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BackgroundAsthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results.ObjectivesWe sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze.MethodsWheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed.Resultsrs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10−4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed.ConclusionsAmong dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.

Background Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. Methods Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. Results From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10–189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). Conclusions Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information.

Biomedical research faces a scarcity of scientists able to work effectively at the interface of diverse scientific disciplines; we reflect on our experience over ten years of interdisciplinary training through our Masters of Research in Translational Medicine, preparing a new generation of researchers for post-genomic interdisciplinary medical research.

In June 2011, the SGO recommended that physical exam and symptoms be the primary surveillance methods in patients with endometrial cancer. We sought to evaluate adherence to these guidelines by comparing the use of CT scans, paps and serum CA125 ordered for endometrial cancer surveillance before and after publication of these guidelines.A retrospective review was performed for all patients undergoing surveillance for endometrial cancer at a single institution between June 2009 and June 2013. We assessed the number of patients without symptoms or abnormal physical exam findings who underwent surveillance CT scans, paps and/or CA125 during the 2years pre- and 2years post-SGO guidelines.92 patients (n=48 pre-6/2011, n=44 post-6/2011) were identified. Mean patient age was 58years. No significant difference in age, ethnicity, body mass index, or disease grade or stage was noted. There was a significant decline in surveillance CT scans (n=13, 27% vs. n=4, 9%, p=0.03), CA125 (n=14, 29% vs. 5, 11%, p=0.035) and paps (n=34, 71% vs. n=8 vs. 18%, p0.001). There was no significant difference in disease status at the last follow-up. Institutional cost of surveillance also declined ($14,102.46 2years pre-guidelines, $3,054.99 2years post-guidelines).In a single urban academic public hospital, after only 2years, clinical adherence to the 2011 SGO endometrial cancer surveillance guidelines resulted in a significant decline in the use of CT scans, CA125 and paps. This reduction does not appear to affect patient outcomes and led to an appreciable decrease in surveillance costs.

Objectives To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity. Methods Recurrent ovarian cancer patients with no limit on prior treatments were eligible. Irinotecan 250mg/m2 (amended to 175mg/m2 after toxicity assessment in first 6 patients) and bevacizumab 15mg/kg were administered every 3weeks until progression or toxicity. Response was assessed by RECIST or CA-125 criteria every 2cycles. Results Twenty nine patients enrolled (10 were platinum-sensitive and 19 were platinum-resistant). The median number of prior regimens was 5 (range 1–12); 13 patients had prior bevacizumab and 11 prior topotecan. The PFS rate at 6months was 55.2% (95% CI: 40%–77%). The median number of study cycles given was 7 (range 1–34). Median PFS was 6.8months (95% CI: 5.1–12.1months); median OS was 15.4months (95% CI: 11.9–20.4months). In this study, no complete response (CR) was observed. The objective response rate (ORR; PR or CR) for all patients entered was 27.6% (95% CI: 12.7%–47.2%) and the clinical benefit rate (CR+PR+SD) was 72.4% (95% CI: 52.8%–87.3%); twelve patients experienced duration of response longer than 6months. In the 24 patients with measurable disease, a partial response (PR) was documented in 8 (30%) patients; 13 patients maintained stable disease (SD) at first assessment. The most common grade 3/4 toxicity was diarrhea. No treatment-related deaths were observed. Conclusions Irinotecan and bevacizumab has activity in heavily pre-treated patients with recurrent ovarian cancer, including those with prior bevacizumab and topoisomerase inhibitor use.

Objective To determine factors influencing discharge patterns after laparoscopic hysterectomy for endometrial cancer and to evaluate the safety of same-day discharge during the 30-day postoperative period. Methods Using the American College of Surgeons' National Surgical Quality Improvement Project's database, patients who underwent hysterectomy for endometrial cancer from 2010 to 2014 were identified and categorized by their hospital length of stay. Statistical analyses were performed to assess the relationship between hospital stay and demographics, medical comorbidities, intraoperative surgical factors and postoperative outcomes. Results A total of 9020 patients had laparoscopic hysterectomies for endometrial cancer and of these, 729 patients (8.1%) were successfully discharged on the day of surgery. These patients were younger and had lower body mass indexes and fewer medical comorbidities than patients who were admitted after their procedure. The same-day discharge group underwent surgical procedures of less complexity than the hospital admission group based on shorter operative times and fewer relative value units (RVUs). There was a lower rate of surgical site infections in the same-day discharge group, and no difference in rates of other postoperative complications including hospital readmissions and reoperations. Conclusions Rates of laparoscopic hysterectomy for endometrial cancer are gradually increasing but the rates of same-day discharge have increased at a much slower rate. Same-day discharge has been successful despite differences in preoperative demographics, medical comorbidities and intraoperative surgical complexity. Overall postoperative complication rates were equivalent despite length of hospital stay, demonstrating the safety and feasibility of same-day discharge after laparoscopic hysterectomy for endometrial cancer.

Up to 70% of endometrioid endometrial cancers carry PTEN gene deletions that can upregulate mTOR activity. Investigational mTOR kinase inhibitors may provide a novel therapeutic approach for these tumors. Using a xenograft tumor model of endometrial cancer, we assessed the activity of mTOR and downstream effector proteins in the mTOR translational control pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) catalytic inhibitor (PP242) compared to that of an allosteric mTOR complex 1 (mTORC1) inhibitor (everolimus, RAD001).Grade 3 endometrioid endometrial cancer cells (AN3CA) were xenografted into nude mice. Animals were treated with PP242, PP242 and carboplatin, carboplatin, RAD001, and RAD001 and carboplatin. Mean tumor volume was compared across groups by ANOVA. Immunoblot analysis was performed to assess mTORC1/2 activity using P-Akt, P-S6 and P-4E-BP1.The mean tumor volume of PP242+carboplatin was significantly lower than in all other treatment groups, P0.001 (89% smaller). The RAD001+carboplatin group was also smaller, but this did not reach statistical significance (P = 0.097). Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated P-Akt.Catalytic mTORC1/2 inhibition demonstrates clear efficacy in tumor growth control that is enhanced by the addition of a DNA damage agent, carboplatin. Targeting mTORC1/2 leads to inhibition of Akt activation and strong downregulation of effectors of mTORC1, resulting in downregulation of protein synthesis. Based on this study, mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for endometrial cancer.

a b s t r a c t Externalizing traits are characterized by exaggerated emotional (e.g., frustration, anger) and behavioral (e.g., drug seeking, reactive aggression) reactions to motivationally significant stimuli. Explanations for this exaggerated reactivity emphasize attention, executive function, and affective processes, but the associations among these processes are rarely investigated. To examine these interactions, we measure fear potentiated startle (FPS; Experiment 1) and neural activation (Experiment 2) in an instructed fear paradigm that manipulates attentional focus, demands on executive functioning, and emotion. In both studies, exaggerated emotional reactivity associated with externalizing was specific to conditions that focused attention on threat information and placed minimal demands on executive functioning. Results suggest that a crucial cognition-emotion interaction affecting externalizing is the over-prioritization and over-allocation of attention to motivationally significant information, which in turn, may impair executive functions and affective regulation.

The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC).Patients with stage III-IV OFPC initiated treatment within 12 weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175 mg/m²) and carboplatin (AUC 6) every 3 weeks for up to 6 cycles, plus oral erlotinib 150 mg daily. The primary objective was to determine whether the pCR rate at reassessment surgery was at least 60% after optimal cytoreduction at initial surgery (1cm residual disease), or at least 40% after suboptimal cytoreduction (at least 1cm residual disease) using a two-stage design (alpha=0.10, beta=0.10).The study population included 56 patients with stage III-IV OFPC. EGFR gene amplification was present in 15% of the 20 tumors evaluated. Twenty-eight patients had protocol therapy after optimal cytoreduction (stratum I), 23 had protocol therapy either after suboptimal cytoreduction (stratum II), and 5 received neoadjuvant therapy prior to cytoreduction (stratum III). Pathologic CR was confirmed in 8 patients (29%; 95% confidence intervals 13%, 49%) in stratum I and 3 patients (11%, 95% C.I. 2%, 28%) in stratum II, which did not meet the prespecified efficacy endpoint in either stratum.Among unselected patients, erlotinib plus carboplatin-paclitaxel did not improve pCR rates compared with historical experience with carboplatin-paclitaxel alone in patients with stage III-IV OFPC.

The distinction of complex atypical endometrial hyperplasia from endometrial adenocarcinoma is often problematic. Foci of back-to-back arrangement of glands or foci of cribriform arrangement of glands smaller than 2.1 mm in diameter are considered insufficient for the diagnosis of endometrial adenocarcinoma by some authors, and sufficient to be diagnosed as endometrial adenocarcinoma by other authors. We refer to these foci as endometrial adenocarcinoma in situ. In this study, we evaluated findings in subsequent hysterectomy in complex atypical endometrial hyperplasia patients with and without adenocarcinoma in situ. Follow-up findings, including the presence or absence of endometrial adenocarcinoma in the hysterectomy specimen, the grade of the carcinoma and the depth of myometrial invasion were analyzed. Of the total 87 patients with complex atypical endometrial hyperplasia, 33 patients had adenocarcinoma in situ and 54 lacked adenocarcinoma in situ. Of 33 patients 22 (66%) with adenocarcinoma in situ had endometrial adenocarcinoma on subsequent hysterectomy vs 13 of 54 (24%) patients without adenocarcinoma in situ (P=0.0001). Myoinvasive endometrial adenocarcinoma was present in 20 of 33 (61%) patients with adenocarcinoma in situ vs 8 of the 54 (15%) patients without adenocarcinoma in situ (P< or =0.0001). The depth of myometrial invasion in cases with myoinvasion was 24.5+19.4% in patients with adenocarcinoma in situ and 12.8+8.5% in patients without adenocarcinoma in situ (P=0.05). Among patients younger than age of 50, 5 of the 7 (71%) with adenocarcinoma in situ had myoinvasive carcinoma vs 2 of the 13 (15%) without adenocarcinoma in situ (P=0.02). The likelihood of finding endometrial adenocarcinoma in subsequent hysterectomy in patients with complex atypical endometrial hyperplasia is significantly increased if adenocarcinoma in situ is present in prior endometrial sampling. Endometrial adenocarcinomas in patients with adenocarcinoma in situ are far more frequently myoinvasive, and invade to a greater depth than endometrial adenocarcinomas seen in patients without adenocarcinoma in situ. Use of adenocarcinoma in situ terminology could lead to improved management of patients with complex atypical endometrial hyperplasia.

Most melanocytic nevi develop on sun-exposed skin during childhood and adolescence and commonly harbor BRAF mutations or, less frequently, NRAS mutations. A small subset of nevi is present at birth, and therefore must develop independently of UV light. To assess whether these nevi have a different mutation spectrum than those that develop on sun-exposed skin, we determined the BRAF and NRAS mutation frequencies in 32 truly congenital nevi. We found no BRAF mutations, but 81% (26/32) harbored mutations in NRAS. Consistently, seven of 10 (70%) proliferating nodules that developed early in life in congenital nevi showed mutations in NRAS. A separate set of nevi that displayed histological features frequently found in nevi present at birth ("congenital pattern nevi") but lacked a definitive history of presence at birth showed an inverse mutation pattern with common BRAF mutations (20/28 or 71%) and less frequent NRAS mutations (7/28 or 25%). Thus, nevi that develop in utero are genetically distinct from those that develop later, and histopathologic criteria alone are unable to reliably distinguish the two groups. The results are consistent with the finding in melanoma that BRAF mutations are uncommon in neoplasms that develop in the absence of sun-exposure.

Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a third phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on Intraperitoneal Therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.

Behavioral and neuroelectric indices of action monitoring were compared for 53 high and low physically active older (60-71 years) and younger (18-21 years) adults during a task-switching paradigm in which they performed a task repeatedly or switched between two different tasks. The error-related negativity (ERN) of a response-locked event-related brain potential (ERP) and behavioral measures of response speed and accuracy were measured during the heterogeneous condition (switching randomly between two tasks) of the switch task. Results indicated that older adults exhibited a greater relative slowing in RT during heterogeneous blocks and smaller ERN amplitude compared to younger adults. Additionally, physical activity differences revealed a relatively smaller global switch cost for physically active older adults and decreased ERN amplitude, as well as increased post-error response slowing for older and younger physically active participants, compared to their less physically active counterparts. The findings suggest that both age and physical activity participation influence behavioral and neuroelectric indices of action monitoring and provide further evidence for the beneficial effects of physical activity on executive control.

The current study utilized a sample of 123 inner-city drug users in residential treatment, comparing sexual risk behavior (SRB) across primary users of (a) heroin and not crack/cocaine, (b) crack/cocaine and not heroin, and (c) both heroin and crack/cocaine. Additional analyses also examined impulsivity as a mediator of drug choice and SRB. Results indicated that SRB was higher in primary crack/cocaine users than in primary heroin users, with those using both drugs evidencing intermediate levels of SRB. Beyond differences in SRB, a similar pattern across drugs was found for impulsivity. Finally, impulsivity mediated the relationship between drug choice and SRB. Although further research is necessary to establish causal relationships, these results support a relationship between SBR and crack/cocaine, and suggest that disinhibition processes including impulsivity may underlie this relationship.

Intraperitoneal chemotherapy (IP) for the treatment of ovarian cancer has been studied in clinical trials and has shown clinical benefit when used as primary adjuvant therapy. IP chemotherapy also may play a role as consolidation after intravenous treatment. In 1998, a pilot study seas initiated using IP cisplatin (or carboplatin) combined with floxuridine (FUDR). Patients received a mean of 3.2 cycles of FUDR, which was accompanied by cisplatin or carboplatin in 88% of cycles. The median follow-up time was 20 months (range 6.0 to 57.6 months). Eight patients have had disease recurrence, with median time to recurrence 19.4 months from onset of protocol treatment. Only one patient has died of disease at 38.8 months from onset of protocol. Extra-abdominal recurrences (lung, brain, inguinal nodes) tended to occur earlier than peritoneal recurrences. Demonstration of an impact on progression-free survival and overall survival requires confirmation in a phase III trial.

We identified two novel mouse mutants with abnormal head-shaking behavior and neural tube defects during the course of independent ENU mutagenesis experiments. The heterozygous and homozygous mutants exhibit defects in the orientation of sensory hair cells in the organ of Corti, indicating a defect in planar cell polarity. The homozygous mutants exhibit severe neural tube defects as a result of failure to initiate neural tube closure. We show that these mutants, spin cycle and crash, carry independent missense mutations within the coding region of Celsr1, encoding a large protocadherin molecule [1]. Celsr1 is one of three mammalian homologs of Drosophila flamingo/starry night, which is essential for the planar cell polarity pathway in Drosophila together with frizzled, dishevelled, prickle, strabismus/van gogh, and rhoA[2, 3]. The identification of mouse mutants of Celsr1 provides the first evidence for the function of the Celsr family in planar cell polarity in mammals and further supports the involvement of a planar cell polarity pathway in vertebrate neurulation.

The clinical presentations of 119 canine seizures from 41 Standard Poodles and 11 Dalmatians were classified according to a modified version of the International League Against Epilepsy (ILAE) seizure classification system. Standardized use of the ILAE system with dogs not only should facilitate research in veterinary medicine, which has no standard criteria for seizure classification, but also should facilitate comparisons between canine and human seizures. We found that for more than 80% of both breeds, at least some of their seizures had partial onsets. However, because it was common for partial seizures to secondarily generalize, the majority of Poodles (81%) and Dalmatians (91%) experienced at least some generalized seizures. Among partial seizures, complex partial were more frequent than simple partial. For both breeds, two thirds of those with partial onset seizures had exclusively complex partial. Among dogs with primary or secondarily generalized seizures, 80% of both breeds had tonic-clonic seizures.

Background. Mullerianadenosarcoma is a rare pelvic malignancy that most commonly arises from the endometrium. These tumors are relatively insensitive to chemotherapy and radiation and are primarily treated by surgical resection. We report a case of mullerian adenosarcoma arising outside of the uterus from a background of endometriosis treated with a combination of surgical resection and medroxyprogesterone acetate. Case. A 43-year-old woman with a history of endometriosis was diagnosed with advanced extrauterine mullerian adenosarcoma. After suboptimal tumor dubulking surgery she was treated with medroxyprogesterone acetate. Ten months postoperatively she remains without evidence of disease. Conclusion. Medroxyprogesterone acetate may be a useful drug in the treatment of advanced mullerian adenosarcoma.

To determine the outcome for patients with recurrent gynecologic tumors treated with radical resection and combined high-dose intraoperative radiation therapy (HDR-IORT).Between November 1993 and June 1998, 17 patients with recurrent gynecologic malignancies underwent radical surgical resection and high-dose-rate brachytherapy. The mean age of the study group was 49 years (range 28-72 years). The site of the primary tumor was the cervix in 9 (53%) patients, the uterus in 7 (41%) patients, and the vagina in 1 (6%) patient. The treatment for the primary disease was surgery with or without adjuvant radiation in 14 (82%) patients and definitive radiation in 3 (18%) patients. The current surgery consisted of exenterative surgery in 10 (59%) patients and tumor resection in 7 (41%) patients. Complete gross resection was achieved in 13 (76%) patients. The mean HDR-IORT dose was 14 Gy (range 12-15). Additional radiation in the form of permanent Iodine-125 implant was given to 3 of 4 patients with gross residual disease. The median peripheral dose was 140 Gy.With a median follow-up of 20 months (range 3-65 months), the 3-year actuarial local control (LC) rate was 67%. In patients with complete gross resection, the 3-year LC rate was 83%, compared to 25% in patients with gross residual disease, p0.01. The 3-year distant metastasis disease-free and overall survival rates were 54% and 54%, respectively. The complications were as follows: gastrointestinal obstruction, 4 (24%); wound complications, 4 (24%); abscesses, 3 (18%); peripheral neuropathy, 3 (18%); rectovaginal fistula, 2 (12%); and ureteral obstruction, 2 (12%).Radical surgical resection and combined IORT for patients with recurrent gynecologic tumors seems to provide a reasonable local-control rate in patients who have failed prior surgery and/or definitive radiation. Patient selection is very important, however, as only those patients with complete gross resection at completion of surgery appear to benefit most from this radical approach in the salvage setting.

This study introduces a new methodology for investigating the impact of active avoidance and behavioral control on defensive emotional reactivity using the startle reflex. A between-groups yoked design was devised that permitted manipulation of participants' perception of control over an aversive event (loud noise) while precisely controlling motor activity and noxious stimulation. Startle responses to tactile (airpuff) probes were compared during threat/performance trials and neutral trials. Results conclusively demonstrated cross-modal startle potentiation in the context of a continuous motor performance task. Also, consistent with prior research, heart rate increased with perceived control. However, behavioral control per se did not appear to mitigate defensive emotion as indexed by startle potentiation. These findings indicate that other parameters may mediate the efficacy of active coping in addition to control, and that the startle probe paradigm can provide a valuable tool for investigating these parameters in future research.

Objective. The aim of this study was to determine the feasibility and efficacy of intraperitoneal cisplatin and mitoxantrone in patients with very small-volume residual disease at second-look surgery after completion of primary platinum-based intravenous chemotherapy. Patients and methods. Between February 1992 and February 1994, 42 patients were treated with up to five cycles of intraperitoneal cisplatin (100 mg/m 2 )/mitoxantrone (10 mg/m 2 ). Patients were evaluated for surgically defined response rate and followed for progression-free (PFS) and overall survival (OS) using an intention-to-treat analysis, and grouped according to disease volume at initiation of treatment. Results. The mean age of all patients was 48.5 years. Thirty patients (71%) were Stage III at diagnosis; 18 patients (43%) had microscopic disease at the initiation of IP therapy, and 24 patients (57%) had macroscopic disease. Twenty-eight patients completed three or more cycles of protocol therapy, and 14 patients were changed to standard intravenous therapy after receiving fewer than three cycles of treatment secondary to catheter-related problems (12 patients), cisplatin ototoxicity (1 patient), or withdrawal from study (1 patient). Using an intention-to-treat analysis, the median PFS was 22.5 months, and the median OS of all patients ( N = 42) was 47 months (6–72 months) with a median follow-up of 62.7 months. When grouped according to size of disease at initiation of treatment, the OS has not been reached at 62.7 months of follow-up in patients ( N = 18) with microscopic disease. Conclusions. (1) The combination of IP mitoxantrone and cisplatin has an unacceptable catheter failure rate due to mitoxantrone toxicity; (2) PFS and OS is longer in patients with microscopic rather than macroscopic residual disease; and (3) intraperitoneal platinum-based chemotherapy in patients with very small-volume residual disease may result in improved survival.

Objective. To report a series of patients with recurrent epithelial ovarian cancer who underwent splenectomy for isolated parenchymal metastases. Methods. We performed a retrospective review of all patients who had a splenectomy for ovarian cancer at our institution during the period 1991 to 1997. Results. Six patients were identified who had a splenectomy performed for recurrent epithelial ovarian cancer confined to the splenic parenchyma. All had initial cytoreductive surgery for Stage III disease followed by platinum-based chemotherapy. Five patients underwent second-look surgery and four of them had pathologically confirmed persistent disease. All five patients who underwent second-look surgery had an intraperitoneal (ip) port placed and received platinum-based ip chemotherapy. Computed tomography (CT) scan performed during the posttreatment surveillance period demonstrated recurrent disease confined to the spleen in all six patients. Splenectomy was performed at a median of 57 months (range 28–88 months) after the initial surgery. The only major complication was a diaphragmatic tear necessitating chest tube placement. With a median follow-up of 25.5 months (range 6–65 months), all six patients are alive and free of disease. Conclusion. Splenectomy is a safe and feasible procedure in recurrent epithelial ovarian cancer. Isolated parenchymal splenic metastasis may occur as a late recurrence in epithelial ovarian cancer and splenectomy should be considered a part of the management of this group of patients.

While surgery is the primary treatment for the management of gynecologic malignancies, adjuvant chemotherapy and radiation therapy play a critical role in survival for many patients. In this article, we discuss the feasibility and effectiveness of adjuvant therapy for ovarian, cervical, and endometrial cancers, and discuss current recommendations.

A 61-year-old woman developed severe subacute cerebellar degeneration in association with a neuronal antinuclear autoantibody. Neurologic investigations were remarkable only for mild CSF leukocytosis. Despite no radiographic evidence of cancer, a salpingo-oophorectomy was performed on the basis of an increased gynecologic cancer marker (CA-125) and the neurologic symptoms that were strongly suggestive of paraneoplastic cerebellar degeneration. Although no tumor was detected in the surgical specimen, CA-125 levels normalized after surgery. The patient remains stable 12 months after surgery with a severe cerebellar syndrome, no evidence of cancer, and persistent circulating antineuronal autoantibodies. An elevated tumor marker in a patient with a presumed paraneoplastic neurologic disorder should suffice as evidence of an occult neoplasm, and guide definitive treatment.

Objective: To evaluate the influence of surgical debulking performed on patients with Stage IV ovarian cancer and to determine prognostic factors which identify pts who may benefit from aggressive initial surgical debulking. Methods: A retrospective chart review was conducted (1/1/87–12/31/93). Eligible patients included all women with FIGO Stage IV ovarian cancer. Clinical information abstracted included age at diagnosis, histology type, tumor grade, criteria for Stage IV classification, surgical procedure performed, and tumor residuum. Optimal surgical status was defined as ≤2 cm residual disease. Chemotherapy treatment was recorded, as was follow-up. Survival estimates were computed by Kaplan–Meier method with differences in survival calculated by the log-rank test. The Cox proportional hazards regression model was used to identify independent variables which were associated with an improved survival rate. Results: One hundred five women were found in our database with Stage IV ovarian cancer and 97 had complete information available. Median age of the patients was 57 years (range 24–81 years). Papillary-serous histology was found in 55/97 patients (57%) and 50 patients (52%) had grade 3 tumors. Forty-one of 97 patients (42%) had malignant pleural effusion and 20/97 (21%) had liver metastases. Ninety-two patients underwent a primary attempt at surgical debulking and 40/92 were optimally debulked. Twenty-one of 41 patients (51%) with pleural effusion were optimally debulked compared to 20/51 (39%) with other criteria for Stage IV disease (P= NS). Overall median survival was 21 months; optimally debulked patients’ median survival was 40 months compared to 18 months for patients with bulky residual disease (P= 0.01). The survival advantage for optimally debulked patients was statistically significant for the two subgroups of patients with and without malignant pleural effusion. In the multivariate analysis only age less than 65 years and optimal debulking were independent predictors of outcome. Conclusions: Surgical debulking appears to be an important determinant of prognosis in women with Stage IV ovarian cancer, including patients with malignant pleural effusion.

The methods for preoperative diagnosis and evaluation of the woman with a suspected ovarian neoplasm have evolved significantly with little or no impact on the surgical treatment, which remains removal of the abnormal ovary. Although most adnexal masses are benign, the primary goal of the diagnostic evaluation is the exclusion of malignancy. A complete history, physical examination, and ultrasonic imaging are vital in evaluating a suspected ovarian mass. In postmenopausal women, serum CA-125 determinations further improve sensitivity and specificity. Once the presence of an ovarian mass is established, the crucial decision is whether to observe the patient or proceed with surgical removal. If surgical removal is indicated, the proper procedure is important for staging and initiation of effective therapy. While many surgeons are now using the less invasive laparoscopic approach, the standard of care continues to be a laparotomy with either an ovarian cystectomy or oophorectomy. Future clinical research in the management of adnexal masses should focus on decreasing the number of patients undergoing a surgical procedure, and in patients who require surgery, further evaluation of laparoscopy as a safe, cost-effective means of treatment. Improved imaging techniques may allow for nonoperative management of probably benign ovarian neoplasms.

Pelvic exenteration for treatment of malignant gynecologic disease is most often done for recurrent cervical cancer, although cytologic screening has substantially decreased the number of patients considered for the operation. The authors prefer the Indiana pouch for urinary diversion, and all patients in whom it has been used in the past 2 years have achieved continence. To avoid reoperation, a diverting, rather than a protective, colostomy is constructed during the exenteration. Postoperative management of fistulae may include the use of somatostatin analog and percutaneous nephrostomy. Survival depends on the extent of resection and various clinical and pathological factors. Newer techniques for delivering additional radiation to recurrent tumors may increase the number of patients eligible for curative exenteration.

In a Phase II trial, patients with refractory ovarian cancer were given 10 mg/m 2 mitomycin-C iv every 8 weeks and 1000 mg/m 2 /day 5-fluorouracil for 3 consecutive days by continous intravenous infusion repeated every 4 weeks. Sixteen heavily pretreated patients with platinum-resistant disease were treated and no major responses were observed. Only 2 patients required subsequent dose reduction for myelotoxocity. No sign of gastrointestinal toxicity was seen. This regimen is inactive as salvage treatment for refractory ovarian cancer.

Purpose: To examine the relative efficacy of cisplatin-based intraperitoneal (IP) therapy versus carboplatin-based IP therapy as salvage treatment of small-volume residual ovarian cancer. Patients and methods: We retrospectively examined the surgically defined response rates of patients with ovarian cancer treated at the Memorial SIoan-Kettering Cancer Center on four organoplatinum-based salvage IP trials (cisplatin/etoposide, cisplatin/cytarabine, carboplatin/etoposide, carboplatin/etoposide + recombinant human erythropoietin). Additional criteria for inclusion in this analysis were: (a) small-volume residual disease (microscopic disease only or largest residual tumor mass ⩽ 0.5 cm) when IP therapy was initiated; (b) prior response to organoplatinum-based systemic therapy; (c) laparotomy evaluation for response to the IP salvage program. Results: The surgically documented complete response rate for patients with microscopic disease treated with cisplatin-based or carboplatin-based therapy was 46% (6/13) versus 38% (6/16), respectively ( P > 0.25). In contrast, the surgically documented overall and complete response rates for patients with small-volume macroscopic disease treated with cisplatin or carboplatin were 71% (12/17) versus 32% (6/19) ( P 2 test with Yates' correction), and 41% (6/17) versus 11% (2/19) (p Conclusion: In agreement with experimental data demonstrating that the concentration of platinum within tumor is higher following equimolar doses of cisplatin, compared to carboplatin, we have observed, in this retrospective analysis, a higher surgically documented response rate for patients with small-volume residual macroscopic ovarian cancer receiving salvage cisplatin-based IP therapy. While a randomized trial will be required to definitively address the question of the relative effectiveness of the two commercially available organoplatinum agents for IP treatment of ovarian cancer, our data suggest that cisplatin is the superior agent for regional therapy in this disease.

In clinical trials examining the intraperitoneal (ip) administration of mitoxantrone as therapy of platinum-refractory small-volume residual ovarian cancer, the characteristic "blue color" of the agent has been demonstrated to stain the surface of the peritoneal cavity and to persist foror = 1 month following the last course of therapy. To determine if this blue staining material contains potentially cytotoxic concentrations of mitoxantrone, we analyzed tissue obtained at exploratory laparotomy in six women who had last received the agent administered ip from 6-22 weeks prior to surgery. Concentrations of mitoxantrone ranged from0.1 to 13.8 micrograms/g of tissue examined. Since any mitoxantrone present on the peritoneal surface will be highly protein bound, any residual drug may not have cytotoxic potential. The dose-response curves of mitoxantrone in a human clonogenic cytotoxicity assay against the RPMI 2780/S human ovarian cell line were virtually identical when the cells were incubated in either 5 or 50% fetal bovine serum, suggesting that protein binding will not significantly impair mitoxantrone-induced tumor cell killing. We conclude that the ip administration of mitoxantrone may lead to prolonged exposure of surface tumor to the high local concentrations of the active cytotoxic agent. This effect may contribute significantly to the antineoplastic potential of ip mitoxantrone in patients with small-volume residual ovarian cancer.

Ifosfamide is an active chemotherapeutic agent in a wide range of gynecologic tumors; favorable response rates have been reported in ovarian (epithelial and germ cell), uterine, and cervical neoplasms. Central neurotoxicity is a known, but poorly described side effect. We report 23 patients who received a total of 75 cycles of ifosfamide, either as a single agent or in combination with other chemotherapeutic agents. Six of twenty-three (26%) experienced grade 4 neurotoxicity; clinical presentation included confusion, aphasia, hallucinations, and coma. All patients exhibited the first evidence of neurotoxicity by the end of the 24-hr infusion. Three of six patients with grade 4 neurotoxicity expired within 14 days of receiving ifosfamide. The neurotoxicity resolved over 2 to 4 days in the remaining patients. Serum albumin was normal (greater than 3.5 g/dl) in 63 cycles of ifosfamide not associated with neurotoxicity. When serum albumin was less than 3.5 g/dl, 6 of 12 cycles were associated with severe neurotoxicity (P less than 0.001). Low serum albumin (less than 3.5 g/dl) appears to be associated with a high risk of severe neurotoxicity in patients receiving single-dose ifosfamide therapy.

MRI evaluation of primary cervical lymphoma has not been reported. We report such a case of primary cervical lymphoma, a lesion well seen and well delineated from normal tissue by MRI. Although primary lymphoma of the cervix is a rare entity, the disease does exist and can be well demonstrated by MRI. We evaluated the MR appearance of this lesion with both nonenhanced and gadolinium-enhanced imaging.