Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals.

BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.

ImmunoTyper-SR: A computational approach for genotyping immunoglobulin heavy chain variable genes using short-read data.

Human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which are critical for the structure of antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype when using standard short-read sequencing technologies. Here, we introduce ImmunoTyper-SR, an algorithmic tool for the genotyping and CNV analysis of the germline IGHV genes on Illumina whole-genome sequencing (WGS) data using a combinatorial optimization formulation that resolves ambiguous read mappings. We have validated ImmunoTyper-SR on 12 individuals, whose IGHV allele composition had been independently validated, as well as concordance between WGS replicates from nine individuals. We then applied ImmunoTyper-SR on 585 COVID patients to investigate the associations between IGHV alleles and anti-type I IFN autoantibodies, which were previously associated with COVID-19 severity.

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

ImmunoTyper-SR: A Novel Computational Approach for Genotyping Immunoglobulin Heavy Chain Variable Genes using Short Read Data.

Human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which, together with the joining genes (IGHJ), diversity genes (IGHD), constant genes (IGHC) and immunoglobulin light chains, code for antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype through the use of standard short read sequencing technologies. Here we introduce ImmunoTyper-SR, an algorithmic method for genotype and CNV analysis of the germline IGHV genes using Illumina whole genome sequencing (WGS) data. ImmunoTyper-SR is based on a novel combinatorial optimization formulation that aims to minimize the total edit distance between reads and their assigned IGHV alleles from a given database, with constraints on the number and distribution of reads across each called allele. We have validated ImmunoTyper-SR on 12 individuals with Illumina WGS data from the 1000 Genomes Project, whose IGHV allele composition have been studied extensively through the use of long read and targeted sequencing platforms, as well as nine individuals from the NIAID COVID Consortium who have been subjected to WGS twice. We have then applied ImmunoTyper-SR on 585 samples from the NIAID COVID Consortium to investigate associations between distinct IGHV alleles and anti-type I IFN autoantibodies which have been linked to COVID-19 severity.

A randomized controlled trial to determine whether a video presentation improves informed consent for hysterectomy.

BACKGROUND: Informed consent is an integral part of the preoperative counseling process. It is important that we know the best way to relay this information to patients undergoing surgery, specifically, hysterectomy. OBJECTIVE: We sought to determine whether supplementing normal physician counseling with a video presentation improves patient comprehension during the informed consent process for hysterectomy. STUDY DESIGN: In a randomized, mixed factorial controlled trial, standard physician counseling (control arm) was compared to physician counseling plus video presentation (video arm) during the prehysterectomy informed consent process. Primary outcome was improvement in patient comprehension measured by assessments at baseline, postcounseling, day of surgery, and postsurgery. Patient satisfaction was measured by a validated questionnaire. Audiotaped patient-physician interactions were analyzed to determine time spent counseling, number of patient questions, and whether standard counseling included 11 predetermined critical components included in the video. A sample size of 60 per group (N = 120) was planned to compare both groups. RESULTS: From May 2014 through June 2015, 120 patients were enrolled and 116 randomized: 59 to the video arm and 57 to the control arm. All characteristics were similar between groups. Video arm subjects demonstrated greater improvement in comprehension scores in both postcounseling (9.9% improvement; 95% confidence interval, 4.2-15.7%; P = .0009) and day-of-surgery questionnaires (7.2% improvement; 95% confidence interval, 0.96-13.4%; P = .02). Scores 4-6 weeks after surgery returned to baseline for both groups. Control subjects were less likely to be counseled about risk of thrombosis (P < .0001), colostomy (P < .0001), further medical/surgical therapy (P = .002), hormone replacement therapy (P < .0001), or postoperative expectations (P < .0001). Physicians spent more time counseling patients who did not watch the video (8 vs 12 minutes, P = .003) but number of questions asked by patients in each group was similar. CONCLUSION: Enhancing prehysterectomy counseling with a video improves patient comprehension through day of surgery, increases thoroughness of counseling, and reduces physician time.

Polypoid endometriosis mimicking invasive cancer in an obese, postmenopausal tamoxifen user.

BACKGROUND: Tamoxifen is a medication often used for the treatment and prevention of breast cancer. It is classically associated with several gynecological side effects to include a thickened endometrial stripe, increased uterine polyp formation, and an increased risk of uterine cancer. Rarely tamoxifen use has been associated with proliferation of endometriosis often severe enough to mimic a late-stage gynecologic malignancy. CASE: A 62-year-old Gravida 0 postmenopausal female with a medical history of severe obesity, infertility, and preventative tamoxifen use presented for evaluation of gross hematuria. A CT urogram was performed and demonstrated findings concerning for carcinomatosis, likely gynecologic in origin. Cervical cancer screening was up-to-date and she had a negative colonoscopy within the prior 2 years. Serum tumor markers were remarkable only for a mildly elevated CA125 of 37.6. Diagnostic laparoscopy demonstrated apparent operable carcinomatosis limited to the pelvis. The procedure was converted to an exploratory laparotomy, where radical tumor cytoreduction was performed to no gross residual disease. Frozen sections performed intraoperatively were unclear of origin but suggestive of low malignant potential. Final pathology resulted for endometriosis. CONCLUSION: This case illustrates a presentation of endometriosis in a postmenopausal woman mimicking advanced mullerian malignancy. The patient's estrogenic state from obesity in combination with the agonist action of the tamoxifen likely contributed to her rare presentation. While findings such as a thickened endometrial stripe are typical of tamoxifen use, such widespread proliferation of endometriosis resulting in a pelvic mass, genito-urinary obstruction, and plaque-like pelvic spread are not. PRÉCIS: Endometriosis is a benign estrogen dependent condition rarely problematic in a postmenopausal patient. Tamoxifen use in the setting of an obese patient may contribute to a proliferation of pre-existing endometriosis which resembles an aggressive late-stage gynecological malignancy.

Are different methotrexate regimens as first line therapy for low risk gestational trophoblastic neoplasia more cost effective than the dactinomycin regimen used in GOG 0174?

OBJECTIVES: Gynecologic Oncology Group (GOG) 0174 compared weekly intramuscular methotrexate (MTX) with biweekly pulsed intravenous dactinomycin (Act-D) as single-agent chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). Act-D had a higher rate of initial complete response (CR) (70% vs. 53%, p=0.01), but multi-day regimens of MTX have higher historic success rates. We assessed the cost-effectiveness of Act-D vs. MTX per GOG 0174 and explored multi-day MTX regimens. METHODS: A cost effectiveness decision model was constructed with data from GOG 0174. Outcome was cost per first-line treatment success expressed in terms of incremental cost-effectiveness ratio (ICER). Front-line failures were assumed to receive cross-over single agent therapy, second line failures; multi-agent chemotherapy. GOG 0174 had no quality of life (QOL) evaluation, so equal QOL (utility 1.0) was assumed but varied in sensitivity analysis. A second exploratory model included 5-day and 8-day MTX regimens. RESULTS: Act-D ($18,505) was more expensive compared to weekly MTX ($8950) with an ICER of $56,215 per first-line treatment success compared to weekly MTX. Small decreases in QOL dramatically increased the ICER during sensitivity analysis. Models with multi-day MTX regimens were also more cost-effective than Act-D. If effectiveness was redefined as avoidance of multi-agent chemotherapy, weekly MTX was more effective. CONCLUSIONS: With a complete cure rate for low-risk GTN regardless of initial agent, our model supports provider hesitation toward first line Act-D for low risk GTN. While Act-D is more effective for first line treatment success, it is more costly, and does not decrease rate of multi-agent chemotherapy use.

Is FDA-Approved Bevacizumab Cost-Effective When Included in the Treatment of Platinum-Resistant Recurrent Ovarian Cancer?

PURPOSE: Although the Food and Drug Administration has approved incorporation of bevacizumab (BEV) into the treatment of platinum-resistant ovarian cancer (PROC), cost-value measures are an essential consideration, as evidenced by the recent ASCO Value Framework initiative. We assessed the cost-effectiveness and reviewed the net health benefit (NHB) of this expensive treatment. METHODS: A cost-effectiveness decision model was constructed using results from a phase III trial comparing BEV plus cytotoxic chemotherapy with chemotherapy alone in patients with PROC. The Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer (AURELIA) trial demonstrated improvement in progression-free survival and quality of life in patients receiving BEV. Costs, paracentesis rates, and adverse events were incorporated, including subgroup analysis of different partner chemotherapy agents. RESULTS: Inclusion of BEV in the treatment of platinum-resistant recurrent ovarian cancer meets the common willingness-to-pay incremental cost-effectiveness ratio (ICER) threshold of $100,000 per progression-free life-year saved (LYS) for 15-mg/kg dosing and approaches this threshold for 10-mg/kg dosing, with an ICER of $160,000. In sensitivity analysis, reducing the cost of BEV by 13% (from $9,338 to $8,100 per cycle) allows 10-mg/kg dosing to reach a $100,000 ICER. Exploratory analysis of different BEV chemotherapy partners showed an ICER of $76,000 per progression-free LYS (6.5-month progression-free survival improvement) and $54,000 per LYS (9.1-month overall survival improvement) for the addition of BEV to paclitaxel once per week. Using the ASCO framework for value assessment, the NHB score for BEV plus paclitaxel once per week is 48. CONCLUSION: Using a willingness-to-pay threshold of $100,000 ICER, the addition of BEV to chemotherapy either demonstrates or approaches cost-effectiveness and NHB when added to the treatment of patients with PROC.

Does Routine Posttreatment PET/CT Add Value to the Care of Women With Locally Advanced Cervical Cancer?

OBJECTIVES: The aim of this study was to determine the necessary reduction in recurrence rate that would make postchemoradiation positron emission tomography (PET)/computed tomography (CT) to direct completion hysterectomy for locally advanced cervical cancer (LACC) cost-effective. METHODS: A decision model evaluated costs and recurrence rates of 2 posttreatment surveillance strategies in LACC: (1) routine surveillance without PET/CT and (2) PET/CT after 3 months to triage to completion hysterectomy. Incremental cost-effectiveness ratios were expressed in dollars per additional cancer recurrence avoided. Model parameters included expected rates of recurrence using each strategy, true- and false-positive rates of posttreatment PET/CT, and major complications of completion hysterectomy. From published data, we modeled an LACC baseline recurrence rate of 32%, PET/CT false-positive rate of 33%, and false-negative rate of 19%. We assumed that PET/CT revealed persistent local cervical cancer in 16% and progressive or distant disease in 6%. Costs of PET/CT, hysterectomy, and treatment for recurrence were based on Medicare reimbursements. A 50% salvage rate with hysterectomy was assumed and varied in sensitivity analysis. RESULTS: Routine use of PET/CT to direct completion hysterectomy was associated with a higher average cost ($16,579 vs $15,450) and a lower recurrence rate (26% vs 32%). The incremental cost-effectiveness ratio of PET was $20,761 per recurrence prevented. When the probability of recurrence after hysterectomy dropped to 25% or less, PET/CT was a dominant strategy. CONCLUSIONS: Routine use of PET/CT to determine which patients may benefit from a completion hysterectomy after chemoradiation for LACC has the potential to be highly cost-effective.

Effect of Copper and Other Trace Metal Addition to Pulp and Paper Wastewater.

Porous pots were used to mimic, on a laboratory scale, an industrial activated sludge plant from a thermomechanical pulp and news print paper mill. Trace metal additions of Ca, Co, Cu, Fe(III), and Mg were found to improve chemical oxygen demand removal from 82% to 86 to 87%. Copper (0.1 to 1.0 mg/L) was also found to be beneficial in significantly inhibiting the growth of filamentous bacteria, contributing to a reduction of 20 to 45% in sludge volume index (SVI) with improved settle ability and decreased bulking. However, at levels of 1.0 mg/L and higher, the concentration of Cu in the porous pot effluent would potentially exceed guidelines for receiving waters. The fate and impact of Cu was affected by the presence of other trace metals, in particular Mg and Ca. The addition of Mg or Ca along with 0.5 mg/L Cu increased the amount of Cu in the aqueous phase to levels that would potentially exceed government environmental guidelines. Calcium addition was also found to inhibit the effect of Cu in reducing filamentous bacteria and SVI.

Laparoscopic staging of ovarian immature teratomas: a report on three cases.

BACKGROUND: Ovarian malignant germ cell tumors (MGCT) tend to occur in younger women and are amenable to fertility sparing surgery. Traditionally, most ovarian cancers are staged via laparotomy; however, laparoscopy is a potential alternative to laparotomy for surgical staging in malignant germ cell tumors. CASE: Three patients with immature teratoma were surgically staged with laparoscopy over a 1-year period at our institution. All patients underwent an initial surgery, unilateral salpingo-oophorectomy, for a complex adnexal mass that demonstrated immature teratoma on final pathology. Laparoscopic surgical staging was performed for all patients, with peritoneal and omental biopsies and pelvic and para-aortic lymph node dissection. Two patients with Stage IA disease secondary to negative biopsies and lymph nodes were observed. One patient was found to have omental disease; she underwent chemotherapy and remains in remission. As of last follow-up, no recurrences have been documented. CONCLUSION: Laparoscopic surgical staging of immature teratomas discovered occult disease in one case allowing for appropriate treatment decisions based on minimally invasive surgical findings. Laparoscopy represents a viable, and potentially preferable, option for surgical staging in patients with immature teratoma not initially diagnosed on frozen section. Determination of adequacy of laparoscopic staging needs long-term surveillance and outcome results.

Bevacizumab in recurrent, persistent, or advanced stage carcinoma of the cervix: is it cost-effective?

OBJECTIVE: Evaluate the cost-effectiveness of incorporating bevacizumab into the treatment regimen for recurrent, persistent, or advanced stage carcinoma of the cervix following publication of a recent phase III trial that demonstrated an overall survival (OS) benefit with the addition of bevacizumab. METHODS: A cost-effectiveness decision model was constructed using recently published results from a Gynecologic Oncology Group phase III study, comparing a standard chemotherapy regimen (Chemo) to the experimental regimen (Chemo + Bev) consisting of the standard regimen+bevacizumab. Costs and adverse events were incorporated and sensitivity analyses assessed model uncertainties. RESULTS: The cost of Chemo + Bev was $53,784 compared to $5,688 for the Chemo arm. The 3.7 month OS advantage with Chemo+Bev came at an incremental cost-effectiveness ratio (ICER) of $155K per quality-adjusted life year (QALY). Chemo + Bev becomes cost-effective with an ICER ≤ $100K in sensitivity analysis when the cost of bevacizumab is discounted >37.5% or the dose is reduced from 15 to 7.5 mg/kg, an effective dose in ovarian cancer. CONCLUSIONS: With an ICER of $155K/QALY, the addition of bevacizumab to standard chemotherapy approaches common cost-effectiveness standards. Moderately discounting the cost of bevacizumab or using a smaller dose significantly alters its affordability.

A cost-utility analysis of NRG Oncology/Gynecologic Oncology Group Protocol 218: incorporating prospectively collected quality-of-life scores in an economic model of treatment of ovarian cancer.

OBJECTIVE: To estimate quality-of-life (QOL)-adjusted cost-utility with addition of bevacizumab (B) to intravenous paclitaxel/carboplatin (PC) for primary treatment of advanced-stage epithelial ovarian cancer. METHODS: A modified Markov state transition model of 3 regimens evaluated in GOG 218 (PC, PC+concurrent B [PCB], and PCB+maintenance B [PCB+B]) was populated by prospectively collected survival, adverse event, and QOL data from GOG 218. Progression-free survival (PFS) and overall survival (OS) were modeled using primary event data. Costs of grade 4 hypertension, grade 3-5 bowel events, and growth factor support were incorporated. QOL scores were converted to utilities and incorporated into the model. Monte Carlo probabilistic sensitivity analysis was performed to account for uncertainty in estimates. RESULTS: PC was the least expensive ($4044) and least effective (mean 1.1 quality-adjusted progression-free years [QA-PFY]) regimen. PCB ($43,703 and 1.13 QA-PFY) was dominated by a combination of PC and PCB+B. PCB+B ($122,700 and 1.25 QA-PFY) was the most expensive regimen with an incremental cost-effectiveness ratio of $792,380/QA-PFY compared to PC. In a model not incorporating QOL, the incremental cost-effectiveness ratio (ICER) of PCB+B was $632,571/PFY compared to PC. CONCLUSIONS: In this cost-utility model, incorporation of QOL into an analysis of GOG 218 led to less favorable ICER (by >$150,000/QA-PFY) in regimens containing B compared with those that do not include B. Continued investigation of populations with ovarian cancer in whom the efficacy of treatment with bevacizumab is expected to be increased (or in whom QOL is expected to increase with use) is critical.

Costs, effectiveness, and workload impact of management strategies for women with an adnexal mass.

BACKGROUND: We compared the estimated clinical outcomes, costs, and physician workload resulting from available strategies for deciding which women with an adnexal mass should be referred to a gynecologic oncologist. METHODS: We used a microsimulation model to compare five referral strategies: 1) American Congress of Obstetricians and Gynecologists (ACOG) guidelines, 2) Multivariate Index Assay (MIA) algorithm, 3) Risk of Malignancy Algorithm (ROMA), 4) CA125 alone with lowered cutoff values to prioritize test sensitivity over specificity, 5) referral of all women (Refer All). Test characteristics and relative survival were obtained from the literature and data from a biomarker validation study. Medical costs were estimated using Medicare reimbursements. Travel costs were estimated using discharge data from Surveillance, Epidemiology and End Results-Medicare and State Inpatient Databases. Analyses were performed separately for pre- and postmenopausal women (60 000 "subjects" in each), repeated 10 000 times. RESULTS: Refer All was cost-effective compared with less expensive strategies in both postmenopausal (incremental cost-effectiveness ratio [ICER] $9423/year of life saved (LYS) compared with CA125) and premenopausal women (ICER $10 644/YLS compared with CA125), but would result in an additional 73 cases/year/subspecialist. MIA was more expensive and less effective than Refer All in pre- and postmenopausal women. If Refer All is not a viable option, CA125 is an optimal strategy in postmenopausal women. CONCLUSIONS: Referral of all women to a subspecialist is an efficient strategy for managing women with adnexal masses requiring surgery, assuming sufficient capacity for additional surgical volume. If a test-based triage strategy is needed, CA125 with lowered cutoff values is a cost-effective strategy.

The cost-effectiveness of selective lymphadenectomy based on a preoperative prediction model in patients with endometrial cancer: insights from the US and Korean healthcare systems.

OBJECTIVE: The aim of this study was to determine the cost-effectiveness of selective lymphadenectomy using a preoperative prediction model compared to routine lymphadenectomy for patients undergoing surgery for endometrial cancer in the US and Korea. METHODS: We used a modified Markov model to estimate clinical and economic outcomes for newly diagnosed, apparent early-stage endometrial cancer patients under two different strategies: (1) selective lymphadenectomy, where patients classified as low risk based on the preoperative prediction model did not undergo complete surgical staging, and (2) routine lymphadenectomy, where all patients underwent complete surgical staging. Published data were used to estimate the rates of adjuvant therapy and survival. Costs were calculated from the perspective of US or Korean payers. Cost-effectiveness ratios were analyzed separately using data from each country. RESULTS: Base-case analysis indicated that selective lymphadenectomy was less costly ($6454 vs. $7079 in Korea; $23,995 vs. $26,318 in the US) and more effective (6.91 quality-adjusted life years (QALYs) vs. 6.85 QALYs in Korea; 6.87 QALYs vs. 6.81 QALYs in the US) than routine lymphadenectomy in both countries. This result was robust in a deterministic sensitivity analysis, with the exception of when the utility scores for patients with lymphedema were varied. So long as a modest preference for avoiding lymphedema (disutility of 0.04) was obtained, selective lymphadenectomy remained the dominant strategy. CONCLUSIONS: A selective lymphadenectomy strategy based on a preoperative prediction model was shown to be more cost-effective than routine lymphadenectomy for endometrial cancer patients in the US and Korea.

Primary invasive breast carcinoma arising in mammary-like glands of the vulva managed with excision and sentinel lymph node biopsy.

•Primary invasive breast carcinoma can be found arising from within mammary-like glands in the vulva.•There is no standard management strategy for this rare disease; treatment recommendations should be similar to that for primary breast carcinoma.•The use of sentinel lymph node biopsy may offer another management option for this disease.

Cost effectiveness of alternative strategies for incorporating bevacizumab into the primary treatment of ovarian cancer.

BACKGROUND: The objective of this study was to evaluate the comparative effectiveness of strategies that incorporated bevacizumab into the primary platinum-based treatment of ovarian cancer: 1) no bevacizumab; 2) concurrent and maintenance bevacizumab for all; 3) bevacizumab for suboptimally debulked stage III and stage IV disease (high-risk cohort); and the evaluation of an alternative exploratory strategy of 4) directed bevacizumab therapy based on a predictive test for bevacizumab responsiveness. METHODS: A modified Markov state transition model with a 3-year time horizon that simulated publically available International Collaboration on Ovarian Neoplasms (ICON7) trial outcomes was used to evaluate the cost effectiveness of each strategy. Costs and adverse events were incorporated. An alternative strategy was used to model the impact on overall survival of a genetic-based predictive test. A Monte Carlo simulation simultaneously accounted for uncertainty in key parameters. RESULTS: The incorporation of bevacizumab for high-risk patients had an incremental cost-effectiveness ratio of $168,000 per quality-adjusted life-year (QALY) saved compared with chemotherapy alone and dominated a strategy of giving bevacizumab to all patients with ovarian cancer. Monte Carlo simulation acceptability curves indicated that, at a willingness-to-pay threshold of $200,000 per QALY, the treatment of high-risk women with bevacizumab was the strategy of choice in 84% of simulations. A predictive test had an incremental cost-effectiveness ratio of $129,000 per QALY compared with chemotherapy alone and dominated other bevacizumab treatment strategies. CONCLUSIONS: The selective treatment of women with suboptimal and/or stage IV ovarian cancer was a more cost-effective use of bevacizumab than universal treatment but still did not fall within the limits of common willingness-to-pay thresholds. Continued investigation of potentially cost-effective strategies, such as a predictive test, is necessary to optimize the use of this expensive treatment.

Surgical outcomes and national comprehensive cancer network compliance in advanced ovarian cancer surgery in a low volume military treatment facility.

OBJECTIVE: To evaluate the optimal cytoreduction (OPT) rate, National Comprehensive Cancer Network (NCCN) treatment guideline compliance rate and patient outcomes for advanced stage epithelial ovarian cancer (EOC) patients at our low volume institution. METHODS: Following IRB approval, records of patients with Stage III-IV EOC, primary peritoneal, or fallopian tube carcinoma completing both primary surgery and adjuvant chemotherapy were reviewed. Patient demographics, clinicopathologic variables, cytoreduction status (optimal or suboptimal), NCCN treatment guideline compliance, and survival were reviewed. Standard statistical tests including the t-test, Chi-square or Fisher's exact test and Kaplan-Meier Survival curves were utilized. RESULTS: Overall, 48 patients met all inclusion criteria. 35(73%) and 13 (27%) achieved optimal and suboptimal cytoreduction, respectively. Median overall survival (OS) for all patients was 37.1 months (95% CI 23.2 - 51.1 months) and NCCN treatment guideline compliance was 85.4%. Compared to sub-optimally cytoreduced patients the optimally cytoreduced patients were significantly older (62.2 vs. 53.5 yrs; p=0.015); no other significant clinicopathologic differences were observed between the two groups. 19 of 48 (39.6%) patients enrolled in an upfront cooperative group trial. Median OS was 43.4 months for optimally compared to 15.6 months in sub-optimally cytoreduced patients (p=0.012). CONCLUSIONS: NCCN treatment guideline compliance, OPT, and median OS rates in our low volume institution are similar to those reported nationally, and argue against using volume alone as a rationale for centralization of care.

Cost-effectiveness of early palliative care intervention in recurrent platinum-resistant ovarian cancer.

OBJECTIVE: To determine if early palliative care intervention in patients with recurrent, platinum-resistant ovarian cancer is potentially cost saving or cost-effective. METHODS: A decision model with a 6 month time horizon evaluated routine care versus routine care plus early referral to a palliative medicine specialist (EPC) for recurrent platinum-resistant ovarian cancer. Model parameters included rates of inpatient admissions, emergency department (ED) visits, chemotherapy administration, and quality of life (QOL). From published ovarian cancer data, we assumed baseline rates over the final 6 months: hospitalization 70%, chemotherapy 60%, and ED visit 30%. Published data from a randomized trial evaluating EPC in metastatic lung cancer were used to model odds ratios (ORs) for potential reductions in hospitalization (OR 0.69), chemotherapy (OR 0.77), and emergency department care (OR 0.74) and improvement in QOL (OR 1.07). The costs of hospitalization, ED visit, chemotherapy, and EPC were based on published data. Ranges were used for sensitivity analysis. Effectiveness was quantified in quality adjusted life years (QALYs); survival was assumed equivalent between strategies. RESULTS: EPC was associated with a cost savings of $1285 per patient over routine care. In sensitivity analysis incorporating QOL, EPC was either dominant or cost-effective, with an incremental cost-effectiveness ratio (ICER) <$50,000/QALY, unless the cost of outpatient EPC exceeded $2400. Assuming no clinical benefit other than QOL (no change in chemotherapy administration, hospitalizations or ED visits), EPC remained highly cost-effective with ICER $37,440/QALY. CONCLUSION: Early palliative care intervention has the potential to reduce costs associated with end of life care in patients with ovarian cancer.