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.

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.

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.

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.

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.

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.

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.

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.

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.

Are supportive care-based treatment strategies preferable to standard chemotherapy in recurrent cervical cancer?

OBJECTIVE: Recurrent cervical cancer has a poor prognosis despite aggressive treatment. We evaluate the comparative-effectiveness of four management strategies in recurrent cervix cancer incorporating risk prognostication categories derived from pooled collaborative group trials: 1) standard doublet chemotherapy; 2) selective chemotherapy (home hospice with no chemotherapy for poorest prognosis patients with remainder receiving standard doublet chemotherapy); 3) single-agent chemotherapy with home hospice; and 4) home hospice. METHODS: A cost-effectiveness decision model was constructed. Survival reduction of 24% was assumed for single-agent chemotherapy and 40% for hospice only compared to standard doublet chemotherapy. Overall survival and strategy cost for each arm were modeled as follows: standard doublet chemotherapy 8.9 months ($33K); selective chemotherapy 8.7 months ($29K); single-agent chemotherapy with home hospice 6.7 months ($16K); and home hospice alone 5.3 months ($11K). Base case analysis assumed equal quality of life (QOL). Sensitivity analyses assessed model uncertainties. RESULTS: Standard doublet chemotherapy for all is not cost-effective compared to selective chemotherapy with an incremental cost-effectiveness ratio (ICER) of $276K per quality-adjusted life-year (QALY). Sensitivity analysis predicted that a 90% improvement in survival is required before standard doublet chemotherapy is cost-effective in the poorest prognosis patients. Selective chemotherapy is the most cost-effective strategy compared to single-agent chemotherapy with home hospice with an ICER of $78K/QALY. Chemotherapy containing regimens become cost-prohibitive with small decreases in QOL. CONCLUSIONS: Supportive care based treatment strategies are potentially more cost-effective than the current standard of doublet chemotherapy for all patients with recurrent cervical cancer and warrant prospective evaluation.

Cost-effectiveness of BRCA1 and BRCA2 mutation testing to target PARP inhibitor use in platinum-sensitive recurrent ovarian cancer.

OBJECTIVES: (1) To determine whether use of a PARP inhibitor or (2) BRCA1/2 mutation testing followed by a PARP inhibitor for test positives is potentially cost-effective for maintenance treatment of platinum-sensitive recurrent high-grade serous ovarian cancer. METHODS: A modified Markov decision analysis compared 3 strategies: (1) observe; (2) olaparib to progression; (3) BRCA1/2 mutation testing; treat mutation carriers with olaparib to progression. Progression-free survival and rates of adverse events were derived from a phase 2 randomized trial. Key assumptions are as follows: (1) 14% of patients harbor a BRCA1/2 mutation; (2) progression-free survival of individuals treated with olaparib is improved for BCRA1/2 carriers compared with noncarriers (estimated hazard ratio, approximately 0.4). Costs derived from national data were assigned to treatments, adverse events, and BRCA1/2 test. Monte Carlo probabilistic sensitivity analysis was performed. RESULTS: Global olaparib was the most effective strategy, followed by BRCA1/2 testing and no olaparib. BRCA1/2 testing had an incremental cost-effectiveness ratio (ICER) of $193,442 per progression-free year of life saved (PF-YLS) compared to no olaparib, whereas global olaparib had an ICER of $234,128 per PF-YLS compared to BRCA1/2 testing. At a 52% lower-than-baseline olaparib cost estimate of $3000 per month, BRCA1/2 testing became potentially cost-effective compared with observation, with an ICER of $100,000 per PF-YLS. When strategy (1) was removed from the analysis, BRCA1/2 testing was the preferred strategy. CONCLUSIONS: The use of maintenance olaparib in women with high-grade serous ovarian cancer is not cost-effective regardless of whether BRCA1/2 testing is used to direct treatment. However, BRCA1/2 testing is a preferred strategy compared to global maintenance olaparib alone.

Economic impact of paclitaxel shortage in patients with newly diagnosed ovarian cancer.

OBJECTIVE: To determine the potential economic impact of a paclitaxel drug shortage in patients with newly diagnosed, untreated ovarian cancer. METHODS: A modified Markov state transition model with a 6 cycle time horizon compared two scenarios: (1) Standard treatment (STD): paclitaxel 175 mg/m2/carboplatin AUC 5 × 6 cycles; (2) Paclitaxel drug shortage (DS): docetaxel 75 mg/m2/carboplatin AUC 5 × 6 cycles. Adverse events, quality of life, and costs of chemotherapy, neuropathy, febrile neutropenia, and anemia were incorporated. Key assumptions: (1) Costs and consequences were assigned only to grade 2+ neuropathy, febrile neutropenia, and grade 3-4 anemia; (2) Grade 2+ neuropathy prompted a switch from paclitaxel/carboplatin to docetaxel/carboplatin or from docetaxel/carboplatin to carboplatin alone; (3) Febrile neutropenia resulted in inpatient hospitalization followed by G-CSF prophylaxis. RESULTS: The mean cost of 6 cycles of chemotherapy was $4939 in the STD and $16,107 in the DS scenario, for a cost difference of $11,168 per patient over 6 cycles of treatment. STD was the dominant strategy (less expensive and more effective than the drug shortage scenario). In sensitivity analysis, DS was more costly over a wide range of clinical estimates in each arm. A drug shortage that affects approximately 50% of women initiating chemotherapy is expected to impact 779 women and cost third party payers an additional $8,699,872 monthly. CONCLUSIONS: Our model indicates that chemotherapy drug shortages can have a significant negative impact on the average cost of primary treatment for ovarian cancer and have the potential to negatively impact health system costs.

Cost effectiveness of concurrent gemcitabine and cisplatin with radiation followed by adjuvant gemcitabine and cisplatin in patients with stages IIB to IVA carcinoma of the cervix.

OBJECTIVE: A recent phase III trial reported gemcitabine with cisplatin chemoradiation followed by 2 cycles of gemcitabine and cisplatin (G) significantly improved progression-free (PFS) and overall survival (OS) compared to standard cisplatin chemoradiation (C) for locally advanced cervix cancer. We evaluate the cost effectiveness (CE) of these treatment regimens. METHODS: A modified Markov model was constructed comparing CE between treatment arms using the published trial's five-year OS and treatment-related toxicity rates. Quality of life (QOL) utility scores during treatment were obtained from published literature and modeled for sensitivity analysis. Cost data was obtained from Medicare reimbursement figures and the Healthcare Cost and Utilization Project. One-way sensitivity analyses assessed variations in cost and adverse events. RESULTS: Mean cost was $41,330 (US$) for C versus $60,974 for G. Incremental cost-effectiveness ratio (ICER) for G compared to C was $33,080 per quality-adjusted life year (QALY). In sensitivity analyses (SA), the ICER increased to common willingness-to-pay thresholds of 50 K and 100 K when QOL utility scores during G active treatment declined to 0.64 and 0.53 (baseline 0.76), respectively. The model was insensitive to changes in adverse event rates, costs of treatment, or adverse event hospitalization costs. CONCLUSIONS: Gemcitabine with cisplatin chemoradiation followed by 2 cycles of adjuvant gemcitabine and cisplatin is a cost effective treatment for locally advanced cervix cancer compared to standard cisplatin chemoradiation. Common willingness to pay thresholds are exceeded during sensitivity analyses with realistic declines in QOL. Our results support ongoing investigations of novel adjuvants to standard cisplatin chemoradiation with potentially less toxicity.

Cost analysis of abdominal, laparoscopic, and robotic-assisted myomectomies.

STUDY OBJECTIVE: To perform a cost-minimization analysis of abdominal, traditional laparoscopic and robotic-assisted myomectomy. DESIGN: Cost analysis (Canadian Task Force Classification III). SETTING: Academic medical center. PATIENTS: Women undergoing myomectomy by various surgical approaches. INTERVENTIONS: We developed a decision model to compare the costs ($2009) of different approaches to myomectomy from a healthcare system perspective. The model included operative time, conversion risk, transfusion risk, and length of stay (LOS) for each modality. Baseline estimates and ranges were based on reported values extracted from existing literature. We analyzed two different models: #1) Existing Robot model and #2) Robot Purchase model. MEASUREMENTS AND MAIN RESULTS: In the baseline analysis for the Existing Robot model, abdominal myomectomy (AM) was the least expensive at $4937 compared with laparoscopic myomectomy (LM) at $6219 and robotic-assisted laparoscopic myomectomy (RM) at $7299. The abdominal route remained the least expensive when varying all parameters and costs except for two cases in which LM became least expensive: 1) If AM length of stay was greater than 4.6 days, and 2) If the surgeon's fee for AM was greater than $2410. When comparing LM to RM, the cost of RM was consistently higher unless the robotic disposable equipment costs were less than $1400. In the Robot Purchase model, only the RM costs increased while AM and LM costs remained the same. CONCLUSION: In this cost-minimization analysis, abdominal myomectomy is the least expensive approach when compared to laparoscopy and robotic-assisted laparoscopy.

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.

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.

Incidence of subsequent abnormal cytology in cervical cancer patients completing five-years of post treatment surveillance without evidence of recurrence.

OBJECTIVE: To determine the incidence of subsequent abnormal cervical or vaginal cytology and confirmatory histology in women completing five-years of surveillance for cervical cancer without recurrence. METHODS: Following IRB approval, a tumor registry database identified women managed for all stages of cervical cancer from 1990 to 2003 who after completion of 60 months of active surveillance following primary therapy underwent continued vaginal or cervical cytologic surveillance. Retrospective review was performed to determine demographics, clinicopathologic variables, vaginal or cervical cytology and outcomes. RESULTS: Sixty-one women were identified with a median age at diagnosis of 41 (range 23-81). 72% of women were Caucasian, 16% were African-American with the remainder primarily Asian. Squamous cell carcinoma was the most common histology and present in 47 women (77%) with an equal proportion of women having G1 and G2 tumors. 80% of patients had early stage disease (Stages IA1-IIA). Median follow-up after completing five-years of active surveillance for all patients was 143 months and a total of 303 Pap tests were performed with the mean/median number of five cytologic evaluations per patient. A total of 17 (5.6%) [95% CI, 3.5-8.8%] abnormal Pap tests were reported, which led to the performance of three diagnostic procedures. One case of moderate vaginal dysplasia was diagnosed and treated. CONCLUSIONS: Continued annual cytologic screening is of low yield in women completing five-years of surveillance that have remained free of recurrence. The incorporation of newer testing modalities including HPV testing may allow increases in the screening interval in this group of patients at relatively low risk for recurrence.