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Quantitative CD8+ Counts in patients with Liver and skin metastases.

Univariate Analysis of Pretreatment prognostic factors in the Discovery cohort.

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Supplemental Figure 1. Schematic presentation of the analyzed parameters in the correlative cohort per progression survival (PFS). TMB: total mutational burden. PR: partial response. SD: stable disease. PD: progressive disease. â-³: mutation. Supplemental Figure 2. Progression Free Survival (PFS) and subgroup survival analysis of the correlative cohort (N=38) by Log-rank (Mantel-Cox) test. PFS By PD-L1 categories ( 0-49% n=23 vs 50-100% n=9, p75th percentile n=6, p=0.142) PFS By CD8 categories (0-5% n=18 vs 6-25% n=14, p=0.037) PFS By CD4 categories (0-5% n=21 vs 6-25% n=9 vs >25% n=2, p=0.123) Supplemental Figure 3. Association among the four correlative parameters. Supplemental Table 1. Association of the four correlative parameters and with other clinical characteristics. Supplemental Table 2. Correlation of patient characteristics and ORR per irRC (PR vs SD/PD). Supplemental Table 3. Patient characteristics (as categorical variables) in the correlative cohort per prior lines of therapy. Supplemental Table 4. PFS and OS of correlative characteristics (as categorical variables) by year. Supplemental Table 5. Characteristics as continuous variables of long term benefiters (Overall survival > 3 years with no intervening therapies) vs all other patients in the correlative cohort.

Purpose:Several biomarkers have been individually associated with response to PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non–small cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the relationship between these distinct variables with response to PD-1 blockade and long-term benefit.Experimental Design:We assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4, and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of 4.5 years, range 3.8–5.5 years).Results:PD-L1 expression and CD8 infiltration correlated with each other and each significantly associated with objective response rate (ORR) and progression-free survival (PFS). TMB was independent of PD-L1 and CD8 expression, and trended towards association with ORR and PFS. There was no association between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with overall survival (OS). Among 5 patients with long-term survival >3 years with no additional systemic therapy, PD-L1 expression was the only discriminating feature. The increased predictive value for PFS and OS of composite biomarker inclusive of PD-L1, CD8, CD4, and TMB was limited.Conclusions:In patients with NSCLC treated with PD-1 blockade with long-term follow up, TMB, PD-L1, and CD8 were each associated with benefit from PD-1 blockade. Pretreatment PD-L1 expression was correlated with T lymphocyte infiltration and OS, whereas models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.

Increased utilization of glucose is a hallmark of cancer. Several studies are investigating the efficacy of glucose restriction by glucose transporter blockade or glycolysis inhibition. However, the adaptations of cancer cells to glucose restriction are unknown. Here, we report the discovery that glucose restriction in lung adenocarcinoma (LUAD) induces cancer cell de-differentiation, leading to a more aggressive phenotype. Glucose deprivation causes a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. We further show that this de-differentiated phenotype depends on unbalanced EZH2 activity, causing inhibition of prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1α (HIF1α), triggering epithelial to mesenchymal transition. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying novel targets to prevent the development of resistance to therapies targeting glucose metabolism.

PURPOSE We hypothesized that depressive symptoms and health-related quality of life (HRQOL) reported by patients before their cancer diagnoses would be associated with treatment choice for stage II and III rectal cancer, specifically whether patients underwent surgery. METHODS The Surveillance, Epidemiology, and End Results and Medicare Health Outcomes Survey linked data set was used to identify patients with stage II-III rectal adenocarcinoma diagnosed between 2004 and 2013 who had completed the health outcomes survey within 36 months before their cancer diagnoses. Risk for major depressive disorder (MDD) was determined on the basis of responses to screening questions for depressive disorders. HRQOL was assessed using the Mental Component Summary and Physical Component Summary of the 36-Item Short Form Survey and Veterans RAND 12-Item Health Survey. Using univariable and multivariable analyses, we assessed for associations between health survey responses and ultimate treatment modality. RESULTS We identified 142 evaluable patients, of whom 109 (76.8%) underwent surgery. Thirty patients (21.1%) met criteria for being at risk for MDD before their cancer diagnoses. Patients at risk for MDD underwent surgery less often than those not at risk ( P = .0499), and this association strengthened after adjusting for patient characteristics (odds ratio, 0.17; 95% CI, 0.04 to 0.82; P = .027). There was a nonsignificant trend between higher Mental Component Summary scores (indicating higher self-reported mental HRQOL) and increased frequency of undergoing surgery ( P = .081). There were no significant associations between the Physical Component Summary and treatment modality. CONCLUSION In Medicare beneficiaries with stage II-III rectal cancer, those at risk for MDD underwent standard-of-care treatment with surgery less frequently. Further studies are warranted to assess the effect of mental health on clinical decision making in this patient population.

Our objective was to develop version 1.0 of a novel framework for response evaluation criteria in prostate-specific membrane antigen (PSMA) PET/CT (RECIP) and a composite response classification that combines responses by prostate-specific antigen (PSA) measurements and by RECIP 1.0 (PSA + RECIP). Methods: This was an international multicenter, retrospective study. One hundred twenty-four men with metastatic castration-specific prostate cancer (mCRPC) who underwent 177Lu-PSMA therapy and received PSMA PET/CT at baseline and at an interim time point of 12 wk were included. Pairs of baseline interim PET/CT scans were interpreted by consensus among 3 masked readers for appearance of new lesions. Tumor lesions were segmented, and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which included classifications of complete response (RECIP-CR: absence of any PSMA-ligand uptake on interim PET/CT), partial response (RECIP-PR: decline ≥ 30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥ 20% in PSMA-VOL and appearance of new lesions), and stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 wk by Prostate Cancer Working Group Criteria 3 were recorded. PSA + RECIP results were defined as response (PSA decline ≥ 50% or RECIP-PR/CR) or progression (PSA increase ≥ 25% or RECIP-PD). The study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). The secondary outcome measure was the prognostic accuracy (C-index) of PSA + RECIP versus PSA responses. Results: Patients with RECIP-PD (n = 39; 8.3 mo) had a shorter OS than patients with stable disease (RECIP-SD) (n = 47; 13.1 mo; P < 0.001) or RECIP-PR (n = 38; 21.7 mo; P < 0.001). In identifying responders and progressors, PSA + RECIP had C-indices superior to those of PSA only: 0.65 versus 0.62 (P = 0.028) and 0.66 versus 0.63 (P = 0.044), respectively. Conclusion: PSMA PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor early efficacy of 177Lu-PSMA in men with mCRPC. PSA + RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.

Background and objectives: Previous studies evaluating patients in the Intensive Care Unit with established lactic acidosis determined that the anion gap is an insensitive screening tool for elevated blood lactate. No prior study has examined the relationship between anion gap and serum lactate within the first hours of the development of lactic acidosis. Design, setting, participants, & measurements: Data were obtained prospectively from a convenience sample of adult trauma patients at a single level 1 trauma center. Venous samples were drawn prior to initiation of intravenous fluid resuscitation. A linear regression model was constructed to assess the relationship between serum lactate and anion gap, and 95% prediction intervals were computed. Logistic regression models were constructed to determine the sensitivity and specificity for several different anion gap and lactate cutpoints. Results: 128 patients with elevated serum lactate levels (>2.1 mmol/L) and 63 patients with normal serum lactate levels (< 2.1 mmol/L) were included. The sensitivity of an elevated anion gap (> 10) to reveal hyperlactatemia was only 43% whereas specificity was 84%. Sensitivity improved if the upper limit of normal anion gap was lowered and with increasing levels of serum lactate. The coefficient of determination between serum lactate level and AG yielded an R2 of 0.30 (p < 0.001) and the slope of this relationship was 2.185 with a 95% confidence interval of 2.011–2.359. The mean 95% prediction interval was + 8.9. Conclusions: Within the first hour of the development of lactic acidosis due to hypovolemic shock, the anion gap was not a sensitive indicator of an elevated serum lactate level, but it was fairly specific. The anion gap increased to a greater extent than the serum lactate, the 95% mean prediction interval was wide and approximately 70% of the change in anion gap could not be explained by increases in serum lactate, suggesting that other anions contribute to the anion gap in lactic acidosis.

To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism.A double-blind, placebo-controlled randomized clinical trial.An academic medical center.Twelve normal-weight women with PCOS and 12 age- and body mass index-matched controls.Women underwent circulating hormonal and metabolic determinations, intravenous glucose tolerance testing, total body dual-energy roentgenogram absorptiometry, and SC abdominal fat biopsy. Interventions were repeated in women with PCOS after 6-month administration of flutamide (125 mg orally daily) vs. placebo.Clinical parameters and lipid accumulation in newly formed adipocytes derived from SC abdominal ASCs in vitro were compared between controls and the women with PCOS receiving flutamide vs. placebo.Serum luteinizing hormone and androgen levels as well as lipid accumulation in newly formed SC abdominal adipocytes were greater in the women with PCOS than controls. Flutamide vs. placebo reduced percent android fat, lowered serum log low-density lipoprotein and log non-high-density lipoprotein levels, and increased fasting circulating glucose levels. In all women with PCOS, changes in percent android fat positively correlated with serum log non-high-density lipoprotein and log low-density lipoprotein levels, with correlations influenced by serum free testosterone levels. Flutamide vs. placebo also attenuated lipid accumulation in newly-formed PCOS SC abdominal adipocytes in vitro relative to controls, which was unrelated to serum lipid levels.Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated lipid accumulation in newly-formed adipocytes derived from SC abdominal ASCs in vitro, and alters glucose-lipid homeostasis.NCT01889199 (URL, clinicaltrials.gov; date of registration, 6/28/2013; enrollment date of first subject, 6/28/2013).

Immune check point blockade (ICB) has recently transformed the treatment of non-small cell lung (NSCLC). However, the majority of patients do not respond to ICB. For ICB to be effective, tumor neoantigens need to be presented in a human leukocyte antigen (HLA) class I-restricted manner. Recent studies by our group and others have shown that HLA-B44 supertype is associated with extended survival in patients treated with ICB. Herein, we hypothesize that HLA-B44-specific motif neoepitopes generate an active tumor immune microenvironment and a favorable ICB response in NSCLC. Utilizing the TCGA database, we found that nearly half of the NSCLC patients have at least one HLA-B44 allele, of whom 36.8% and 37.3% of patients harbor at least one B44 motif neoepitope in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC), respectively. In a pooled analysis of patients with LUAD and LUSC, gene expression of PD-L1, CTLA-4, LAG-3, CXCL9, CXCL10, CXCL13, CD8A and cytolytic gene signature (includes GZMA and PRF1) is elevated in patients with B44 motif neoepitopes compared to those without motif neoepitopes. Immune cell component analysis showed increased infiltration of Th1, Th2 and CD8 T cells in LUAD and regulatory and CD8 T cells in LUSC. Although a linear regression model revealed a positive correlation between tumor mutational burden (TMB) and number of B44 motif neoepitopes, pooled analysis of LUAD and LUSC with similar TMB showed significant elevation of CTLA-4, LAG3, CXCL10 and a trend of increased expression of CXCL9 in motif patients. Upon investigation of possible immune editing, we found a significantly higher proportion of genes containing B44 neoepitope downregulated at the RNA level both in LUAD and LUSC. Lastly, we showed that combining B44 motif with either PD-L1 or TMB improved prediction of progression-free survival in NSCLC patients treated with ICB. In summary, we demonstrate that HLA-B44 motif neoepitopes are associated with a favorable tumor immune microenvironment and can serve as a potential biomarker for ICB benefit in NSCLC patients. Citation Format: Rui Li, Charlene M. Fares, Tristan R. Grogan, Tianhao Zhang, Debory Li, Matthew Theisen, Maria A. Velez, Paige M. Brodrick, Jackson P. Lind-Lebuffe, Yazeed Radwan, Gregory A. Ayzenberg, David Elashoff, Bin Liu, Aaron E. Lisberg, Amy L. Cumming, Edward B. Garon. HLA-B44 motif neoepitope is associated with a favorable tumor immune microenvironment and predicts ICB response in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4340.

Fibroblast activation protein (FAP)-expressing cancer-associated fibroblasts confer treatment resistance and promote metastasis and immunosuppression. Because FAP is overexpressed in many cancers, radiolabeled molecules targeting FAP are studied for their use as pancancer theranostic agents. This study aimed to establish the spectrum of FAP expression across various cancers by immunohistochemistry and to explore whether

Anesthesiologists are at high risk for needlestick injury. Such injuries pose a serious health threat from exposure to bloodborne pathogens. This retrospective analysis aimed to examine needlestick injury rate among anesthesia providers between 2010 and 2020 at the University of California Los Angeles, Department of Anesthesiology and Perioperative Medicine to determine specialty-specific factors associated with these injuries.Retrospective analysis.Academic Anesthesiology Department.None.All reported incidents of needlestick injuries to employees are sent to the Injury and Illness Prevention Committee. We included all anesthesia residents, fellows, nurse anesthetists, solo anesthesiologists, and supervising anesthesiologists.The overall rate of reported needlestick injuries was 5.3%. The rates for anesthesia residents were 2.1%, 13.5%, 7.9%, and 6.7% for post graduate year 1-4 (PGY 1-4) residents. The rates were 14.3%, 4.7%, 2.1%, and 6.9% for fellows, nurse anesthetists, supervising anesthesiologists, and solo anesthesiologists, respectively. We found that PGY2 residents had a higher injury rate than PGY1 residents (p-value0.001). When grouping PGY2, PGY3, and PGY4 residents together, they had a collective rate of 9.4%. Furthermore, residents had a higher needlestick injury rate than supervising anesthesiologists (p-value0.001).PGY2 residents and fellows had the highest rate of needlestick injury. Our study highlights the trend of increasing sharps injuries after PGY1 while supervising anesthesiologists had the lowest rate. Proposed mechanisms for the increased sharps injuries include residents' transition from medicine-based internship to the operating room environment with increased exposure to potentially injurious equipment, overnight call, and increased work-related and cognitive stress. Improving understanding of institution-specific prevention programs, raising awareness during their initial high-intensity training period with one-to-one supervision when habits are formed, and reducing exposure to sharps using a needleless system are some steps toward reducing the incidence of sharps injuries in a field where the risk remains high.

Despite a renewed focus in recent years on pain management in the inpatient hospital setting, postoperative pain after elective craniotomy remains under investigated. This study aims to identify which perioperative factors associate most strongly with postoperative pain and opioid medication requirements after inpatient craniotomy.Using an existing dataset, we selected a restricted cohort of patients who underwent elective craniotomy surgery requiring an inpatient postoperative stay during a 7-year period at our institution (n=1832). We examined pain scores and opioid medication usage and analyzed the relative contribution of specific perioperative risk factors to postoperative pain and opioid medication intake (morphine milligram equivalents).Postoperative pain was found to be highest on postoperative day 1 and decreased thereafter (up to day 5). Factors associated with greater postoperative opioid medication requirement were preoperative opioid medication use, duration of anesthesia, degree of pain in the preoperative setting, and patient age. Notably, the most significant factor associated with a higher postoperative pain score and Morphine milligram equivalents requirement was the time elapsed between the end of general anesthesia and a patient's first intravenous opioid medication.Postcraniotomy patients are at higher risk for requiring opioid pain medications if they have a history of preoperative opioid use, are of younger age, or undergo a longer surgery. Moreover, early requirement of intravenous opioid medications in the postoperative period should alert treating physicians that a patient's pain may require additional or alternative methods of pain control than routinely administered, to avoid over-reliance on opioid medications.

Lutetium-177 (In this multicentre, retrospective study, we screened patients with mCRPC who had receivedBetween April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [These externally validated nomograms that are predictive of outcomes afterProstate Cancer Foundation.

Quality of life (QOL) in hidradenitis suppurativa (HS) patients is negatively impacted by physical and psychosocial problems. The aim of this study was to investigate the frequency and severity of HS-specific symptoms and to correlate these with disease severity. Methods We analyzed medical record data from 145 patients seen in an academic HS specialty clinic between August 2009 to March 2018. Results Hurley stage III patients had significantly higher mean Dermatology Life Quality Index (DLQI) scores (20.2) compared to patients with Hurley stage I (11.3) and II (13.9), (Plt;0.001 and P=0.001, respectively). More than 75% of patients reported physical symptoms of drainage, irritation, pain, itching, bleeding, and odor. There were associated psychosocial problems of embarrassment and self-consciousness. Symptom severity was most strongly correlated with disease severity for odor (correlation coefficient 0.4, Plt;0.001), difficulty moving arms (0.323, Plt;0.001), negative impact on job/school (0.303, Plt;0.001), and negative impact on relationships (0.298, Plt;0.001). Conclusion Our results highlight the significant burden of HS and the need for a more comprehensive, HS-specific evaluation tool to better assess the QOL of this patient population. Limitations A small cohort in a single academic center.

Our purpose was to determine the relationship between serum prostate-specific antigen (PSA) level categories (20 ng/mL) and the incidence of bone metastases detected by total-body (68)Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT and to assess if expanding the (68)Ga-PSMA-11 PET/CT imaging field to include the vertex and lower extremities (total-body acquisition) affects bone metastasis detection rates and patient management. Methods: This was a retrospective analysis of 388 prostate cancer patients enrolled in 5 prospective studies (NCT02940262, NCT03368547, NCT03042312, NCT04050215, and NCT03515577). All underwent (68)Ga-PSMA-11 PET/CT scans acquired from vertex to toes for primary staging (n = 93/388, 24%), biochemical recurrence (BCR) localization (n = 225/388, 58%), or restaging metastatic disease (M1) before or during systemic therapy (n = 70/388, 18%) between September 2017 and May 2018. Results: In total, 321 of 388 patients (83%) had a positive (68)Ga-PSMA-11 study. PSMA-positive bone lesions were found in 105 of 388 (27%) patients, with an incidence that was positively associated with serum PSA level (

OBJECTIVES: To explore whether differences exist in the clinical and radiographic presentation of oncologic vs osteoporotic patients with medication-related osteonecrosis of the jaw (MRONJ). METHODS: We retrospectively assessed panoramic radiographs and CBCT examinations of 70 MRONJ patients receiving antiresorptive medications for the management of either osteoporosis or bone malignancy. Radiographic features of MRONJ were documented and categorized according to severity. A composite radiographic index (CRI) was constructed to account for the heterogeneity in radiographic manifestations of MRONJ and further stratify extent of osseous changes. RESULTS: Patients with osteoporosis were mostly older females and presented more frequently with Stage 2 MRONJ, while patients with malignancy were equally distributed between males and females, and presented mostly with Stage 1 MRONJ. Most MRONJ lesions in oncologic patients occurred in the mandible, whereas the maxilla and mandible were equally affected in osteoporotic patients. Patients with minimal radiographic changes (low CRI score) often presented with MRONJ in dentate areas, while most patients in medium and high CRI groups presented with MRONJ after recent tooth extraction. The low CRI group consisted of primarily oncologic patients, while osteoporotic vs oncologic patients were divided more evenly in the other CRI groups (p = 0.083). While CRI scores increased with clinical staging, a Spearman’s rank correlation coefficient of 0.49 suggests that clinical appearance does not reliably predict osseous changes. CONCLUSIONS: Our data identify differences in the MRONJ appearance of patients with osteoporosis vs malignancy and emphasize the significance of detailed radiographic assessment, in addition to the clinical appearance, in characterizing the osseous changes of the disease.

Background/Purpose Gastroschisis is a resource-intensive birth defect without consensus regarding optimal surgical and medical management. We sought to determine best-practice guidelines by examining differences in multi-institutional practices and outcomes. Methods Site-specific practice patterns were queried, and infant–maternal chart review was retrospectively performed for gastroschisis infants treated at 5 UCfC institutions (2007–2012). The primary outcome was length of stay. Univariate analysis was done to assess variation practices and outcomes by site. Multivariate models were constructed with site as an instrumental variable and with sites grouped by silo practice pattern adjusting for confounding factors. Results Of 191 gastroschisis infants, 164 infants were uncomplicated. Among uncomplicated patients, there were no deaths and only one case of necrotizing enterocolitis. Bivariate analysis revealed significant differences in practices and outcomes by site. Despite wide variations in practice patterns, there were no major differences in outcome among sites or by silo practice, after adjusting for confounding factors. Conclusions Wide variability exists in institutional practice patterns for infants with gastroschisis, but poor outcomes were not associated with expeditious silo or primary closure, avoidance of routine paralysis, or limited central line and antibiotic durations. Development of clinical pathways incorporating these practices may help standardize care and reduce health care costs.