery were graded using the Accordion grading system. Logistic regression was used to analyze potential risk factors for severe postoperative complications. RESULTS: A total of 138 patients were included in the cohort. Forty-five patients underwent total PE, 52 anterior PE, and 41 posterior PE. Among the 137 patients with follow-up, a severe postoperative complication was experienced by 37 patients (27.0%) and 3 patients (2.2%) experienced death within 90 days. The most frequent grade 3 complications were complications of urinary reconstruction (n = 15), wound dehiscence (n = 9), and abdominal abscess requiring intervention with drain or return to the operating room (n = 6). On multivariable analysis, independent predictors of severe postoperative complications were anterior or total PE (adjusted odds ratio (aOR): 11.66, 95% CI 2.56-53.18), pre-operative hemoglobin ≤10 mg/dl (aOR 2.70, 95% CI 1.02-7.14) and presence of 3+ comorbidities (aOR: 2.76, 95% CI 1.07-7.10). CONCLUSIONS: Major complications after exenteration are common. Surgical complexity and patient selection play a considerable role in predicting complications. These data can be used to better risk stratify patients undergoing PE.

Vaginal vs. robotic hysterectomy for patients with endometrial cancer: A comparison of outcomes and cost of care.

OBJECTIVE: To compare outcomes and cost for patients with endometrial cancer undergoing vaginal hysterectomy (VH) or robotic hysterectomy (RH), with or without lymphadenectomy (LND). METHODS: Patients undergoing planned VH (and laparoscopic LND) or RH (and robotic LND) between January 2007 and November 2012 were reviewed. Patients with stage IV disease, synchronous cancer, synchronous surgery, or treated with palliative intent were excluded. Patients were objectively triaged to LND per institutional protocol based on frozen section. Outcomes were compared between VH and RH groups matched 1:1 on propensity scores. RESULTS: VH was planned in 153 patients; 60 (39%) had concurrent LND while 93 (61%) were low risk and did not require LND. RH was planned in 398 patients; 225 (56%) required concurrent LND and 173 (44%) did not. Among 50 PS-matched pairs without LND, there was no significant difference in complications, length of stay, readmission, or progression free survival. However, median operative time was 1.3h longer and median 30-day cost $3150 higher for RH compared to VH (both p<0.001). Among patients requiring LND, 42 PS-matched pairs were identified. Median operative time was not different when pelvic and para-aortic LND was performed, and 12min longer in the VH group for pelvic LND alone (p=0.03). Median 30-day cost was $921 higher for RH compared to VH when LND was required (p=0.08). CONCLUSION: Utilization of vaginal hysterectomy for endometrial cancer results in similar surgical and oncologic outcomes and lower costs compared to RH and should be considered for appropriate patients with a low risk of requiring LND.

A prospective algorithm to reduce anastomotic leaks after rectosigmoid resection for gynecologic malignancies.

OBJECTIVE: Determine whether a standardized protocol for temporary bowel diversion after rectosigmoid resection (RSR) for cytoreduction can reduce the rate of anastomotic leak (AL). METHODS: A prospective quality improvement project for patients undergoing RSR during debulking surgery from 07/2013 to 01/2016 was conducted. Patients with any of the following underwent temporary diversion: preoperative albumin ≤3.0g/dL, prior pelvic radiation, RSR plus additional large bowel resection (LBR), anastomosis (AS) ≤6cm from the anal verge, failed leak test or contamination of the pelvis with stool. The AL rate was compared to the historic AL rate from 01/04-06/11. RESULTS: Seventy-seven patients underwent RSR, with 27 (35.1%) receiving diverting stomas vs. 25/309 (8.1%) in the historic cohort. Additional LBR (33.3%) and AS at ≤6cm from anal verge (26.3%) were the most common indications for diversion. No AL was observed among diverted patients. If one AL which occurred following protocol violation (failed leak test but not diverted) is excluded, the theoretical AL rate is 1.3% (1/77) vs. 7.8% (24/309; P=0.039) in the historic cohort. Not excluding this case, the AL rate was 2.6% (2/77) vs. 7.8% (P=0.11). Short-term outcomes following primary surgery were not different between diverted and non-diverted patients. Stoma-related complications were observed in 7/27 (25.9%) patients, primarily related to dehydration. Reversal surgery was successfully performed in 24/75 (88.9%) patients. CONCLUSIONS: Criteria-based temporary bowel diversion for patients undergoing RSR for gynecologic cancer reduced the AL rate. Diversion was associated with acceptable morbidity and high reversal rate.

Management of endometrial cancer: issues and controversies.

Although endometrial cancer (EC) is the most common gynecologic cancer in developed countries, several aspects of its management are still controversial. In particular, the need to perform lymphadenectomy represents an important matter of discussion. Because of the discordant results in the literature, it is still not possible to draft any definitive conclusions regarding the therapeutic value of lymph node dissection. The present review discusses the role of lymphadenectomy in the setting of EC, risk factors for lymphatic spread, identification of patients at risk for lymph node dissemination, and the current evidence for adjuvant therapies in patients with positive nodes. Reasons for the difficulty in demonstrating any therapeutic value of pelvic and para-aortic lymphadenectomy are also discussed.

Patterns of Müllerian Inhibiting Substance Type II and Candidate Type I Receptors in Epithelial Ovarian Cancer.

The MIS pathway is a potential therapeutic target in epithelial ovarian cancer (EOC): signaling requires both type II (T2R) and type I receptors (T1R), and results in growth inhibition. MISR2 is expressed in EOC, but the prevalence and relative contributions of candidate T1R remain unknown. We sought to: a) determine expression of T1R in EOC; b) assess impact of T1R expression with clinical outcomes; c) verify MIS-dependent Smad signaling and growth inhibition in primary EOC cell cultures. Tissue microarrays (TMA) were developed for analysis of T1Rs (ALK2/3/6) and MISR2 expression. Primary cell cultures were initiated from ascites harvested at surgery which were used to characterize response to MIS. TMA's from 311 primary cancers demonstrated the most common receptor combinations were: MISR2+/ALK2+3+6+ (36%); MISR2+/ALK2+3+6- (34%); MISR2-/ALK2+3+6- (18%); and MISR2-/ALK2+3+6+ (6.8%). No differences in overall survival (OS) were noted between combinations. The ALK6 receptor was least often expressed T1R and was associated with lower OS in early stage disease only (p =0.03). Most primary cell cultures expressed MISR2 (14/22 (63.6%)): 95% of these express ALK 2 and ALK3, whereas 54.5% expressed ALK6. MIS-dependent Smad phosphorylation was seen in the majority of cultures (75%). Treatment with MIS led to reduced cell viability at an average of 71% (range: 57-87%) in primary cultures. MIS signaling is dependent upon the presence of both MISR2 and specific T1R. In the majority of EOC, the T1R required for MIS-dependent signaling are present and such cells demonstrate appropriate response to MIS.

Surgical morbidity and clinical outcomes in ovarian cancer - the role of obesity.

OBJECTIVE: To evaluate the effect of body mass index on the surgical outcomes in ovarian cancer patients. In addition, we performed a systematic review to compare our outcomes with the current literature. DESIGN: Retrospective cohort study and a systematic review of the literature. SETTING: Gynaecology department at the Royal Cornwall Hospital Trust. POPULATION: Surgically managed stage I-IV ovarian cancer patients between September 2006 and September 2014. METHODS: Primary and secondary outcome measures were evaluated across BMI categories; BMI <25 kg/m², BMI 25­29.9 kg/m², BMI ≥30 kg/m² and BMI ≥40 kg/m². A systematic review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. MAIN OUTCOME MEASURES: The primary outcome measure was surgical complications. Secondary outcome measures were other intra- and postoperative outcomes. RESULTS: Two hundred twenty-eight women were included in the study, of which 84 had a BMI <25 kg/m², 84 women had a BMI 25­29.9 kg/m², and 60 women were obese (BMI ≥30 kg/m²), 13 of whom were morbidly obese. Morbid obesity was associated with increased rates of wound complications. However, BMI did not show an association with other outcomes. In the review, an increasing BMI was associated with increased rates of wound complications and prolonged hospital stay, but did not impact other surgical outcomes. CONCLUSION: Obesity is associated with increased rates of wound complications and a prolonged hospital stay, but does not appear to affect other operative outcomes including cytoreduction status and 30-day mortality. Therefore, operative management and postoperative care require a multifactorial approach to minimise adverse outcomes.

Intake of coffee, caffeine and other methylxanthines and risk of Type I vs Type II endometrial cancer.

BACKGROUND: Coffee and other sources of methylxanthines and risk of Type I vs Type II endometrial cancer (EC) have not been evaluated previously. METHODS: Prospective cohort of 23,356 postmenopausal women with 471 Type I and 71 Type II EC cases. RESULTS: Type I EC was statistically significantly associated with caffeinated (relative risk (RR)=0.65 for 4+ cups per day vs ≤1 cup per month: 95% confidence interval (CI): 0.47-0.89) but not decaffeinated (RR=0.76; 95% CI: 0.50-1.15) coffee intake; there were no associations with tea, cola or chocolate, or for Type II EC. The inverse association with caffeinated coffee intake was specific to women with a body mass index 30+ kg m(-2) (RR=0.56; 95% CI: 0.36-0.89). CONCLUSION: Coffee may protect against Type I EC in obese postmenopausal women.

Risk-scoring system for the individualized prediction of lymphatic dissemination in patients with endometrioid endometrial cancer.

OBJECTIVE: To develop a risk-scoring system (RSS) for the prediction of lymphatic dissemination after hysterectomy in endometrioid endometrial carcinoma (EC). METHODS: Patients who underwent surgery from 1/1/1999-12/31/2008 were evaluated. Patients with non-endometrioid histology, stage IV with macroscopic extrauterine disease, or receiving adjuvant therapy (excluding brachytherapy) without pelvic and/or paraaortic (P/PA) lymphadenectomy (LND) were excluded. Lymph node dissemination was defined as nodal metastasis when P/PA LND was performed or P/PA lymph node recurrence after negative LND or when LND was not performed. Logistic regression analysis was used to identify predictors for lymphatic dissemination and develop a RSS and nomogram. The RSS was assessed for calibration and verified for discrimination. RESULTS: Overall, 883 patients were assessed of which 521 (59.0%) underwent P/PA LND and 57 (10.9%) had positive lymph nodes. Of patients who did not undergo P/PA LND (N=362) or had negative nodes (N=464), 10 (1.2%) patients had P/PA lymph node recurrence. Myometrial invasion, tumor diameter (TD), FIGO grade, cervical stromal invasion and lymphovascular space invasion were significant on univariable analysis. All preceding variables were included in a multivariable logistic model. A parsimonious model and an alternative full model not including TD were considered. The full model with TD (illustrated in nomogram) had the highest predictive ability (concordance index 0.88). CONCLUSION: Our RSS allows accurate quantification of the probability of lymphatic dissemination and can be used as an adjunct to clinical decision-making after hysterectomy in the absence of staging. TD is an important component of the RSS and should be routinely assessed.

Risk factors that mitigate the role of paraaortic lymphadenectomy in uterine endometrioid cancer.

OBJECTIVE: Paraaortic lymph node (PA) dissemination in endometrial cancer (EC) is uncommon and a systematic infrarenal PA dissection carries morbidity. Our objective was to identify a subgroup of EC patients who may potentially forego PA lymphadenectomy (LND). METHODS: The study endpoint (PA Metastasis or Recurrence; PAMR) was defined as detection of metastasis to PA nodes (among those with any type of PA LND) or PA recurrence within 2 years (among patients without PA LND or those with negative nodes in the context of an inadequate (<5 nodes) PA LND). Patients with non-endometrioid histology, stage IV disease, synchronous cancers, gross extrauterine or gross adnexal disease, neoadjuvant therapy, or insufficient follow-up were excluded. Multivariable logistic regression analysis identified predictors of PAMR. RESULTS: Of the 946 patients, PAMR was observed in 4% (36/946). Multivariable analysis identified positive pelvic nodes (odds ratio (OR) 24.2; p<0.001), >50% MI (OR 5.3; p<0.001) and lymphovascular space invasion (LVSI) (OR 3.7; p=0.005) as the only three independent predictors of PAMR. When all three factors were absent (77% of study cohort), the predicted probability of PAMR was 0.6%. If intraoperative frozen section is not available on pelvic lymph nodes and LVSI, omitting PA LND in all patients with ≤ 50% MI would affect 84% (792/946) of the total cohort, with a 1.1% risk of PAMR (9/792). CONCLUSION: The majority of patients with endometrioid EC may potentially forgo PA LND with expected reductions in surgical morbidity and cost. This cohort may be identified by a combined absence of: positive pelvic nodes, >50% MI and LVSI.

Risk of postoperative venous thromboembolism after minimally invasive surgery for endometrial and cervical cancer is low: a multi-institutional study.

OBJECTIVE: To determine the 30-day prevalence of venous thromboembolism (VTE) after minimally invasive surgery (MIS) for endometrial (EC) and cervical cancers (CC). METHODS: A retrospective cohort study at two large tertiary care centers between 2006 and 2011. Patients having MIS for EC or CC were included. Cases converted to laparotomy were excluded. The primary outcome measure was clinically diagnosed VTE within 30 days of operation. RESULTS: Of the 558 patients, 90% had EC and 10% had CC. Modalities of hysterectomy included robotic (88%), vaginal (9%), and laparoscopic (3%). A total of 66% had pelvic and 35% had paraaortic lymphadenectomy. The VTE prophylaxes were sequential compression devices (100%) and heparin (39%). There were no VTE events during hospital stay (95% CI, 0.0%-0.7%). The 30-day prevalence of VTE was (0.5%; 95% CI, 0.1%-1.6%). The hitherto recommended risk criteria for giving extended 30-day thromboprophylaxis by the American College of Obstetrics and Gynecologists (ACOG) or by the American Society of Clinical Oncology (ASCO) did not predict risk of VTE in our population. CONCLUSIONS: The prevalence of VTE in EC and CC undergoing MIS is very low. The existing 30-day risk prediction models proposed by the ACOG and ASCO stem from open surgery patients and do not appear to apply to MIS patients. Certainly, we found no evidence supporting the use of extended prophylactic heparin in this setting. Further research is urgently needed to define the role of any duration of thromboprophylaxis in MIS patients with endometrial or cervix cancer.

Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines.

BACKGROUND: The ataxia telangiectasia mutated and Rad3-related kinase (ATR) has a key role in the signalling of stalled replication forks and DNA damage to cell cycle checkpoints and DNA repair. It has long been recognised as an important target for cancer therapy but inhibitors have proved elusive. As NU6027, originally developed as a CDK2 inhibitor, potentiated cisplatin in a CDK2-independent manner we postulated that it may inhibit ATR. METHODS: Cellular ATR kinase activity was determined by CHK1 phosphorylation in human fibroblasts with inducible dominant-negative ATR-kinase dead expression and human breast cancer MCF7 cells. Cell cycle effects and chemo- and radiopotentiation by NU6027 were determined in MCF7 cells and the role of mismatch repair and p53 was determined in isogenically matched ovarian cancer A2780 cells. RESULTS: NU6027 is a potent inhibitor of cellular ATR activity (IC(50)=6.7 µM) and enhanced hydroxyurea and cisplatin cytotoxicity in an ATR-dependent manner. NU6027 attenuated G2/M arrest following DNA damage, inhibited RAD51 focus formation and increased the cytotoxicity of the major classes of DNA-damaging anticancer cytotoxic therapy but not the antimitotic, paclitaxel. In A2780 cells sensitisation to cisplatin was greatest in cells with functional p53 and mismatch repair (MMR) and sensitisation to temozolomide was greatest in p53 mutant cells with functional MMR. Importantly, NU6027 was synthetically lethal when DNA single-strand break repair is impaired either through poly(ADP-ribose) polymerase (PARP) inhibition or defects in XRCC1. CONCLUSION: NU6027 inhibits ATR, impairing G2/M arrest and homologous recombination thus increasing sensitivity to DNA-damaging agents and PARP inhibitors. It provides proof of concept data for clinical development of ATR inhibitors.

Morbidity, mortality and overall survival in elderly women undergoing primary surgical debulking for ovarian cancer: a delicate balance requiring individualization.

OBJECTIVE: To assess outcomes and identify underlying predictors of outcomes in a cohort of women over the age of 65 treated for primary ovarian cancer (OC). METHODS: Consecutive patients ≥ 65 with stage IIIC or IV OC treated with primary surgery and adjuvant chemotherapy at Mayo Clinic between January 1, 1994 and December 31, 2004 were retrospectively assessed. We analyzed the impact of perioperative factors (age, albumin, CA125, American Society of Anesthesiologist (ASA) score, amount of ascites, presence of carcinomatosis, creatinine, need for urgent surgery, stage of disease, surgical complexity score and amount of residual disease) on surgical outcomes (morbidity, mortality, overall survival (OS) and ability to receive chemotherapy). RESULTS: Two hundred eighty patients met inclusion criteria. Age was associated with higher ASA score, lower albumin, and higher creatinine; stage, diffuse peritoneal disease, and surgical complexity were not associated with age. Median OS decreased with increasing age and residual disease (RD), and the impact of RD was greater on older patients. All patients benefited similarly when RD=0 [median OS 5.9 years for age 65-69 vs. 5.0 years in those ≥ 80 (p=0.5516)], for RD<1cm, and OS was 3.4 vs. 2.1 years respectively for youngest vs. oldest patients (p=0.068). Perioperative morbidity was observed in 37.5% of patients ≥ 75. Independent predictors of poor perioperative outcome included preoperative albumin ≤ 3g/dL, urgent surgery, age, and stage (p<0.05). Independent predictors of overall survival included creatinine, albumin, surgical complexity score, amount of residual disease, stage and age. CONCLUSION: Age is an independent predictor of OS in OC. A significant number of elderly women are able to undergo a complete cytoreduction and experience OS similar to that of younger patients. However, the benefits to incomplete cytoreduction are less clear in women ≥ 75. These observations highlight the need to use emerging predictors of outcomes in decision making and to focus care in centers able to render patients with no visible residual disease.

From randomized trial to practice: single institution experience using the GOG 172 i.p. chemotherapy regimen for ovarian cancer.

BACKGROUND: The objective of the study was to evaluate completion rates and toxic effects of an i.p. chemotherapy regimen in a cross-section of nonselected patients with ovarian cancer (OC). PATIENTS AND METHODS: All patients with stage IIIC OC consecutively operated at our institution from January 2006 to December 2007 were prospectively collected and analyzed. RESULTS: Eighty-nine patients with stage IIIC OC optimally debulked were evaluated for this study. An i.p. port was primarily placed in 53 of 89 (60%), and i.p. chemotherapy was recommended in 55 patients. Reasons for not recommending i.p. chemotherapy in patients optimally debulked included postoperative complications (n = 7: 8%), poor nutritional/functional status (n = 5: 6%), and extensive surgery including bowel resection (n = 9: 10%). Thirty-three patients (33/55: 60%) recommended to receive i.p. chemotherapy-initiated i.p. treatment. Fifty-two percent of those beginning i.p. therapy (17/33) received three or more cycles with 36% (12/33) successfully completing six cycles. Reasons for discontinuation included grade 3-4 nephrotoxicity in 3 of 21 (14%), febrile neutropenia/sepsis in 3 of 21 (14%), port infection or malfunction in 8 of 21 (38%). CONCLUSIONS: The i.p. chemotherapy regimen used in a consecutive cohort of patients carries could be completed in only a small percentage of patients. Less toxic regimens with higher acceptability should be considered.

Genetic analysis of early- versus late-stage ovarian tumors.

In the United States, ovarian cancer is the fourth most common cause of cancer-related deaths among women. The most important prognostic factor for this cancer is tumor stage, or extent of disease at diagnosis. Although women with low-stage tumors have a relatively good prognosis, most women diagnosed with late-stage disease eventually succumb to their cancer. In an attempt to understand early events in ovarian carcinogenesis, and to explore steps in its progression, we have applied multiple molecular genetic techniques to the analysis of 21 early-stage (stage I/II) and 17 advanced-stage (stage III/IV) ovarian tumors. These techniques included expression profiling with cDNA microarrays containing approximately 18,000 expressed sequences, and comparative genomic hybridization to address the chromosomal locations of copy number gains as well as losses. Results from the analysis indicate that early-stage ovarian cancers exhibit profound alterations in gene expression, many of which are similar to those identified in late-stage tumors. However, differences observed at the genomic level suggest differences between the early- and late-stage tumors and provide support for a progression model for ovarian cancer development.

Somatic mutations in the STK11/LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz-Jegher's syndrome.

Peutz-Jegher's syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyposis, and predisposition to benign and malignant tumors of the gastrointestinal tract, breast, ovary, uterine cervix, and testis. Germline-inactivating mutations in one allele of the STK11/LKB1 gene at chromosome 19p13.3 have been found in most PJS patients. Although ovarian sex cord tumors with annular tubules (SCTATs) and minimal deviation adenocarcinomas (MDAs) of the uterine cervix are very rare in the general population, both tumor types occur with increased frequency in women with PJS. An earlier report indicated that the 19p13.3 region containing the STK11 gene was affected by loss of heterozygosity (LOH) in nearly 50% of MDAs of the uterine cervix. We investigated the role of STK11 mutations and LOH of the 19p13.3 region in two PJS-associated SCTATs and in five SCTATs and eight MDAs of the uterine cervix, which occurred in patients lacking features of PJS (referred to here as "sporadic" cases). Germline mutations in the STK11 gene, accompanied by LOH of markers near the wild-type STK11 allele, were found in the two PJS-associated SCTATs. Somatic mutations in the coding region of STK11 were not found in any of the sporadic SCTATs or MDAs studied, although LOH of the 19p13.3 region was seen in three of eight MDAs. Our findings indicate that STK11, like other tumor suppressor genes, is affected by biallelic inactivation in gynecological tumors of PJS patients. In addition, although LOH of the 19p13.3 region was seen in sporadic MDAs, somatic STK11 mutations are rare. A yet-to-be-defined tumor suppressor gene in the 19p13.3 region may be the specific target of inactivation in these tumors.

Involvement of H-cadherin (CDH13) on 16q in the region of frequent deletion in ovarian cancer.

Ovarian cancer is one of the leading causes of mortality unique to women. Deletions within chromosome 6q are the most frequent events in high-grade invasive epithelial ovarian cancer (IEOC). While previous reports seem to indicate that there is loss of 16q sequences in IOEC, only a very small number of markers (single marker in two different reports) were used. In order to more precisely define the regions of deletions on 16q, we first analyzed LOH with 13 polymorphic markers on 16q in 10 benign, 3 low-grade and 21 high-grade invasive ovarian cancer samples. There was no loss with any of the markers with the benign ovarian samples and loss of one marker in one of three low-grade tumors. In contrast, 14 of 21 (67%) high-grade invasive ovarian tumors showed loss of one or more markers. Detailed deletion mapping revealed three distinct commonly deleted regions on this chromosomal arm: 10/21 (48%) of high-grade tumors showed loss at 16q23.1-23.2 (D16S518, D16S3049 and D16S3029). The second region of loss at 16q23.3-16q24.1 (D16S3144, D16S504, HSD17B2 and D16S507) was observed in 11/21 (52%) of the tumors. The highest frequency of loss was seen at 16q24.2-16q24.3 (D16S422, D16S402 and D16S520) in 12/21 (57%) of tumors. The genomic map of CDH13 indicates that the marker D16S422 that was lost in 5 of these 12 tumors is part of this gene. Three of these 5 tumors showed very low levels of CDH13 expression. Three tumors with LOH of other markers in this region also showed lower levels of CDH13 expression. Analysis of the methylation status of CDH13 in tumors with low levels of expression with methylation-specific PCR revealed that four of six (67%) tumors had methylation of one of the CDH13 alleles. These results suggest that a combination of hyper-methylation and deletion cause the inactivation of CDH13 in ovarian tumors.

Unusual recurrence of ovarian carcinoma 9 years after initial diagnosis.

Ovarian carcinomas typically metastasize to multiple sites via exfoliation, lymphatic spread, or direct invasion. Gastrointestinal tract involvement is usually the result of exfoliation with direct invasion of tumor within the mesentery or through serosal surfaces. We present a case of late recurrence of ovarian carcinoma isolated to the sigmoid mucosa, heralded only by brief left lower quadrant pain with hematochezia in a patient otherwise disease free for 9 years. This unusual presentation illustrates the therapeutic dilemma faced by clinicians when a tumor is of uncertain origin and underscores the need for continued follow-up and close scrutiny of new symptoms in patients with stage I disease and for those who enjoy prolonged disease-free intervals.

A novel region of deletion on chromosome 6q23.3 spanning less than 500 Kb in high grade invasive epithelial ovarian cancer.

Detailed deletion mapping of chromosome 6q sequences in invasive ovarian tumors have implicated several broad regions involving 6q14-16, 6q21-23, 6q25-26, and the telomeric portion in band 6q27 as regions of frequent loss in this malignancy. In order to define regions of loss involved in the development of ovarian cancer, we used 23 polymorphic markers on 6q to examine allelic loss in 25 high-grade, late stage ovarian tumors. Four non-overlapping deletion regions were observed: (1) at 6q21-22.3 (D6S301-D6S292); (2) within a 1 cM region at 23.2-23.3 between markers D6S978-D6S1637 (at D6S311); (3) at 6q26 (between markers D6S411-D6S1277) and (4) at 6q27 with the markers D6S297 and D6S193. The highest region of loss was observed with marker D6S311 (lost in 17 of 19 informative cases, 89%) in 6q23.3, followed by D6S977 and D6S1637 (71 and 55%, respectively). The average fractional allele loss in the high-grade tumors was around 35%. Previous reports have shown 6q27 as the region of most frequent loss in invasive ovarian cancer. However, our results indicate a novel region in 6q23.3 (spanning less than 500 Kb distance between the markers) with the highest loss, implicating this region of chromosome 6q to harbor a putative tumor suppressor gene involved in the development of invasive epithelial ovarian cancer.