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The existing performance evaluation methods in robot-assisted surgery (RAS) are mainly subjective, costly, and affected by shortcomings such as the inconsistency of results and dependency on the raters' opinions. The aim of this study was to develop models for an objective evaluation of performance and rate of learning RAS skills while practicing surgical simulator tasks. The electroencephalogram (EEG) and eye-tracking data were recorded from 26 subjects while performing Tubes, Suture Sponge, and Dots and Needles tasks. Performance scores were generated by the simulator program. The functional brain networks were extracted using EEG data and coherence analysis. Then these networks, along with community detection analysis, facilitated the extraction of average search information and average temporal flexibility features at 21 Brodmann areas (BA) and four band frequencies. Twelve eye-tracking features were extracted and used to develop linear random intercept models for performance evaluation and multivariate linear regression models for the evaluation of the learning rate. Results showed that subject-wise standardization of features improved the R[superscript 2] of the models. Average pupil diameter and rate of saccade were associated with performance in the Tubes task (multivariate analysis; p-value = 0.01 and p-value = 0.04, respectively). Entropy of pupil diameter was associated with performance in Dots and Needles task (multivariate analysis; p-value = 0.01). Average temporal flexibility and search information in several BAs and band frequencies were associated with performance and rate of learning. The models may be used to objectify performance and learning rate evaluation in RAS once validated with a broader sample size and tasks.

Objective Health-related quality of life (HRQoL) outcomes are important in making clinical and policy decisions. This study aimed to examine the HRQoL reporting in cancer drug trials leading to Food and Drug Administration (FDA) approvals.Methods and analysis This retrospective cohort study analysed HRQoL data for trials leading to FDA approvals between July 2015 and May 2020. Proportion of included trials that reported HRQoL, latency between FDA approval and first report of HRQoL data, HRQoL outcomes, and their correlation with OS (overall survival) and PFS (progression-free survival) were analysed.Results Of the 233 trials associated with 207 FDA approvals, HRQoL was reported in 50% of trials, of which only 42% had the data reported by the time of FDA approval. There were no changes in frequency of HRQoL reporting between 2015 and 2020. HRQoL data were first reported in the primary publication in only 30% trials. Of the 115 trials with HRQoL data available, HRQoL improved in 43%, remained stable in 53% and worsened in 4% of trials. Among the trials that led to FDA approvals based on surrogate endpoints (79%), HRQoL was reported in 45% and improved only in 18% trials. There was no association between OS and PFS benefit and HRQoL outcomes.Conclusion Rates of HRQoL reporting were suboptimal in trials that led to FDA approvals with no improvements seen between 2015 and 2020. HRQoL reporting was often delayed and not presented in the primary publication. HRQoL reporting was further sparse in trials with approvals based on surrogate endpoints and HRQoL improved in only a minority of them.

Background: Multiple randomized controlled trials (RCTs) have investigated the impact of adding checkpoint inhibitors to neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) patients. However, there is a lack of biomarkers that can help identify patients who would benefit from combination therapy. Our research identifies response predictors and assesses the effectiveness of adding immunotherapy to neoadjuvant chemotherapy for TNBC patients. Methods: We identified eligible RCTs by searching PubMed, Cochrane CENTRAL, Embase, and oncological meetings. For this meta-analysis, we obtained odds ratios using the standard random effects model. To assess the heterogeneity of the study outcomes, the I2 statistic was obtained. Potential bias was assessed using a funnel plot and the corresponding Egger’s test. Results: In total, 1637 patients with TNBC were included from five RCTs. Neoadjuvant chemoimmunotherapy significantly improved pCR when compared to neoadjuvant chemotherapy alone. In the subgroup analysis, neoadjuvant chemoimmunotherapy showed higher pCR rates in both Programmed death-ligand 1 (PD-L1)-positive and PD-L1-negative TNBC patients. An Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 correlated with increased pCRs (OR = 1.9, p < 0.001) in neoadjuvant chemoimmunotherapy vs. neoadjuvant chemotherapy, but no benefit was observed for patients with ECOG PS 1. Nodal positivity was significantly associated with pCR (OR = 2.52, p < 0.001), while neoadjuvant chemoimmunotherapy did not benefit patients with negative lymph nodes. Conclusions: Checkpoint inhibition and neoadjuvant chemotherapy significantly increased pCRs in TNBC patients, regardless of their PDL-1 status. Additional checkpoint inhibitors improved pCR rates, mainly for patients with ECOG PS 0 and lymph node-positive disease.

BackgroundThis study investigated demographic and socioeconomic factors contributing to disparities in the time to treatment for rectal cancer. Subgroup analysis based on age < 50 and ≥ 50 was performed to identify differences in time to treatment among young adults (age < 50) compared to older adults with rectal cancer.MethodsAn analysis was performed using data from the National Cancer Database, spanning from 2004 to 2019. The study encompassed 281,849 patients diagnosed with rectal cancer. We compared time intervals from diagnosis to surgery, radiation, and chemotherapy, considering age, sex, race, and socioeconomic variables. Analyses were performed for the entire cohort and for two subgroups based on age (< 50 and ≥ 50).ResultsOverall, Hispanic patients experienced longer times to surgery, radiation, and chemotherapy compared to non-Hispanic patients (surgery: 94.2 vs. 79.1 days, radiation: 65.0 vs. 55.6 days, chemotherapy: 56.4 vs. 47.8 days, all p < 0.001). Patients with private insurance had shorter times to any treatment (32.5 days) compared to those with government insurance or no insurance (30.6 and 32.5 days, respectively, p < 0.001). Black patients experienced longer wait times for both radiation (63.4 days) and chemotherapy (55.2 days) compared to White patients (54.9 days for radiation and 47.3 days for chemotherapy, both p < 0.001). Interestingly, patients treated at academic facilities had longer times to treatment in surgery, radiation, and chemotherapy compared to those treated at comprehensive and community facilities. When analyzed by age, many of the overall differences persisted despite the age stratification, suggesting that these disparities were driven more by demographic and socioeconomic variables rather than by age.ConclusionSignificant differences in the time to treatment for rectal cancer have been identified. Hispanic patients, individuals lacking private insurance, Black patients, and patients receiving care at academic facilities had the longest times to treatment. However, these differences were largely unaffected by the age (< 50 and ≥ 50) subgroup analysis. Further investigation into the causes of these disparities is warranted to develop effective strategies for reducing treatment gaps and enhancing overall care for rectal cancer patients.

Abstract In this note, we present an innovative approach called “homologous hypothesis tests” that focuses on cross-sectional comparisons of average tumor volumes at different time-points. By leveraging the correlation structure between time-points, our method enables highly efficient per time-point comparisons, providing inferences that are highly efficient as compared to those obtained from a standard two-sample t test. The key advantage of this approach lies in its user-friendliness and accessibility, as it can be easily employed by the broader scientific community through standard statistical software packages.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care, with increasing data demonstrating improved survival outcomes using ICIs among patients with advanced gastroesophageal cancer (GEC). ICIs are also associated with a lower incidence of grade ≥ 3 adverse events (AEs) compared to chemotherapy, suggesting that ICIs may have favorable effects on health-related quality of life (HRQoL). This meta-analysis sought to evaluate the effects of ICIs on the HRQoL of patients with advanced GEC. Methods: We conducted an online bibliographic search on Medline via PubMed using MeSH-based terms to retrieve randomized controlled trials (RCTs) that evaluated the effects of ICIs on HRQoL in patients with advanced GEC (we searched for all studies between 2018 and 2021). We included RCTs that incorporated ICIs as part of the intervention arm either as monotherapy (first or second line) or as a combination therapy (first-line) with another ICI or chemotherapy. We combined the HRQoL measures into a meta-analysis using standard random effects models, from which estimates of the average mean difference (MD) were obtained with 95% confidence intervals. We assessed the heterogeneity of the study outcomes using the Q and I2 statistics. Results: We identified 11 phase 3 RCTs that met the inclusion criteria, with a mean enrollment of 820 patients. Eight RCTs used an ICI plus chemotherapy combination in the intervention arm, three had ICIs as monotherapy, and one had doublet ICI therapy in the intervention arm. All RCTs used chemotherapy for the control arm. Collectively, the trials reported 37 HRQoL measures using five different HRQoL tools. The pooled analysis favored the intervention over the control arm in terms of the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores [MD 2.7 (95% CI 0.1 to 5.3), p < 0.041]. In a subgroup analysis of eight RCTs comparing combination therapy with ICIs plus chemotherapy versus chemotherapy alone, the effect estimates favored the ICI arm regarding the FACT-E [MD 2.7 (95% CI 0.1 to 5.3), p < 0.041] and the EORTC QLQ-OES18 pain scale [MD −2.2 (95% CI −4.3 to −0.2), p < 0.030]. Likewise, the effect estimates favored the ICI monotherapy arm over the chemotherapy arm regarding the QLQ-STO22 hair loss subscale [MD −23.2 (95% CI −29.7 to −16.7), p < 0.001], QLQ-STO22 dysphagia subscale [MD 6.7 (95% CI 1.7 to 11.7), p = 0.009], EQ-5D pain scale [MD 6.9 (95% CI 2.9 to 10.9), p < 0.001], and QLQ-OES18 saliva subscale [MD 5.8 (95% CI 0.1 to 11.6), p = 0.046]. Conclusions: In this meta-analysis, we found that the inclusion of ICIs as a first-line treatment for advanced GEC yielded better HRQoL outcomes than chemotherapy alone. Further research on the impact of ICIs on HRQoL is needed, with increasing evidence that ICIs improve the survival outcomes in patients with advanced GEC.

Abstract Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middle‐aged, and elderly Black and White KTRs. The 12‐h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stable KTRs greater than or equal to 6 months post‐transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration‐time curve 0–12 h (AUC0‐12h), clearance (CL), and CL/body mass index (BMI) with 0‐h troughs. MPA enterohepatic recirculation (EHR), MPA‐AUC6‐12h/MPA‐AUC0‐12h, and MPA glucuronide (MPAG)‐AUC0‐12h/MPA‐AUC0‐12h were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA‐AUC6‐12h/MPA‐AUC0‐12h (p = 0.049) and increased MPAG‐AUC0‐12h/MPA‐AUC0‐12h (p = 0.036). MPA troughs (p = 0.045) were reduced in the elderly. TAC CL/BMI (p = 0.043) was reduced in the elderly. For therapeutic MPA AUC0‐12h: 30–60 mg·h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC0‐12h target: 100–190 ng·h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle‐age and 7.8% elderly subjects achieved target AUC0‐12h for both medications (p = 0.036). Neurologic AEs were manifested in the elderly (p = 0.014). Immunosuppressive pharmacokinetics demonstrated age‐related differences with reduced TAC CL/BMI and MPA EHR and increased neurologic AE in the elderly. This immunosuppressive regimen may require age‐adjusted individualization to optimize allograft function.

Background Presence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts the effectiveness of cancer immunotherapies. The ability of toll-like receptor 3 (TLR3) ligands, interferons (IFNs) and COX2 inhibitors to synergistically induce CTL-attracting chemokines (but not regulatory T cell (Treg)-attractants) in the TME, but not in healthy tissues, observed in our preclinical studies, suggested that their systemic application can reprogram local TMEs.Methods Six evaluable patients (33–69 years) with metastatic triple-negative breast cancer received six doses of systemic chemokine-modulating (CKM) regimen composed of TLR3 ligand (rintatolimod; 200 mg; intravenous), IFN-α2b (20 MU/m2; intravenous) and COX2 inhibitor (celecoxib; 2×200 mg; oral) over 2 weeks. The predetermined primary endpoint was the intratumoral change in the expression of CTL marker, CD8α, in the post-CKM versus pre-CKM tumor biopsies. Patients received follow-up pembrolizumab (200 mg, intravenously, every 3 weeks), starting 3–8 days after completion of CKM.Results Post-CKM biopsies showed selectively increased CTL markers CD8α (average 10.2-fold, median 5.5-fold, p=0.034) and granzyme B (GZMB; 6.1-fold, median 5.8-fold, p=0.02), but not FOXP3 (Treg marker) relative to HPRT1 expression, resulting in the increases in average CD8α/FOXP3 ratio and GZMB/FOXP3 ratio. CKM increased intratumoral CTL-attractants CCL5 and CXCL10, but not Treg-attractants CCL22 or CXCL12. In contrast, CD8+ T cells and their CXCR3+ subset showed transient decreases in blood. One clinical response (breast tumor autoamputation) and three stable diseases were observed. The patient with clinical response remains disease free, with a follow-up of 46 months as of data cut-off.Conclusions Short-term systemic CKM selectively increases CTL numbers and CTL/Treg ratios in the TME, while transiently decreasing CTL numbers in the blood. Transient effects of CKM suggest that its simultaneous application with checkpoint blockade and other forms of immunotherapy may be needed for optimal outcomes.

Objectives To evaluate outcomes and cost-effectiveness of targeted therapy sequencing for metastatic and recurrent cervical cancer. Method Models were simulated based on phase II and III trials on bevacizumab (bev) from GOG-240, cemiplimab (cemi) from GOG 3016, pembrolizumab (pembro) from KEYNOTE-826, and tisotumab vedotin (tiso) from GOG 3023. Costs were based on IBM Micromedex RED BOOK™ and company listed costs. Results For [chemo + bev → chemo], total cost was $125,918.04, with median overall survival (mOS) of 21.8 months, and cost-effectiveness ratio (CER) of $119,835.79. For [chemo + bev → cemi], total cost was $187,562.99 with mOS of 28.5 months and CER of $162,039.16. For [chemo + bev + pembro → chemo], total cost was $319,963.78 with mOS 32.9 months and CER of $249,930.10. For [chemo + bev + pembro → tiso], total cost was $455,204.45, with mOS 36.5 months and CER of $320,072.99. Conclusion The combination of immunotherapies and biologics have significantly increased overall survival, but with associated higher costs, primarily related to drug costs.

Objective:. Assessment of surgical skills is crucial for improving training standards and ensuring the quality of primary care. This study aimed to develop a gradient-boosting classification model to classify surgical expertise into inexperienced, competent, and experienced levels in robot-assisted surgery (RAS) using visual metrics. Methods:. Eye gaze data were recorded from 11 participants performing 4 subtasks; blunt dissection, retraction, cold dissection, and hot dissection using live pigs and the da Vinci robot. Eye gaze data were used to extract the visual metrics. One expert RAS surgeon evaluated each participant’s performance and expertise level using the modified Global Evaluative Assessment of Robotic Skills (GEARS) assessment tool. The extracted visual metrics were used to classify surgical skill levels and to evaluate individual GEARS metrics. Analysis of Variance (ANOVA) was used to test the differences for each feature across skill levels. Results:. Classification accuracies for blunt dissection, retraction, cold dissection, and burn dissection were 95%, 96%, 96%, and 96%, respectively. The time to complete only the retraction was significantly different among the 3 skill levels (P value = 0.04). Performance was significantly different for 3 categories of surgical skill level for all subtasks (P values < 0.01). The extracted visual metrics were strongly associated with GEARS metrics (R2 > 0.7 for GEARS metrics evaluation models). Conclusions:. Machine learning algorithms trained by visual metrics of RAS surgeons can classify surgical skill levels and evaluate GEARS measures. The time to complete a surgical subtask may not be considered a stand-alone factor for skill level assessment.

Abstract Breast cancer is more common on the left side than the right side. We aim to evaluate differences in clinicopathological and genomic characteristics based on laterality. We analyzed survival outcomes and clinical characteristics of 881,320 patients recorded by the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer Genome Atlas (TCGA) was used to explore genomic and clinical features from 1,062 patients. Gene expression data was used to quantitate cytolytic activity and hallmark gene-sets were used for gene set enrichment analysis. An institutional retrospective review was conducted on 155 patients treated with neoadjuvant chemotherapy (NACT). Patient characteristics were summarized by pathological complete response (pCR). Left sided tumors were found to be more prevalent than right sided tumors. No major clinicopathological differences were noted by laterality. Left sided breast cancer demonstrated poorer outcomes versus right sided tumors (HR 1.05, 95% CI 1.01–1.08; p = 0.011). Cell proliferation gene sets, including E2F Targets, G2M Checkpoint, Mitotic spindle, and MYC Targets, were enriched on the left side compared to the right. Left sided tumors had lower pCR rates versus right sided tumors (15.4% versus 29.9%, p = 0.036). Our findings suggest that left sided breast cancer is associated with aggressive biology and worse outcomes compared to right sided breast cancer.

Summary: Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT. In both major and minor histocompatibility-mismatched models of murine aGvHD, expression of Gal-3 is associated with decreased T cell activation and suppression of the secretion of effector cytokines, including IFN-γ and GM-CSF. Mechanistically, Gal-3 results in activation of NFAT signaling, which can induce T cell exhaustion. Gal-3 overexpression in human T cells prevents severe disease by suppressing cytotoxic T cells in xenogeneic aGvHD models. Together, these data identify the Gal-3-dependent regulatory pathway in donor T cells as a critical component of inflammation in aGvHD.

BackgroundIt is critically important to study the real-world data of FDA-approved medications to understand the response rates and toxicities observed in the real-world population not represented in the clinical trials.MethodsWe reviewed charts of patients diagnosed with metastatic, hormone receptor-positive, human epidermal growth factor receptor 2 negative, PIK3CA-mutated breast cancer treated with alpelisib from May 2019 to January 2022. Clinical characteristics and treatment outcomes were collected. The association of clinical characteristics with responses and adverse events (AEs) was evaluated using the logistic regression model.Results27 patients were included. Median age at alpelisib initiation 67 years (range: 44, 77 years). Majority of patients had excellent performance status at time of alpelisib initiation. Most patients had chronic comorbidities, notably; 2 patients had controlled type 2 diabetes mellitus at time of alpelisib initiation. Majority had a median of three lines of therapy (range: 1, 7) before alpelisib. Clinical responses were determined using RECIST v1.1. 3/27 (11.11%) patients discontinued therapy before response assessment due to grade 3 AEs. Overall response rate was 12.5% (3/24), with all partial responses (PR). The median duration of response was 5.77 months (range: 5.54, 8.98). 14/27 (51.9%) of patients required dose interruption/reduction. Overall, 23/27 (85.19%) patients discontinued alpelisib of which 11 (47.83%) discontinued alpelisib due to AEs. Median duration of treatment was 2 months in patients who had grade 3 AEs (range:

The pemphigus group of autoimmune blistering diseases encompasses pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Lesion location in pemphigus has been elegantly postulated by the Desmoglein Compensation Hypothesis (DCH), which references the distribution of desmoglein (Dsg) proteins in the epidermis along with a patient’s autoantibody profile to describe three different lesion phenotypes: PF is characterized by subcorneal lesions in the presence of anti-Dsg1 antibodies only, while lesions in PV are suprabasilar and accompanied by anti-Dsg3 antibodies only in mucosal PV, or both anti-Dsg3 and anti-Dsg1 in the case of mucocutaneous PV. While the validity of this hypothesis has been supported by several studies and is prominently featured in textbooks of dermatology, a number of logical inconsistencies have been noted and exceptions have been published in several small-scale studies. We sought to comprehensively assess the extent to which patient clinical and autoantibody profiles contradict the DCH, and characterize these contradictions in a large sample size of 266 pemphigus patients. Remarkably, we find that roughly half of active PV and PF patients surveyed present with a combination of lesion morphology and anti-Dsg3/1 levels that contradict the DCH, including: patients with a cutaneous only PV presentation, mucocutaneous disease in the absence of either Dsg3, Dsg1, or both, and mucosal disease in the absence of Dsg3 or presence of Dsg1. We also find stark differences in fidelity to the DCH based on ethnicity and HLA-association, with the lowest proportion of adherence in previously understudied populations. These findings underscore the need to expand our understanding of pemphigus morphology beyond the DCH, in particular for populations that have not been a focus in previous investigation.

Objectives Radiation emergencies are rare but can have minor confined effects to catastrophic consequences across the large geographical territories. Geographical disparities in the preparedness for radiation emergencies can negatively impact public-safety and delay protective actions. We examined such disparities using the global and regional radiation preparedness data from the revised annual International Health Regulations (IHR) data sets.Settings We used IHR State Party Annual Reporting (SPAR) tool and its associated health indicators developed to mitigate public health risk from radiation emergencies. Using the most recent (2019) SPAR database developed for radiation emergencies, along with 12 other cross-sector indicators, we examined the disparities among WHO state and region-wide capacity scores for operational preparedness.Results Based on the analysis of the 2019 annual reporting data sets from 171 countries, radiation emergency was one of the top three global challenges with an average global preparedness capacity of 55%. Radiation emergency preparedness capacity scores showed highest dispersion score among all 13 capacities suggesting higher disparities for preparedness across the globe. Only 38% of the countries had advanced functional capacity with ≥80% operational readiness, with 28% countries having low to very low operational readiness. No geographical regions had ≥80% operational readiness for radiation emergencies, with 4/6 geographical regions showing limited capacity or effectiveness. Global data from 171 countries showed that the capacity to respond to radiation emergencies correlated with the capacity for chemical events with a correlation coefficient (ρ) of 0.70 (CI 0.61 to 0.77).Conclusion We found major global disparities for the operational preparedness against radiation emergencies. Collaborative approaches involving the public health officials and policymakers at the regional and state levels are needed to develop additional guidance to adapt emergency preparedness plans for radiation incidents.

Iron is a potent catalyst of oxidative stress and cellular proliferation implicated in renal cell carcinoma (RCC) tumorigenesis, yet it also drives ferroptosis that suppresses cancer progression and represents a novel therapeutic target for advanced RCC. The von Hippel Lindau (VHL)/hypoxia-inducible factor-α (HIF-α) axis is a major regulator of cellular iron, and its inactivation underlying most clear cell (cc) RCC tumors introduces both iron dependency and ferroptosis susceptibility. Despite the central role for iron in VHL/HIF-α signaling and ferroptosis, RCC iron levels and their dynamics during RCC initiation/progression are poorly defined. Here, we conducted a large-scale investigation into the incidence and prognostic significance of total tissue iron in ccRCC and non-ccRCC patient primary tumor cancer cells, tumor microenvironment (TME), metastases and non-neoplastic kidneys. Prussian Blue staining was performed to detect non-heme iron accumulation in over 1600 needle-core sections across multiple tissue microarrays. We found that RCC had significantly higher iron staining scores compared with other solid cancers and, on average, >40 times higher than adjacent renal epithelium. RCC cell iron levels correlated positively with TME iron levels and inversely with RCC levels of the main iron uptake protein, transferrin receptor 1 (TfR1/TFRC/CD71). Intriguingly, RCC iron levels, including in the TME, decreased significantly with pathologic (size/stage/grade) progression, sarcomatoid dedifferentiation, and metastasis, particularly among patients with ccRCC, despite increasing TfR1 levels, consistent with an increasingly iron-deficient tumor state. Opposite to tumor iron changes, adjacent renal epithelial iron increased significantly with RCC/ccRCC progression, sarcomatoid dedifferentiation, and metastasis. Lower tumor iron and higher renal epithelial iron each predicted significantly shorter ccRCC patient metastasis-free survival. In conclusion, iron accumulation typifies RCC tumors but declines toward a relative iron-deficient tumor state during progression to metastasis, despite precisely opposite dynamics in adjacent renal epithelium. These findings raise questions regarding the historically presumed selective advantage for high iron during all phases of cancer evolution, suggesting instead distinct tissue-specific roles during RCC carcinogenesis and early tumorigenesis versus later progression. Future study is warranted to determine how the relative iron deficiency of advanced RCC contributes to ferroptosis resistance and/or introduces a heightened susceptibility to iron deprivation that might be therapeutically exploitable.

BackgroundCIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC.MethodsPatients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a “3+3” dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF.FindingsThe combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPRmt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPRmt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPRmt inhibitor that blocked HSP60’s interaction with ClpP and abrogated survival signaling without altering HSP60’s chaperonin function. Disruption of HSP60-ClpP interaction with the UPRmt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPRmt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP–mediated UPRmt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.

Abstract Aberrancies in the tumor microvasculature limit the systemic delivery of anticancer agents, which impedes tumor response. Using human intravital microscopy (HIVM), we hypothesized that HIVM would be feasible in patients with peritoneal carcinomatosis (PC). During cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for PC, HIVM was performed in both tumor and non-tumor areas. The primary outcome was HIVM feasibility to measure vessel characteristics. We secondarily evaluated associations between HIVM vessel characteristics and oncologic outcomes (RECIST response to neoadjuvant therapy and disease-specific survival). Thirty patients with PC were enrolled. Nineteen patients (63.3%) received neoadjuvant therapy. HIVM was feasible in all patients. Compared to non-tumor (control) areas, PC areas had a lower density of functional vessels, higher proportion of non-functional vessels, smaller lumenal diameters, and lower blood flow velocity. Qualitative differences in these vessel characteristics were observed among patients who had partial response, stable disease, or progressive disease after receiving neoadjuvant therapy. However, no statistically significant relationships were found between HIVM vessel characteristics and oncologic outcomes. These novel findings comprise the first-in-human, real-time evidence of the microscopic differences between normal and tumor-associated vessels and form the basis for our larger, ongoing clinical trial appropriately powered to determine the clinical utility of HIVM (NCT03823144).

There is an urgent need to discover blood-based biomarkers to predict response to immune checkpoint inhibitors (ICI). Here the authors show that effective ICI therapy correlates with increased frequency of circulating CX3CR1+CD8+ T cells in preclinical tumor models and in a cohort of patients with non-small cell lung cancer treated with anti-PD-1.

Introduction: Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide and carries a poor prognosis. Historically, sorafenib was the only available systemic treatment for advanced HCC. However, in recent years, 6 new treatments have been approved by the US Food and Drug Administration (FDA): regorafenib, lenvatinib, cabozantinib, pembrolizumab, ramucirumab, and nivolumab. Data are lacking regarding the most appropriate sequencing pathway for these agents. Our objective was to conduct a comprehensive cost effectiveness analysis (CEA) of different 1st- and 2nd-line treatment pathways for HCC reflecting all new drug approvals, and then use our data to provide guidance for clinicians on which pathway is the most cost-effective. Materials and Methods: Markov models were used to evaluate the cost effectiveness of 8 different 1st- and 2nd-line treatment sequences. The model allowed for 9 possible states. Cost effectiveness ratios (CER) and incremental CER (ICER) were calculated to compare costs between different pathways and against a willingness-to-pay (WTP) threshold. Efficacy and toxicity data were extracted from the landmark trials for each agent. All agents except ramucirumab were included. The cost of each agent was based on the wholesale acquisition cost (WAC) in USD as of June 2019. Monte-Carlo methods were used to simulate the experience of 1,000,000 patients per treatment sequence for a 12-month period. Results: The pathway with the lowest CER was sorafenib, followed by pembrolizumab (USD 227,741.03/quality-adjusted life year [QALY]). ICER analysis supported implementing 2nd-line pembrolizumab-based pathways at a higher WTP threshold of 300,000/quality-adjusted life year. Sensitivity analysis did not substantially change these results. Conclusions: The most cost-effective strategy was 1st-line tyrosine kinase inhibitor therapy followed by 2nd-line immunotherapy. All pathways exceeded a commonly accepted WTP of USD 100–150,000/QALY. Our preliminary results warrant further studies to best inform real-world practices.

Abstract Background African American/Black women with breast cancer have poorer survival than White women, and this disparity persists even after adjusting for non-biological factors. Differences in tumor immune biology have been reported between Black and White women, and the tumor immune milieu could potentially drive racial differences in breast cancer etiology and outcome. Methods We examined the association of CD8+ cytotoxic T cells with clinical-pathological variables in the Women’s Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We evaluated 688 invasive breast tumor samples (550 Black, 138 White) using immunohistochemical staining of tissue microarray slides. CD8+ T cells were scored for each patient tumor sample with digital image analysis. Results Black women had a significantly higher percentage of high-grade, estrogen receptor (ER)-negative, and triple-negative tumors than White women and significantly higher CD8+ T cell density (median 87.6/mm2 vs. 53.1/mm2; p

Prostate cancer cells depend on MTAP, the rate-limiting enzyme involved in the methionine salvage pathway, to cope with increased polyamine biosynthesis. Here, the authors show that inducing upregulation of polyamine biosynthesis and targeting MTAP synergize to increase apoptosis in prostate cancer cells.

Dihydrotestosterone (DHT) and testosterone (T), which mediate androgen receptor nuclear translocation and target gene transcription, are crucial androgens and essential molecular triggers required for the proliferation and survival of prostate cancer cells. Therefore, androgen metabolism is commonly targeted in the treatment of prostate cancer. Using a high-pressure liquid chromatographic assay with tandem mass spectral detection, we determined the serum levels of metabolites produced during DHT/T biosynthesis in African American (AA) and European American (EA) men with localized, therapy naïve prostate cancer. Serum progesterone and related metabolites were significantly lower in AA men than in EA men, and these differences were associated with rapid disease progression. Multivariate analysis revealed significant differences between a subset of intermediate androgen metabolites between AA and EA men and between men with =4 + 3 Gleason score disease. AA men have a significantly higher frequency of single nucleotide polymorphisms in CYP11B1 and CYP11B2, enzymes that regulate corticosterone-aldosterone conversion. Finally, higher levels of T and pregnenolone were associated with a lower risk of progression-free survival only in AA men. This work provides new insight into androgen metabolism and racial disparities in prostate cancer by presenting evidence of dysregulated androgen biosynthesis in therapy naïve disease that correlates with clinical variables.

Importance: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for gastroesophageal cancers (GEC). It is important to investigate the factors that influence the response to anti-PD-1/PD-L1 ICIs. Objective: To assess the benefits of PD-1/PD-L1 ICIs in advanced GEC and perform subgroup analysis to identify patient populations who would benefit from ICI. Data sources: PubMed, Embase, Scopus, and the Cochrane Library databases were systematically searched from database inception to September 2021 for all relevant articles. We also reviewed abstracts and presentations from all major conference proceedings including relevant meetings of the American Society of Clinical Oncology (ASCO), and the European Society for Medical Oncology (ESMO) during the last four years (2018 to 2021) and reviewed citation lists. Study selection, data extraction, and synthesis: Full articles and presentations were further assessed if the information suggested that the study was a phase 2/3 randomized controlled trial (RCT) comparing PD-1/PD-L1 inhibitor either alone, or in combination with standard therapy vs. standard therapy in advanced GEC. The full text of the resulting studies/presentations and extracted data were reviewed independently according to PRISMA guidelines. Main outcomes and measures: The main outcomes were OS, PFS, and treatment-related adverse events (TRAEs). Results: A total of 168 studies were assessed for eligibility, and 17 RCTs with 12,312 patients met the inclusion criteria. There was an OS benefit in the overall population with ICIs (HR 0.78; 95% CI 0.73–0.83 p < 0.001). Immunotherapy showed better OS benefit in males (HR 0.77 95% CI 0.72–0.83; p < 0.001) than females (HR 0.89; 95% CI 0.80–0.99 p < 0.03), esophageal primary tumors (HR 0.70 95% CI 0.64–0.76 p < 0.001) vs. gastric cancer (HR 0.84 95% CI 0.74–0.94 p 0.002) or GEJ cancer (HR 0.84 95% CI 0.72–0.98 p 0.024) and in squamous cell carcinoma (HR 0.71 95% CI 0.66–0.77 p < 0.001) vs. adenocarcinoma (HR 0.85 95% CI 0.78–0.93 p < 0.001). PD-L1 positive patients seemed to benefit more (HR 0.74 95% CI 0.67–0.82 p < 0.001) compared to PD-L1 negative patients (HR 0.86 95% CI 0.74–1.00 p < 0.043), and Asians showed OS benefit (HR 0.76 95% CI 0.67–0.87 p < 0.001) compared to their White counterparts (HR 0.92 95% CI 0.74–1.14; p 0.424). Conclusions and relevance: ICIs improve survival in advanced GEC without significantly increasing the side effects. However, certain subgroups of patients such as males, Asians, and those with esophageal primary, PD-L1 positive tumors and squamous cell carcinoma benefit more from such treatments. Further translational research is needed to understand the mechanistic links and develop new biomarkers.

Abstract Background Vitamin D3 (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer (BCa). In addition to cystectomy, patients are treated with cisplatin‐based chemotherapy, however 30%‐50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown. Methods To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D3 (1,25D3). Lastly, using BCa cell lines, T24 and RT‐112, the mechanism of action of 1,25D3 and cisplatin combination treatment was determined by apoptosis assays, as well as western blot and RT‐PCR. Results In this study, we determined that low serum 25 hydroxyvitamin D3 (25D3) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D3, reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D3 pretreatment increased the apoptotic response to cisplatin. 1,25D3 pretreatment increased expression of TAp73 and its pro‐apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D3 treatment and further increased after the combination of 1,25D3 and cisplatin in a TAp73 dependent manner. Conclusions Our data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TAp73 signaling crosstalk.

The anticancer activity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol) has been widely reported in preclinical models. However, systematic investigation into the chemopreventive potential of calcitriol against the spectrum of oral carcinogenesis has not been performed. To address this gap in knowledge, we conducted a preclinical prevention trial of calcitriol in the 4-nitroquinoline-1-oxide (4NQO) oral carcinogenesis model. C57BL/6 mice were exposed to the carcinogen 4NQO in drinking water for 16 weeks and randomized to control (4NQO only) or calcitriol arms. Calcitriol (0.1 μg i.p, Monday, Wednesday, and Friday) was administered for (i) 16 weeks concurrently with 4NQO exposure, (ii) 10 weeks post completion of 4NQO exposure, and, (iii) a period of 26 weeks concurrent with and following 4NQO exposure. Longitudinal magnetic resonance imaging (MRI) was performed to monitor disease progression until end point (week 26). Correlative histopathology of tongue sections was performed to determine incidence and multiplicity of oral dysplastic lesions and squamous cell carcinomas (SCC). Vitamin D metabolites and calcium were measured in the serum using liquid chromatography-mass spectrometry (LC–MS/MS) and colorimetric assay, respectively. Renal CYP24A1 (24-hydroxylase) and CYP27B1 (1α-hydroxylase) expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunostaining of tongue sections for vitamin D receptor (VDR), CYP24A1, and Ki67 was also performed. Non-invasive MRI enabled longitudinal assessment of lesions in the oral cavity. Calcitriol administered concurrently with 4NQO for 16 weeks significantly (P

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both CYP3A5 or ABCB1. Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both CYP3A5 and ABCB1. A metabolic composite based upon the CYP3A5 polymorphisms: ∗3(rs776746), ∗6(10264272), and ∗7(41303343), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of ABCB1 on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: 1236C > T (rs1128503), 2677G > T/A(rs2032582), and 3435C > T(rs1045642). Finally, a combined analysis using both CYP3A5 and ABCB1 polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three CYP3A5 loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance (P < 0.001) with 50% lower AUC∗ (P < 0.001) than Poor metabolizers. No differences in C12 h were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The ABCB1 haplotype analysis detected significant associations of the wildtype 1236T-2677T-3435T haplotype to tacrolimus dose (P = 0.03), CL (P = 0.023), CL/LBW (P = 0.022), and AUC∗ (P = 0.078). Finally, analysis combining CYP3A5 and ABCB1 genotypes indicated that the presence of the ABCB1 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite CYP3A5∗3∗4∗5 and ABCB1 haplotypes. Consideration of multiple alleles using CYP3A5 metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.

Background: Despite the approval of mTOR inhibitor everolimus and CDK4/6 inhibitors in the management of hormone-receptor-positive HER2 non-amplified metastatic breast cancer (HR+ HER2-MBC), the optimal sequence of therapy is unclear. There are no clinical data on efficacy of everolimus in HR+ HER2-MBC after cancer progresses on CDK4/6 inhibitors. Objective: The objective of this study is to find the efficacy of everolimus in HR+ HER2-MBC after they progress on a CDK4/6 inhibitor palbociclib. Methods: This is a retrospective, 2-institute review of HR+ HER2-MBC from Jan 2015 to March 2018 treated with everolimus after progression on palbociclib. Primary end point was median progression-free survival (PFS), secondary end points objective response rate (ORR), clinical benefit ratio (CBR), and overall survival (OS). Results: Out of 41 women with median age 61 years (33, 87) enrolled, 66% had received adjuvant systemic therapy, 61% had visceral disease, and 95% had prior nonsteroidal aromatase inhibitors. About 83% women had 3 or more chemotherapy or hormonal therapies prior to everolimus. Kaplan-Meier estimates showed a median PFS of 4.2 months (95% confidence interval [CI]: 3.2-6.2). The median OS was 18.7 months (95% CI 9.5 to not reached). Objective response rate and CBR were both 17.1%. Conclusion: Everolimus was associated with modest PFS and ORR in HR+ HER2-MBCs postprogression on palbociclib.

Abstract Background Standard therapy for stage III non-small cell lung cancer with chemotherapy and conventional radiation has suboptimal outcomes. We hypothesized that a combination of surgery followed by stereotactic body radiation therapy (SBRT) would be a safe alternative. Methods Patients with stage IIIA (multistation N2) or IIIB non-small cell lung cancer were enrolled from March 2013 to December 2015. The protocol included transcervical extended mediastinal lymphadenectomy (TEMLA) followed by surgical resection, 10 Gy SBRT directed to the involved mediastinum/hilar stations and/or positive surgical margins, and adjuvant systemic therapy. Patients not suitable for anatomic lung resection were treated with 30 Gy to the primary tumor. The primary efficacy end-point was the proportion of patients with grade 3 or higher adverse events (AE) or toxicities. Results Of 10 patients, 7 patients underwent neoadjuvant chemotherapy. All patients had TEMLA. Nine of 10 patients underwent surgical resection. The remaining patient had an unresectable tumor and received 30 Gy SBRT to the primary lesion. All patients had post-operative SBRT. Median follow-up was 18 months. There were no perioperative mortalities. Six patients had any grade 3 AEs with no grade 4–5 AEs. Of these, 4 were not attributable to radiation. Pulmonary-related grade 3 AEs were experienced by 2 patients. There were no failures within the 10 Gy volume. Overall survival and progression-free survival rates at 2 years were 68% (90% CI 36–86) and 40% (90% CI 16–63), respectively. Conclusions In carefully selected patients with locally advanced non-small cell lung cancer, combining surgery with SBRT was well tolerated with no local failure. Trial registration ClinicalTrials.gov identifying number NCT01781741. Registered February 1, 2013.

Bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare chronic autoimmune disorders characterized by subepidermal blistering. For the United States, there is a limited amount of studies in BP and MMP that address disease demographics and clinical data. In order to more comprehensively examine disease demographics and clinical factors, we performed a retrospective analysis of patient-reported data of 138 BP and 165 MMP patients enrolled in the International Pemphigus & Pemphigoid Foundation (IPPF) disease registry from 2010–2016. Patient-reported data was compared to Physician/Investigator reported data generated in our own local patient population (Western New York; 19 BP and 43 MMP patients). We confirm a female predominance in BP (M:F ratio 1:2.1) and MMP (M:F ratio 1:4.3), and a late onset within the 6th decade of life (average age at diagnosis, 59.1 ± 17.5 years for BP and 54.8 ± 11.2 years for MMP). MMP patients were significantly more likely to have a delay in diagnosis >12 months than BP patients (38 vs. 21%, respectively). Similar to other autoimmune conditions, a large number of BP (34%) and MMP (35%) patients present with other co-existing autoimmune disorders, with the most common being thyroid disease for both groups. Increased illness activity was paralleled by an increase in severe limitations of daily activities. The vast majority of of both BP and MMP patients received high intensity immunosuppression (49%). However, the majority of BP patients reported therapy with prednisone combined with other immunosuppressants (40%), while the majority of MMP patients received immunosuppressants other than prednisone (55%). With the exception of age at diagnosis, the clinical and demographic findings from both the national and local datasets were largely consistent with each other, and support those reported in other countries.

Introduction: Renal cell carcinoma (RCC) with sarcomatoid component carries a poor prognosis. Immune checkpoint inhibitors (CPIs) have been approved for the treatment of metastatic RCC, but their efficacy in patients with sarcomatoid component is not known. Materials and Methods: We conducted a retrospective chart review of 30 consecutive patients at our center who were treated for metastatic RCC with sarcomatoid component. Results: Ten patients were treated with CPI group while 20 patients were in No-CPI group. There were no significant differences in age, sex, race, and stage at diagnosis between the two groups. After a median follow-up of 35 months, 3 of 10 patients in CPI arm and 5 of 20 patients in No-CPI group were alive. The median overall survival was 33.8 m in immunotherapy group compared to 8.8 m in nonimmunotherapy group (p = .001). Discussion: In our experience, CPI therapy resulted in better outcomes compared to traditional therapy with molecular-targeted agents or chemotherapy in these patients.

Summary: VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies (“senotherapeutics”)—particularly those that block SASP regulation—may improve outcomes in patients after VEGFR TKI failure. : Mastri et al. show that resistance to antiangiogenic therapy can induce senescence-mimicking secretory phenotypes that contribute to tumor promotion when treatment is stopped. Therapeutic targeting of senescence secretory regulators such as IL-6 and mTOR could improve outcomes after treatment failure. Keywords: antiangiogenic therapy, secretome, senescence, SASP, IL-6, mTOR, VEGF RTKI, resistance, metastasis, rebound