The role of obesity in treatment planning for early-stage cervical cancer.

OBJECTIVES: Optimal management of obese patients with early-stage cervical cancer is debated despite evidence of non-inferior survival in obese patients undergoing radical hysterectomy with pelvic lymphadenectomy (RH) compared to primary radiation with or without radiosensitizing chemotherapy (RT). Objectives included describing patient factors affecting disposition to RH versus RT; comparing RH outcomes for obese (BMI >30 mg/m2) and non-obese patients; and comparing differences in recurrence free survival (RFS) and overall survival (OS). METHODS: This was a single institution cohort study of all cervical cancer patients who underwent RH or were candidates for RH based on clinical stage. Demographic, clinicopathologic and treatment outcomes were collected and analyzed. RESULTS: RT patients (n = 39, 15%) had a higher BMI (p = 0.004), older age (p < 0.001), more life-limiting comorbidities (LLC) (p < 0.001), larger tumor size (p = 0.001), and higher clinical stage (p = 0.013) compared to RH patients (n = 221, 85%). On multivariable survival analysis there was no difference in OS based on treatment modality; significant predictors of worse OS were larger tumor size, higher number of LLC and recurrence. Among the RH group, obese patients had a longer operative time (p = 0.01) and more LLC (p = 0.02); there were no differences in demographic or clinicopathologic characteristics, operative outcomes, RFS or OS compared to non-obese patients. CONCLUSION: In this cohort of RH-eligible cervical cancer patients, BMI was independently associated with disposition to RT. Studies demonstrate that RH is feasible and safe in obese patients with no difference in RFS or OS when compared to non-obese patients. Thus, the decision for disposition to RT should not be based on obesity alone.

Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

Hysterectomy with sentinel lymph node dissection in the setting of preoperative endometrial intraepithelial neoplasia and an endometrial stripe ≥20 mm: a cost-effectiveness analysis .

OBJECTIVES: Routine lymph node assessment in patients with endometrial intraepithelial neoplasia is institution and surgeon-dependent without clear guidelines. We sought to determine if routine sentinel lymph node (SLN) dissection at the time of laparoscopic hysterectomy for patients with a preoperative diagnosis of endometrial intraepithelial neoplasia and a preoperative ultrasound with endometrial stripe ≥20 mm is cost-effective. METHODS: A decision model was created to perform two cost-effectiveness analyses: (1) hysterectomy with frozen section versus hysterectomy with SLN dissection in patients with a preoperative diagnosis of endometrial intraepithelial neoplasia and an endometrial stripe of 20 mm or greater, and (2) the same options in all patients with a preoperative diagnosis of endometrial intraepithelial neoplasia. Costs obtained from Centers for Medicare and Medicaid Services and event probabilities and quality of life utility values were obtained through literature review. RESULTS: In the case of preoperative endometrial stripe ≥20 mm, hysterectomy with SLN dissection cost $2469 more than hysterectomy with frozen section and gained 0.010 quality adjusted life years, or $44,997/quality-adjusted life years gained. In one-way sensitivity analyses, SLN dissection remained the favored strategy at a willingness to pay threshold of $100,000/quality-adjusted life years unless chronic lower extremity lymphedema after full lymphadenectomy had a likelihood <13.1% (base case value 18.1%); otherwise, SLN dissection was favored with individual variation of all other parameters over plausible ranges. When considering all patients with endometrial intraepithelial neoplasia, hysterectomy with frozen section was favored, with results most sensitive to variation of lymphedema risk after full lymphadenectomy. CONCLUSION: Hysterectomy with SLN dissection in patients with a preoperative endometrial stripe ≥20mm on ultrasound is cost-effective when compared with hysterectomy with frozen section.

Cost-effectiveness analysis of tumor molecular testing in stage III endometrial cancer.

BACKGROUND: Standard of care for adjuvant treatment of stage III endometrial cancer includes chemotherapy and radiation. In addition to stage, tumor molecular profiles may predict treatment outcomes, and prospective clinical trials are ongoing. However, tumor molecular testing is costly and time-consuming. Our objective was to evaluate the cost-effectiveness of tumor molecular testing in stage III endometrial cancer. METHODS: A Markov decision model compared two strategies for stage III endometrial cancer: Tumor Molecular Testing (TMT) versus No TMT. TMT included sequential POLE next generation sequencing, mismatch repair immunohistochemistry (IHC), and p53 IHC. POLE-mutated patients were assigned to adjuvant radiation therapy; all others including controls were assigned to adjuvant chemoradiation. First recurrences were treated with 6 cycles of carboplatin and paclitaxel. Second recurrences were treated with pembrolizumab alone for mismatch repair deficient patients and both pembrolizumab and lenvatinib for other patients. Sensitivity analyses were performed to test model robustness. RESULTS: Compared to No TMT, TMT was cost saving with equivalent effectiveness. On one-way sensitivity analysis, TMT remained cost saving over all parameter ranges. TMT was also favored on probabilistic sensitivity analysis in 80% of iterations at a willingness-to-pay threshold of $100,000/quality adjusted life-year (QALY) gained. However, when TMT was compared to mismatch repair IHC alone, TMT cost $182,798/QALY gained. CONCLUSIONS: In this model of patients with stage III endometrial cancer, TMT was cost saving compared to No TMT. However, when compared to mismatch repair IHC alone, TMT was economically unfavorable.

Feasibility of intraoperative injection of radioactive tracer and blue dye for sentinel lymph node biopsy in vulvar cancer.

OBJECTIVE: The objective of this study was to examine the feasibility and success rate of intraoperative injection of radiotracer and blue dye performed by the surgeon without the use of preoperative lymphoscintigraphy for the detection of sentinel lymph nodes in clinically early stage vulvar cancer. METHODS: All patients with clinically early stage vulvar cancer who underwent attempted sentinel lymph node biopsy using intraoperative injection of Technetium-99 m (99mTc) tracer and blue dye performed by the surgeon after induction of anesthesia at single academic institution from 12/2009 to 5/2022 were identified. Demographic and clinicopathologic variables were collected. Data were compared using descriptive statistics. RESULTS: One hundred sixty-four patients (median age 66.4 years) underwent intraoperative injection of radioactive tracer and dye for sentinel lymph node biopsy. Most patients (n = 156, 95.1%) were white. Squamous cell carcinoma accounted for 138 cases (84.1%), melanoma for 10 (6.1%), extra-mammary invasive Paget's disease for 11 (6.7%), and other histologies for 5 (3%). A majority of cases were stage I disease on final pathology (n = 119, 72.6%). Most patients (n = 117, 71%) had tumors located within 2 cm of the midline and underwent planned bilateral groin assessment, while 47 (29%) had well lateralized lesions and underwent unilateral groin assessment. For the patients undergoing unilateral groin assessment, 44 of 47 (93.6%) had successful unilateral mapping. Of the patients who underwent bilateral groin assessment, 87 of 117 (74.4%) had successful bilateral mapping, and 26 of 117 (22.2%) had successful unilateral mapping. Of the 26 patients who underwent bilateral assessment but only had unilateral mapping, 19 had unilateral mapping to ipsilateral groin but failed contralateral mapping, six had midline lesions with successful mapping to one groin but failed mapping to the other groin, and one had unilateral mapping to the contralateral groin but not ipsilateral groin. The total successful sentinel lymph node mapping rate in this cohort was 86.5% (243/281 total sentinel lymph node attempts). CONCLUSION: In this cohort, the overall success rate of sentinel lymph node mapping and biopsy was 86.5%. The high rate of successful sentinel lymph node mapping supports the use of intraoperative radiotracer and blue dye injection by trained providers.

Prophylactic anticoagulation after minimally invasive hysterectomy for endometrial cancer: a cost-effectiveness analysis.

OBJECTIVE: To determine our institutional rate of venous thromboembolism (VTE) following minimally invasive surgery for endometrial cancer and to perform a cost-effectiveness analysis of extended prophylactic anticoagulation after minimally invasive staging surgery for endometrial cancer. METHODS: All patients with newly diagnosed endometrial cancer who underwent minimally invasive staging surgery from January 1, 2017 to December 31, 2020 were identified retrospectively, and clinicopathologic and outcome data were obtained through chart review. Event probabilities and utility decrements were obtained through published clinical data and literature review. A decision model was created to compare 28 days of no post-operative pharmacologic prophylaxis, prophylactic enoxaparin, and prophylactic apixaban. Outcomes included no complications, deep vein thrombosis (DVT), pulmonary embolism, clinically relevant non-major bleeding, and major bleeding. We assumed a willingness-to-pay threshold of $100 000 per quality-adjusted life year (QALY) gained. RESULTS: Three of 844 patients (0.36%) had a VTE following minimally invasive staging surgery for endometrial cancer. In this model, no pharmacologic prophylaxis was less costly and more effective than prophylactic apixaban and prophylactic enoxaparin over all parameters examined. When all patients were assigned prophylaxis, prophylactic apixaban was both less costly and more effective than prophylactic enoxaparin. If the risk of DVT was ≥4.8%, prophylactic apixaban was favored over no pharmacologic prophylaxis. On Monte Carlo probabilistic sensitivity analysis for the base case scenario, no pharmacologic prophylaxis was favored in 41.1% of iterations at a willingness-to-pay threshold of $100 000 per QALY. CONCLUSIONS: In this cost-effectiveness model, no extended pharmacologic anticoagulation was superior to extended prophylactic enoxaparin and apixaban in clinically early-stage endometrial cancer patients undergoing minimally invasive surgery. This model supports use of prophylactic apixaban for 7 days post-operatively in select patients when the risk of DVT is 4.8% or higher.

Survival disparities in vulvar cancer patients in Commission on Cancer®-accredited facilities.

OBJECTIVES: To investigate survival disparities and prognostic factors in vulvar cancer by age at diagnosis. METHODS: Women who underwent surgery and were diagnosed with stage I-IV vulvar cancer from 2004 to 2014 in the National Cancer Database were eligible. Proportions were compared using Chi-Square test. Survival was evaluated using Cox analysis. RESULTS: There were 18,207 eligible women. Median age at diagnosis was 64 years, and 31% diagnosed ≥75 years old were categorized as elderly. Most vulvar cancers were diagnosed at stage I and with squamous histology. Diagnosis with higher stage or non-squamous histology was more common in elderly vs. non-elderly patients (P < 0.001). Survival was 3.5 times worse in the elderly than the non-elderly (P < 0.0001). Risk of death for each 5-year increment in age increased by 22% for non-elderly and 43% for elderly patients (P < 0.0001). The prognostic value of comorbidity score, stage, regional node assessment and histology was smaller in elderly vs. non-elderly women (each P < 0.05). Adjuvant chemoradiotherapy (CTRT) use in the elderly vs. non-elderly was rare for stage I-II disease (3% vs. 2%) and more common for stage III-IV disease (6% vs. 43%), respectively (P < 0.0001). The survival disadvantage for elderly patients persisted following no adjuvant therapy, radiotherapy or chemotherapy alone, or CTRT (P < 0.0001). In stage III-IV disease, survival was superior following CTRT vs. radiotherapy when diagnosed <75 years (HR = 0.80, 95% CI = 0.69-0.93) but not in the elderly (HR = 0.99, P > 0.05). CONCLUSIONS: Age-associated risk of death increased at different rates in vulvar cancer and was larger in elderly vs. non-elderly patients. The impact of other prognostic factors was smaller in elderly vs. non-elderly women. The survival benefit of CTRT over radiotherapy in stage III-IV did not extend to the elderly.

Inherited alterations of TGF beta signaling components in Appalachian cervical cancers.

PURPOSE: This study examined targeted genomic variants of transforming growth factor beta (TGFB) signaling in Appalachian women. Appalachian women with cervical cancer were compared to healthy Appalachian counterparts to determine whether these polymorphic alleles were over-represented within this high-risk cancer population, and whether lifestyle or environmental factors modified the aggregate genetic risk in these Appalachian women. METHODS: Appalachian women's survey data and blood samples from the Community Awareness, Resources, and Education (CARE) CARE I and CARE II studies (n = 163 invasive cervical cancer cases, 842 controls) were used to assess gene-environment interactions and cancer risk. Polymorphic allele frequencies and socio-behavioral demographic measurements were compared using t tests and χ2 tests. Multivariable logistic regression was used to evaluate interaction effects between genomic variance and demographic, behavioral, and environmental characteristics. RESULTS: Several alleles demonstrated significant interaction with smoking (TP53 rs1042522, TGFB1 rs1800469), alcohol consumption (NQO1 rs1800566), and sexual intercourse before the age of 18 (TGFBR1 rs11466445, TGFBR1 rs7034462, TGFBR1 rs11568785). Interestingly, we noted a significant interaction between "Appalachian self-identity" variables and NQO1 rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1 rs1800469/TGFBR1 rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1 rs1800469/TGFBR1 rs7034462 model in subjects who had no sexual intercourse before age 18. CONCLUSIONS: This study reports novel associations between common low-penetrance alleles in the TGFB signaling cascade and modified risk of cervical cancer in Appalachian women. Furthermore, our unexpected findings associating Appalachian identity and NQO1 rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancer patients represent an emerging avenue of scientific exploration.

Second-line Intraperitoneal Platinum-based Therapy Leads to an Increase in Second-line Progression-free Survival for Epithelial Ovarian Cancer.

OBJECTIVE: Only 3% of patients with epithelial ovarian cancer (EOC) have a longer treatment-free interval (TFI) after second-line intravenous (IV) platinum chemotherapy than with frontline IV therapy. We sought to examine what impact second-line combination IV/intraperitoneal (IV/IP) platinum therapy might have on the ratio of second-line to first-line TFI in patients treated with second-line IP platinum chemotherapy for first recurrence after front-line IV therapy. METHODS: A retrospective analysis of women who received combination platinum-based IV/IP chemotherapy for recurrent EOC between January 2005 and March 2011 was conducted. Patients were identified from the tumor registry, and office records from a large gynecologic oncology practice and patient records were reviewed. The first and second TFIs were defined as the time from the end of previous platinum-based therapy to the start of next therapy. RESULTS: Twenty-five women received IV/IP chemotherapy for their first EOC recurrence after IV chemotherapy. In 10 patients (40%), we observed a longer TFI after IV/IP chemotherapy than after primary IV chemotherapy. For these 10 patients, the median TFI for primary response was 22 months (range, 15-28), whereas median TFI after IV/IP chemotherapy for recurrent disease was 37 months (range, 12-61). CONCLUSIONS: For EOC patients with limited peritoneal recurrence, 40% of patients had a second-line IP-platinum TFI that exceeded their frontline IV-platinum TFI compared to published data. These data support the use of IV/IP chemotherapy as a treatment for recurrence.

Cost-utility comparison of neoadjuvant chemotherapy versus primary debulking surgery for treatment of advanced-stage ovarian cancer in patients 65 years old or older.

OBJECTIVE: Treatment for advanced-stage epithelial ovarian cancer (AEOC) includes primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT). A randomized controlled trial comparing these treatments resulted in comparable overall survival (OS). Studies report more complications and lower chemotherapy completion rates in patients 65 years old or older receiving PDS. We sought to evaluate the cost implications of NACT relative to PDS in AEOC patients 65 years old or older. STUDY DESIGN: A 5 year Markov model was created. Arm 1 modeled PDS followed by 6 cycles of carboplatin and paclitaxel (CT). Arm 2 modeled 3 cycles of CT, followed by interval debulking surgery and then 3 additional cycles of CT. Parameters included OS, surgical complications, probability of treatment initiation, treatment cost, and quality of life (QOL). OS was assumed to be equal based on the findings of the international randomized control trial. Differences in surgical complexity were accounted for in base surgical cost plus add-on procedure costs weighted by occurrence rates. Hospital cost was a weighted average of diagnosis-related group costs weighted by composite estimates of complication rates. Sensitivity analyses were performed. RESULTS: Assuming equal survival, NACT produces a cost savings of $5616. If PDS improved median OS by 1.5 months or longer, PDS would be cost effective (CE) at a $100,000/quality-adjusted life-year threshold. If PDS improved OS by 3.2 months or longer, it would be CE at a $50,000 threshold. The model was robust to variation in costs and complication rates. Moderate decreases in the QOL with NACT would result in PDS being CE. CONCLUSION: A model based on the RCT comparing NACT and PDS showed NACT is a cost-saving treatment compared with PDS for AEOC in patients 65 years old or older. Small increases in OS with PDS or moderate declines in QOL with NACT would result in PDS being CE at the $100,000/quality-adjusted life-year threshold. Our results support further evaluation of the effects of PDS on OS, QOL and complications in AEOC patients 65 years old or older.

Use of indocyanine green dye for sentinel lymph node mapping in patients with endometrial cancer and a history of iodinated contrast allergy.

Objectives: Sentinel lymph node (SLN) mapping is a surgical technique with high accuracy in detecting metastases while limiting morbidity associated with full lymphadenectomy in endometrial cancer. Cervical injection of indocyanine green (ICG) dye is associated with very high SLN detection rates; however, iodinated contrast allergy has traditionally been viewed as a contraindication to ICG use. The objective of this study was to describe the use of ICG in a population of patients with iodinated contrast allergies undergoing surgical staging for endometrial cancer. Methods: IRB approval was obtained. All patients with clinically early-stage endometrial cancer who underwent minimally invasive surgical staging with SLN mapping with ICG at a single academic institution from 1/1/2017 to 12/31/2020 were identified retrospectively. Patients with reported iodinated contrast allergies prior to surgery were identified. Data were collected through electronic medical record review and compared using descriptive statistics. Results: 820 patients who underwent minimally invasive surgical staging with SLN mapping with ICG were identified, and 25 had documented iodinated contrast allergies. Documented reactions included rash/hives (n = 10, 40 %), anaphylaxis (n = 6, 24 %), shortness of breath (n = 5, 20 %), diarrhea (n = 1, 4 %), and not specified (n = 3, 12 %). A majority (24/25, 96 %) received 4 mg intravenous dexamethasone during induction of general anesthesia as per the institutional enhanced recovery after surgery (ERAS) protocol. No patients experienced allergic reactions or other adverse events after ICG injection. Conclusions: No patients in this cohort demonstrated an adverse reaction after ICG injection for SLN mapping. This study supports the reasonable safety of ICG in patients with contrast allergies, particularly when routine ERAS protocols containing dexamethasone are utilized.

Clinical outcomes following identification of an incidental p53 signature in the fallopian tube.

Fallopian tube pathology in patients with BRCA1 and BRCA2 mutations suggests a possible pathway to high grade serous ovarian carcinoma originates with a p53 signature, which is thought to represent a potential precursor to serous tubal intraepithelial carcinoma (STIC). The clinical implications of an isolated p53 signature in the average-risk population has not been well-established. This study aims to describe clinical outcomes in patients with incidentally noted p53 signature lesions. All patients diagnosed with a p53 signature lesion on final pathology from 2014 to 2022 were identified at a large academic institution. P53 signature is defined by our lab as morphologically normal to mildly atypical tubal epithelium with focal p53 over-expression on immunohistochemistry. Incidental p53 signature was defined as identification of a fallopian tube lesion excised for benign or unrelated indications in patients without a known hereditary disposition. Demographic, clinicopathologic, and genetic data were collected. A total of 127 patients with p53 signatures were identified. Thirty-six patients were excluded for established ovarian cancer or high-risk history leaving 91 total patients. Five patients (5.5%) developed a malignancy, none of which were ovarian or primary peritoneal, at the end of the eight and a half year follow up period. Twenty-four (26.4%) patients had salpingectomy without any form of oophorectomy at the time of initial surgery, while 67 (73.6%) patients had at least a unilateral oophorectomy at the time of their salpingectomy. Seven patients (7.7%) had additional surgery after p53 signature diagnosis; however, the final pathology yielded no evidence of malignancy in all these patients. After subsequent surgeries, 19 (20.9%) patients maintained their ovaries. The diagnosis of an incidental p53 signature was not associated with any primary peritoneal or ovarian cancer diagnoses during our follow up, and the majority of patients were managed conservatively by their providers with no further intervention after diagnosis.

Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells.

Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E(2) (PGE(2)) and cyclooxygenase 2 (COX2), the key regulator of PGE(2) synthesis, represents the determining factor in redirecting the development of CD1a(+) DCs to CD14(+)CD33(+)CD34(+) monocytic MDSCs. Exogenous PGE(2) and such diverse COX2 activators as lipopolysaccharide, IL-1ß, and IFNγ all induce monocyte expression of COX2, blocking their differentiation into CD1a(+) DCs and inducing endogenous PGE(2), IDO1, IL-4Rα, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE(2) to GM-CSF/IL-4-supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)-suppressive function. In accordance with the key role of PGE(2) in the physiologic induction of human MDSCs, the frequencies of CD11b(+)CD33(+) MDSCs in ovarian cancer are closely correlated with local PGE(2) production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE(2) feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients. The central role of COX2-PGE(2) feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity, or transplantation.

Upfront treatment of locally advanced cervical cancer with intensity modulated radiation therapy compared to four-field radiation therapy: a cost-effectiveness analysis.

OBJECTIVE: Radiation can be delivered via four-field box (BOX-RT) or intensity modulated radiation therapy (IMRT). We sought to evaluate the cost-effectiveness (C/E) of IMRT relative to BOX-RT for the treatment of locally advanced cervical cancer. METHODS: A three-year Markov model with eight-week cycles was developed to compare IMRT to BOX-RT. A proportion (25%) received extended-field radiation therapy (EFRT) to include para-aortic nodes. The model assumed equal overall survival (OS). The model captured costs and utility estimates for BOX-RT, IMRT, and each complication. Modeled complications included acute and chronic toxicities. Baseline model assumptions were obtained by literature review and supplemented by expert opinion. Costs were based on Medicare reimbursement rates and the Agency for Healthcare Research and Quality Database. Treatment strategies were compared using an incremental cost-effectiveness ratio (ICER). One-way, probabilistic and structural sensitivity analyses were performed to account for uncertainty in assumptions. The C/E of each strategy was evaluated from the perspective of the health care system. RESULTS: C/E analysis revealed an ICER for IMRT of $182,777/quality adjusted life year (QALY) gained. Although this value was higher than the willingness to pay threshold of $100,000/QALY, sensitivity analysis revealed several modifications that would make IMRT a C/E option relative to BOX-RT. For patients requiring EFRT, IMRT was C/E with an ICER of $91,580/QALY. CONCLUSIONS: Although IMRT was not C/E at the $100,000 willingness-to-pay threshold, in those requiring EFRT, IMRT was C/E relative to BOX-RT. A randomized trial comparing IMRT to BOX-RT for the treatment of locally advanced cervical cancer is warranted.

VA-ECMO-Facilitated Clot Debulking and PFO Closure in a Patient With Recurrent Pulmonary Thromboses.

A 27-year-old female with stage IIIc cervical cancer presented with dyspnea and stroke symptoms. Work-up revealed bilateral pulmonary embolisms, acute/subacute strokes, and a patent foramen ovale. After multidisciplinary team discussion, the patient underwent patent foramen ovale closure, complicated by cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation. She successfully underwent pulmonary thromboendarterectomy, extracorporeal membrane oxygenation decannulation, and hospital discharge.

Mutation-specific Mismatch Repair-deficient Benign Endometrial Glands in Endometrial Biopsies and Curettings Are a Biomarker of Lynch Syndrome and Associate With Endometrial Carcinoma Development.

Endometrial carcinoma is the most common extraintestinal cancer in Lynch syndrome (LS). Recent studies have demonstrated mismatch repair (MMR) deficiency can be detected in benign endometrial glands in LS. We performed MMR immunohistochemistry in benign endometrium from endometrial biopsies and curettings (EMCs) from a study group of 34 confirmed LS patients and a control group of 38 patients without LS who subsequently developed sporadic MLH1-deficient or MMR-proficient endometrial carcinoma. MMR-deficient benign glands were only identified in patients with LS (19/34, 56%) and were not identified in any control group patient (0/38, 0%) ( P < 0.001). MMR-deficient benign glands were identified as large, contiguous groups in 18 of 19 cases (95%). MMR-deficient benign glands were identified in patients with germline pathogenic variants in MLH1 (6/8, 75%), MSH6 (7/10, 70%), and MSH2 (6/11, 55%) but not in patients with variants in PMS2 (0/4). MMR-deficient benign glands were seen in all EMC samples (100%) but in only 46% of endometrial biopsy samples ( P =0.02). Patients with MMR-deficient benign glands were significantly more likely to have endometrial carcinoma (53%) compared with LS patients with only MMR-proficient glands (13%) ( P =0.03). In conclusion, we demonstrated that MMR-deficient benign endometrial glands are frequently identified in EMB/EMC in women with LS and are a specific marker for LS. Women with LS with MMR-deficient benign glands were more likely to have endometrial carcinoma suggesting that MMR-deficient benign glands may be a biomarker of increased risk of endometrial carcinoma development in LS.

Is Substantial Lymphovascular Space Invasion Prognostic in Patients With Pathologically Lymph Node-Negative Endometrial Cancer?

PURPOSE: Lymphovascular space invasion (LVSI) predicts for higher rates of recurrence and increased mortality in endometrial cancer. Using 3-tier LVSI scoring, a PORTEC-1 and -2 trials analysis demonstrated that substantial LVSI was associated with worse locoregional (LR-DFS) and distant metastasis disease-free survival (DM-DFS), and these patients possibly benefited from external beam radiation therapy (EBRT). Furthermore, LVSI is a predictor for lymph node (LN) involvement, but the significance of substantial LVSI is unknown in patients with a pathologically negative LN assessment. We aimed to evaluate clinical outcomes of these patients in relation to the 3-tier LVSI scoring system. METHODS AND MATERIALS: We performed a single-institutional retrospective review of patients with stage I endometrioid-type endometrial cancer who underwent surgical staging with pathologically negative LN evaluation from 2017 to 2019 with 3-tier LVSI scoring (none, focal, or substantial). Clinical outcomes (LR-DFS, DM-DFS, and overall survival) were analyzed using the Kaplan-Meier method. RESULTS: A total of 335 patients with pathologically LN-negative stage I endometrioid-type endometrial carcinoma were identified. Substantial LVSI was present in 17.6% of patients; 39.7% of patients received adjuvant vaginal brachytherapy and 6.9% of patients received EBRT. Adjuvant radiation treatment varied by LVSI status. In patients with focal LVSI, 81.0% received vaginal brachytherapy. Among patients with substantial LVSI, 57.9% received vaginal brachytherapy alone, and 31.6% of patients received EBRT. The 2-year LR-DFS rates were 92.5%, 98.0%, and 91.4% for no LVSI, focal LVSI, and substantial LVSI, respectively. The 2-year DM-DFS rates were 95.5%, 93.3%, and 93.8% for no LVSI, focal LVSI, and substantial LVSI, respectively. CONCLUSIONS: In our institutional study, patients with pathologically LN-negative stage I endometrial cancer with substantial LVSI had similar rates of LR-DFS and DM-DFS compared with patients with none or focal LVSI. These findings highlight the need for multi-institutional studies to validate the prognostic value of substantial LVSI in this patient population.

Intraperitoneal chemotherapy for recurrent epithelial ovarian cancer is feasible with high completion rates, low complications, and acceptable patient outcomes.

OBJECTIVES: Three large randomized clinical trials have shown a survival benefit for patients treated with intraperitoneal (IP) compared with intravenous chemotherapy for advanced stage epithelial ovarian cancer (EOC). However, the use of IP chemotherapy in recurrent EOC is controversial. The purpose of this study was to determine outcomes, completion rates, and frequency of complications in patients with platinum-sensitive recurrent EOC treated with IP chemotherapy. METHODS: A retrospective, single-institution analysis of women who received IP chemotherapy for recurrent EOC from January 2003 to April 2010 was conducted. Study patients were identified from the Tumor Registry and office records. Demographic factors, stage, histology, surgical findings, cytoreduction status, and subsequent therapies were abstracted. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier methods. RESULTS: Fifty-six women who received IP chemotherapy for their first EOC recurrence were identified. The mean age of patients was 56.7 years (range, 40-79 y). Fifty-five patients (98.3%) had previously completed at least 6 cycles of intravenous chemotherapy. Of all patients, 87.5% were initially diagnosed with advanced stage disease (stage IIA-IV). All patients underwent secondary cytoreduction at the time of IP port placement. Moreover, 67.9% of patients were considered optimally cytoreduced (<1 cm residual disease) at the end of the secondary debulking surgery. Forty-two patients (75%) were able to successfully complete at least 6 cycles of IP chemotherapy. Reasons for noncompletion were disease progression, allergic reaction, renal failure, pain, severe nausea and vomiting, death, and patient refusal. Six patients (10.7%) developed port complications including pain around port site, port malfunction, and port erosion into small bowel. Median PFS since the initiation of IP chemotherapy was 10.5 months (95% confidence interval, 7.5-16.4 months) and median OS was 51 months (95% confidence interval, 40.8-61.1 months). CONCLUSIONS: Intraperitoneal chemotherapy is a feasible option for patients with recurrent EOC, with high completion rates, low frequency of complications, and acceptable PFS and OS.

ARID1A, BRG1, and INI1 deficiency in undifferentiated and dedifferentiated endometrial carcinoma: a clinicopathologic, immunohistochemical, and next-generation sequencing analysis of a case series from a single institution.

Undifferentiated/dedifferentiated endometrial carcinomas (UDEC and DDEC) are rare, aggressive uterine neoplasms, with no specific line of differentiation. A significant proportion of these cases feature mutations of SWI/SNF chromatin remodeling complex members, including ARID1A, SMARCA4, and SMARCB1 genes. To study these entities more comprehensively, we identified 10 UDECs and 10 DDECs from our pathology archives, obtained clinicopathologic findings and follow-up data, and performed immunohistochemical studies for ARID1A, BRG1 (SMARCA4), and INI1 (SMARCB1) proteins. In addition, we successfully conducted targeted next-generation sequencing for 23 samples, including 7 UDECs, and 7 undifferentiated and 9 well/moderately-differentiated components of DDECs. Cases consisted of 18 hysterectomies and 2 curettage/biopsy specimens. Patient age ranged from 47 to 77 years (median, 59 years), with a median tumor size of 8.0 cm (range, 2.5-13.0 cm). All cases demonstrated lymphovascular invasion and the majority (13/20) were FIGO stage III-IV. By immunohistochemistry, ARID1A loss was observed in 15 cases, BRG1 loss in 4, and all cases had intact INI1 expression. A trend for enrichment of the undifferentiated component of DDECs for ARID1A loss was seen, although not statistically significant. Sequencing revealed frequent pathogenic mutations in PTEN, PIK3CA, ARID1A, CTNNB1, and RNF43, a recurrent MAX pathogenic mutation, and MYC and 12p copy number gains. In DDECs, the undifferentiated component featured a higher tumor mutational burden compared to the well/moderately-differentiated component; however, the mutational landscape largely overlapped. Overall, our study provides deep insights into the mutational landscape of UDEC/DDEC, SWI/SNF chromatin remodeling complex member status, and their potential relationships with tumor features.

Phase I trial of ribociclib with platinum chemotherapy in ovarian cancer.

BACKGROUNDNew therapeutic combinations to improve outcomes of patients with ovarian cancer are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer.METHODSThis phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib, followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS).RESULTSThirty-five patients were enrolled. Patients had a mean of 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab. The MTD was 400 mg. The most common adverse events included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). The overall RR was 79.3%, with a stable disease rate of 18%, resulting in a clinical benefit rate of 96.6%. Median PFS was 11.4 months. RR and PFS did not differ based on the number of lines of prior chemotherapy or prior maintenance therapy.CONCLUSIONThis work demonstrates that the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease.TRIAL REGISTRATIONClinicalTrials.gov NCT03056833.FUNDINGThis investigator-initiated trial was supported by Novartis, which provided drugs and funds for trial execution.