A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer.

OBJECTIVES: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. METHODS: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. RESULTS: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). CONCLUSIONS: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01836432.

Prospective Trial of Functional Lung Avoidance Radiation Therapy for Lung Cancer: Quality of Life Report.

PURPOSE: A novel form of lung function imaging has been developed that uses 4-dimensional computed tomography (4DCT) data to generate lung ventilation images (4DCT-ventilation). Functional avoidance uses 4DCT-ventilation to reduce doses to functional lung with the aim of reducing pulmonary side effects. A phase 2, multicenter 4DCT-ventilation functional avoidance clinical trial was completed. The purpose of this work was to quantify changes in patient-reported outcomes (PROs) for patients treated with functional avoidance and determine which metrics are predictive of PRO changes. MATERIALS AND METHODS: Patients with locally advanced lung cancer receiving curative-intent radiation therapy were accrued. Each patient had a 4DCT-ventilation image generated using 4DCT data and image processing. PRO instruments included the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire administered pretreatment; at the end of treatment; and at 3, 6, and 12 months posttreatment. Using the FACT-Trial Outcome Index and the FACT-Lung Cancer Subscale results, the percentage of clinically meaningful declines (CMDs) were determined. A linear mixed-effects model was used to determine which patient, clinical, dose, and dose-function metrics were predictive of PRO decline. RESULTS: Of the 59 patients who completed baseline PRO surveys. 83% had non-small cell lung cancer, with 75% having stage 3 disease. The median dose was 60 Gy in 30 fractions. CMD FACT-Trial Outcome Index decline was 46.3%, 38.5%, and 26.8%, at 3, 6, and 12 months, respectively. CMD FACT-Lung Cancer Subscale decline was 33.3%, 33.3%, and 29.3%, at 3, 6, and 12 months, respectively. Although an increase in most dose and dose-function parameters was associated with a modest decline in PROs, none of the results were significant (all P > .053). CONCLUSIONS: The current work presents an innovative combination of use of functional avoidance and PRO assessment and is the first report of PROs for patients treated with prospective 4DCT-ventilation functional avoidance. Approximately 30% of patients had clinically significant decline in PROs at 12 months posttreatment. The study provides additional data on outcomes with 4DCT-ventilation functional avoidance.

Risk of Secondary Malignancies After Pelvic Radiation: A Population-based Analysis.

Background and objective: Radiation therapy has increasingly been used in the management of pelvic malignancies. However, the use of radiation continues to pose a risk of a secondary malignancy to its recipients. This study investigates the risk of secondary malignancy development following radiation for primary pelvic malignancies. Methods: A retrospective cohort review of the Surveillance, Epidemiology, and End Results database from 1975 to 2016 was performed. Primary pelvic malignancies were subdivided based on the receipt of radiation, and secondary malignancies were stratified as pelvic or nonpelvic to investigate the local effect of radiation. Key findings and limitations: A total of 2 102 192 patients were analyzed (1 189 108 with prostate, 315 026 with bladder, 88 809 with cervical, 249 535 with uterine, and 259 714 with rectal/anal cancer). The incidence rate (defined as cases per 1000 person years) of any secondary malignancies (including but not limited to secondary pelvic malignancies) was higher in radiation patients than in nonradiation patients (incidence rate ratio [IRR] 1.04, confidence interval [CI] 1.03-1.05), with significantly greater rates noted in radiation patients with prostate (IRR 1.22, CI 1.21-1.24), uterine (IRR 1.34), and cervical (IRR 1.80, CI 1.72-1.88) cancer. While the overall incidence rate of any secondary pelvic malignancy was lower in radiation patients (IRR 0.79, CI 0.78-0.81), a greater incidence was still noted in the same cohorts including radiation patients with prostate (IRR 1.42, CI 1.39-1.45), uterine (IRR 1.15, CI 1.08-1.21), and cervical (IRR 1.72, CI 1.59-1.86) cancer. Conclusions and clinical implications: Except for localized cervical cancer, when put in the context of median overall survival, the impact of radiation likely does not carry enough weight to change practice patterns. Radiation for pelvic malignancies increases the risk for several secondary malignancies, and more specifically, secondary pelvic malignancies, but with a relatively low absolute risk of secondary malignancies, the benefits of radiation warrant continued use for most pelvic malignancies. Practice changes should be considered for radiation utilization in malignancies with excellent cancer-specific survival such as cervical cancer. Patient summary: The use of radiation for the management of pelvic malignancies induces a risk of secondary malignancies to its recipients. However, the absolute risk being low, the benefits of radiation warrant its continued use, and a change in practice patterns is unlikely.

Hawks and Doves: Perceptions and Reality of Faculty Evaluations.

OBJECTIVES: Internal medicine clerkship grades are important for residency selection, but inconsistencies between evaluator ratings threaten their ability to accurately represent student performance and perceived fairness. Clerkship grading committees are recommended as best practice, but the mechanisms by which they promote accuracy and fairness are not certain. The ability of a committee to reliably assess and account for grading stringency of individual evaluators has not been previously studied. METHODS: This is a retrospective analysis of evaluations completed by faculty considered to be stringent, lenient, or neutral graders by members of a grading committee of a single medical college. Faculty evaluations were assessed for differences in ratings on individual skills and recommendations for final grade between perceived stringency categories. Logistic regression was used to determine if actual assigned ratings varied based on perceived faculty's grading stringency category. RESULTS: "Easy graders" consistently had the highest probability of awarding an above-average rating, and "hard graders" consistently had the lowest probability of awarding an above-average rating, though this finding only reached statistical significance only for 2 of 8 questions on the evaluation form (P = .033 and P = .001). Odds ratios of assigning a higher final suggested grade followed the expected pattern (higher for "easy" and "neutral" compared to "hard," higher for "easy" compared to "neutral") but did not reach statistical significance. CONCLUSIONS: Perceived differences in faculty grading stringency have basis in reality for clerkship evaluation elements. However, final grades recommended by faculty perceived as "stringent" or "lenient" did not differ. Perceptions of "hawks" and "doves" are not just lore but may not have implications for students' final grades. Continued research to describe the "hawk and dove effect" will be crucial to enable assessment of local grading variation and empower local educational leadership to correct, but not overcorrect, for this effect to maintain fairness in student evaluations.

Is Timing of Steroid Exposure Prior to Immune Checkpoint Inhibitor Initiation Associated with Treatment Outcomes in Melanoma? A Population-Based Study.

Immune checkpoint inhibitors (ICIs) harness the immune system and are the therapy of choice for multiple cancers. Although immunosuppressive agents such as steroids are also used in many cancers, it is unknown how their timing affects treatment outcomes. Thus, we investigated the relationship between the timing of steroid exposure preceding ICI administration and subsequent treatment outcomes in melanoma. This population-based study utilized the SEER-Medicare-linked database to identify patients diagnosed with melanoma between 1991 and 2015 and receiving ICIs between 2010 and 2016, examining last steroid exposure in the 12 months preceding ICI. The main outcome was all-cause mortality (ACM) after ICIs. Modifications of the Cox proportional hazards model were used to calculate time-dependent hazards. Of 1671 patients with melanoma receiving ICIs, 907 received steroids. Compared with no steroids, last steroid exposures ≤1 month and 1-3 months prior to ICIs were associated with a 126% and 51% higher ACM within 3 months post ICI initiation, respectively (hazard ratio (HR): 2.26, 95% CI: 1.65-3.08; and HR: 1.51, 95% CI: 1.01-2.27). Steroid exposure within 3 months of initiating ICIs was associated with increased mortality up to 6 months after ICI. Further investigation is warranted to elucidate mechanisms affecting outcomes due to steroids.

Analysis of blood type for SARS-CoV-2 and correlation for disease acquisition in various sociodemographic groups including women of childbearing age.

BACKGROUND: Multiple studies have occurred to determine if a patient's blood type, Rhesus factor (Rh), and sociodemographic attributes contribute to contracting SARS-CoV-2. True association remains unknown. METHODS: Inclusion criteria included in-patients who were tested for SARS-CoV-2 with blood type assessed. Study endpoints combined ABO, Rh and all-cause inpatient mortality (ACIM) with testing positivity. Pregnancy status was one of several secondary endpoints evaluated. A logistic regression analysis was used to estimate association. RESULTS: Of the 27,662 patients who met inclusion criteria, Type A blood was associated with increased positivity [1.01 (1.0-1.21), P = .03]. Type B [1.10 (0.99-1.23), P = .08] and AB [0.98 (0.81-1.19), P = .84] showed no association. When evaluating ACIM, type A [1.18 (0.91-1.52), P = .22], B [1.13 (0.82- 1.56), P = .480], and AB [1.06 (0.62-1.81), P = .839] were not associated with increased mortality. The female subgroup was less likely to test positive [0.88 (0.82-0.986), P = .002]. Black patients demonstrated a higher likelihood of positivity when compared to White [1.96 (1.79-2.14), P < .001]. Non-pregnant women exhibited a 2.5 times greater likelihood of testing positive [2.49 (2.04-3.04), P < .001]. CONCLUSIONS: This study confirms results of previous research which showed SARS-Co-V-2 positivity related to blood type. It also confirms more recent research demonstrating inequities related to acquisition of SARS-CoV-2 for certain sociodemographic groups. Larger studies are warranted to confirm and further explore novel pregnancy findings.

Trends in PCSK9 Inhibitor Prescriptions before and after the Price Reduction in Patients with Atherosclerotic Cardiovascular Disease.

BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein (LDL) cholesterol and cardiovascular event rates, yet due to their high price remain underutilized and difficult to prescribe in clinical practice. In March 2018, their price was significantly reduced. We evaluated whether the price reduction would improve prescribing patterns of PCSK9 inhibitors in eligible patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: We identified the number of eligible ASCVD patients and those prescribed a PCSK9 inhibitor for each year between July 2015 and December 2019. Patient demographics and clinical characteristics for those prescribed a PCSK9 inhibitor were extracted from their electronic health record. RESULTS: In total 1059 patients of eligible patients received a new prescription for a PCSK9 inhibitor. From 2015 to 2019, the rate of new prescriptions among eligible patients increased from 0.5 to 3.3% (p < 0.001) and continuation rates increased from 18 to 60% (p < 0.001). Following the price reduction, patients who were prescribed a PCSK9 inhibitor were younger and more likely to be female, but less likely to have Medicare insurance. CONCLUSIONS: Despite the reduction in the cost of PCSK9 inhibitors, most eligible patients are not prescribed one. The reduction in cost has improved adherence, primarily in patients with commercial insurance. Older patients and those on Medicare still face significant barriers in accessing a PCSK9 inhibitor. Further reductions in the price of the PCSK9 inhibitors are needed as is further study of the barriers that exist in prescribing one.

Association Between Sex and Immune Checkpoint Inhibitor Outcomes for Patients With Melanoma.

Importance: Immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment and are now standard of care. Although sex is associated with immune function and immune-related diseases, the interaction between sex and ICIs is understudied. Objective: To examine whether cancer immunotherapy effectiveness varies between female and male patients with advanced melanoma treated with either nivolumab plus ipilimumab combination therapy or anti-programmed cell death protein 1 (PD-1) therapy (namely, pembrolizumab or nivolumab). Design, Setting, and Participants: The study population consisted of 1369 older adults (aged ≥65 years) with a record of melanoma diagnosis from January 1, 1991, to December 31, 2015, in the Surveillance, Epidemiology, and End Results-Medicare linked database. Patients with a diagnosis of stage III or stage IV melanoma and a claims record showing nivolumab plus ipilimumab combination therapy or anti-PD-1 therapy (ie, pembrolizumab or nivolumab) as their last type of ICI prescribed were included in the analyses. Patients were followed up through December 31, 2017, for the overall survival analysis. Statistical analysis was performed from September 19, 2019, to February 20, 2021. Exposures: Sex, last prescribed ICI, and prior use of ipilimumab. Main Outcomes and Measures: The primary outcome was overall survival, defined as time from the index date until death from any cause, with patients censored at the end of the study (December 31, 2017). Cox proportional hazards regression modeling was used to examine the association of sex with ICI outcomes while adjusting for prior use of ipilimumab, age at ICI initiation, Charlson Comorbidity Index, cancer stage at the time of diagnosis, and autoimmune disease diagnosis. Results: Among the 1369 patients in the study (982 men [71.7%]; median age, 75 years [IQR, 69-82 years]), the outcome of nivolumab plus ipilimumab combination therapy depended on sex (Wald χ2 = 9.48; P = .009 for interaction). The mortality hazard ratio (HR) for women with prior ipilimumab use receiving combination therapy was 2.06 times (95% CI, 1.28-3.32; P = .003) higher than their male counterparts. No significant difference was observed between women and men receiving anti-PD-1 therapy with (HR, 0.97 [95% CI, 0.68-1.38]; P = .85) or without prior ipilimumab use (HR, 0.85 [95% CI, 0.67-1.07]; P = .16). For women with prior ipilimumab use, combination therapy was associated with 2.82 times higher mortality hazards than anti-PD-1 therapy (95% CI, 1.73-4.60). No statistically significant difference was seen in mortality risk between anti-PD-1 therapy and combination therapy for men. Conclusions and Relevance: This cohort study suggests that female patients with advanced melanoma may not benefit as much from combination ICIs as male patients would. Tumor mutation burden or estrogen level may serve as an important biomarker associated with ICI response in metastatic melanoma.

Inpatient versus outpatient hypomethylating agent induction for acute myeloid leukemia as a predictor for survival.

The hypomethylating agents (HMA) decitabine and azacitidine are used in acute myeloid leukemia (AML) for induction therapy in select patients. They are given on either inpatient (IP) or outpatient (OP) services and the decision where to administer them is complex but ultimately depends on the risk for neutropenic infections, hyperleukocytosis and other complications. In our study, we investigated 100-day survival differences between IP and OP HMA induction. This study reviewed 68 patients, 29 of whom received HMA as an IP while 39 received it as an OP. Using a logistic regression model, we found that IP induction was associated with a significantly lower odds of survival at 100-days (Odds Ratio 5.90; p=0.005). Given these results, we hypothesize the survival difference was related to the inherent risk associated with being admitted for chemotherapy, whether it be neutropenic fever, hyperleukocytosis or other reasons. We advise physicians who are administering IP HMA to consider its' inherent risk associated with its' administration.

An Examination of Cytomegalovirus, Socioeconomic Status, Race, and Ethnicity on Outcomes after Haploidentical Hematopoietic Transplantation.

Previous analyses of the effects of race and socioeconomic status (SES) on outcomes after hematopoietic stem cell transplantation (HSCT) have suggested that minority populations and those in disadvantaged groups have inferior outcomes. However, the results of these studies have been inconsistent, potentially due to a multitude of factors, both medical and nonmedical, that have confounded results. In haploidentical (HI) HSCT, an expanding approach with the potential to enfranchise more minority patients, data on the effect of race and SES on outcomes are very limited. To identify and potentially correct factors that negatively impact outcomes after HI HSCT in disadvantaged groups at our institution, we performed a retrospective, multivariable analysis of the impact of race and SES as single and combined variables on HI HSCT outcomes of relapse, transplantation-related mortality, acute and chronic graft-versus-host disease (GVHD), and overall survival (OS). In addition to controlling for race and SES, all patients had HI donors and were treated with the same 2-step approach, with consistent T cell dosing and GVHD prophylaxis to further reduce the impact of confounders in this complex area. The study cohort of 239 patients was 71% Caucasian, 19.7% African American, 4.6% Hispanic, and 4.2% Asian. The majority of minority patients were in areas of higher deprivation (P = .001) and had the highest incidence of cytomegalovirus (CMV) seropositivity (P = .001) and the lowest likelihood of possessing a CMV immunodominant (IMD) allele (P = .001), which was previously associated with an OS benefit. Positive CMV serostatus was highly linked to post-transplantation CMV reactivation (P = .001) which was associated with higher relapse rates (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.06 to 2.30; P = .026), higher TRM (HR, 2.10; 95% CI, 1.09 to 4.05; P = .027), and lower OS (HR, 1.77; 95% CI, 1.18 to 2.65; P = .006). The lack of a CMV IMD allele largely replicated the results of CMV reactivation on HSCT results. Although race and SES did not directly correlate with either OS or relapse incidence, non-Caucasians in a more disadvantaged group had a higher incidence of chronic GVHD (HR, 2.55; 95% CI, 1.08 to 6.01; P = .033) compared with Caucasians and minorities in less disadvantaged groups. Regardless of SES, minorities had a lower incidence of acute GVHD than Caucasians in a more advantaged SES group (HR, 0.52; 95% CI, 0.30 to 0.90; P = .020). The primary finding of this study is that CMV reactivation was the major driver of mortality after HI HSCT. CMV reactivation may have be associated with poor HSCT outcomes in HI HSCT recipients in disadvantaged areas, most of whom were minorities. The data suggest that the prevention of post-transplantation CMV reactivation possibly could have a major impact on HI HSCT outcomes, especially in minority recipients. The finding of different GVHD manifestations between races are intriguing and merits further study.

Long term outcomes of ureteroscopic management of upper tract urothelial carcinoma.

OBJECTIVES: Upper tract urothelial carcinoma (UTUC) is relatively rare. While nephroureterectomy is considered the gold standard for treatment, endoscopic nephron- sparing techniques have emerged for select cases with equivalent cancer specific survival (CSS). We present the largest series with longest follow-up to date of retrograde ureteroscopy as the primary treatment of UTUC. METHODS: A retrospective review was performed of 258 patients diagnosed with UTUC who were initially evaluated and managed by a single surgeon. Patients were followed from 1994 to 2017. Clinical records were evaluated for patient and tumor characteristics, operative parameters and outcomes. Statistical analysis was performed to identify risk of recurrence, progression, cancer and overall survival. RESULTS: Following exclusion criteria, 168 patients were evaluated. Average tumor size on initial excision was 16.8mm. Mean age of the cohort was 70 years, with mean follow-up of 5.53 years. The 5-year overall survival was 80.9%, but CSS was 92.6%. Recurrence free survival was 30% with average tumor size on recurrence of 6.39mm. Progression free survival was 75% with a renal preservation rate of 71.4%. CONCLUSIONS: Ureteroscopic management of UTUC is a successful alternative to nephroureterectomy in select cases of UTUC. With strict surveillance protocols to manage frequent local recurrence rates, it is possible to achieve high renal preservation rates with acceptable CSS, even in the long-term.