A Multicenter Phase II Trial of Ruxolitinib for Treatment of Corticosteroid Refractory Sclerotic Chronic Graft-Versus-Host Disease.

PURPOSE: Sclerotic chronic graft-versus-host disease (cGVHD) represents a highly morbid and refractory form of cGVHD, and novel therapies for sclerotic cGVHD are critically needed. This study aimed to determine the efficacy of ruxolitinib in patients with corticosteroid refractory sclerotic cGVHD. PATIENTS AND METHODS: In a single-arm multicenter phase II trial (N = 47), adults with sclerotic cGVHD refractory to corticosteroids and ≥one additional line of systemic therapy for cGVHD received ruxolitinib for ≥six months (ClinicalTrials.gov identifier: NCT03616184). The primary end point was complete or partial response (PR) in skin and/or joint defined according to the 2014 National Institute of Health cGVHD Consensus Criteria. RESULTS: Following the use of ruxolitinib for a median of 11 months, PR in skin and/or joints was noted in 49% (95% CI, 34 to 64) at 6 months, with 45% having joint and fascia response and 19% having skin response. The duration of skin/joint response was 77% (95% CI, 48 to 91) at 12 months. Overall cGVHD PR was noted in 47% (95% CI, 32 to 61). Improvement in Lee Symptom Scale summary and skin subscale scores was noted in 38% of patients. With a cumulative incidence of treatment failure of 20.8% (95% CI, 10.0 to 34.1), nonrelapse mortality (NRM) of 2.2% (95% CI, 0.17 to 10.3), and no recurrent malignancy, failure-free survival (FFS) was 77.1% (95% CI, 61.3 to 87.0) at 12 months. Ruxolitinib was overall well tolerated with no new safety signals. CONCLUSION: The use of ruxolitinib was associated with relatively high rates of skin/joint responses and overall cGVHD responses, improvement in patient-reported outcomes, low NRM, and high FFS in patients with refractory sclerotic cGVHD. Ruxolitinib offers an effective treatment option for refractory sclerotic cGVHD.

Series on the Lancet Oncology Commission on Global Cancer Surgery: Introduction-Intent and Content.

BACKGROUND: Surgery plays a key role in the multi-disciplinary cancer care pathway. Nearly 80% of patients with solid tumors will require surgical intervention during the course of their disease. Unfortunately, the vast majority of these patients do not have access to safe, timely, high-quality, and affordable cancer surgical care. The first Lancet Oncology Commission on Global Cancer Surgery shone a light on this grave situation and outlined some strategies to address them. The second Lancet Oncology Commission on Global Cancer Surgery (TLO- II) was conceived to continue the work of its predecessor by developing a roadmap of practical solutions to propel improvements in cancer surgical care globally. METHODS: The Commission was developed by involving approximately 50 cancer care leaders and experts from different parts of the world to ensure diversity of input and global applicability. RESULTS: The Commission identified nine solutional domains that are considered essential to deliver safe, timely, high-quality, and affordable cancer surgical care. These nine domains were further refined to develop solutions specific to each of the six World Health Organization regions. Based on the above solutions, we developed eight action items that are intended to propel improvements in cancer surgical care on the global stage. CONCLUSIONS: The second Lancet Oncology Commission on Global Cancer Surgery builds on the first Commission by developing a pragmatic roadmap of practical solutions that we hope will ensure access to safe, timely, high-quality, and affordable cancer surgical care for everyone regardless of their socioeconomic status or geographic location.

A Rigorous Multi-Laboratory Study of Known PDAC Biomarkers Identifies Increased Sensitivity and Specificity Over CA19-9 Alone.

A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.

Outcomes and factors associated with cryptococcal disease among cirrhotics: A study of the national inpatient sample 2005 to 2014.

BACKGROUND: Cryptococcal disease (CD) confers a higher mortality in cirrhotic patients compared to non-cirrhotic patients. Factor association for CD in cirrhotic patients is poorly understood. Our aim was to determine the incidence, demographic, and comorbidities associated with CD among cirrhotic patients in the United States (US). METHOD: Retrospective analysis of admissions of cirrhotic patients, with or without CD, using the National Inpatient Sample (NIS) database from 2005 to 2014. The number of admissions were reported in raw and weighted frequencies. The trends of CD among cirrhotic patients and overall CD were evaluated. Rao-Scott chi-square, t-tests, and multivariate logistic regressions were performed to evaluate variables and CD among cirrhotic patients. RESULTS: There were 886,962 admissions for cirrhosis, and 164 of these with CD. By adjusted odds ratio (AOR), CD was more often associated with cirrhosis in Southern (2.95; 95 % CI 1.24, 7.02) and Western regions (4.45; 95 % CI 1.91, 10.37), Hispanic patients (1.80; 95 % CI 1.01, 3.20), and patients with chronic kidney disease (CKD) (3.13; 95 % CI 2.09, 4.69). Of note, CD in cirrhotic patients was associated with higher inpatient mortality (AOR of 3.89, 95 % CI 2.53, 5.99), longer length of stay (9.87 vs. 4.88 days), and a higher total charge ($76,880 vs. $ 37,227) when compared to cirrhotic patients without CD. DISCUSSION: Patients with cirrhosis admitted with CD have a high inpatient mortality. The geographical location and CKD were important factors associated with CD among cirrhotic patients. Autoimmune liver diseases and immunosuppression did not appear to increase the risk of CD.

A Prospective Multimodal Education Intervention for Providers Does Not Increase Hepatic Encephalopathy Treatment Rates.

BACKGROUND: Over 50% of hospitalizations from hepatic encephalopathy (HE) are preventable, but patients often do not receive medical treatment. AIMS: To use a multimodal education intervention (MMEI) to increase HE treatment rates and to evaluate (1) trends in HE treatment, (2) predictors of receiving treatment, and (3) the impact of treatment on hospitalization outcomes. METHODS: Prospective single-center cohort study of patients hospitalized with HE from April 1, 2020-September 30, 2022. The first 15 months were a control ("pre-MMEI"), the subsequent 15 months (MMEI) included three phases: (1) prior authorization resources, (2) electronic order set, and (3) in-person provider education. Treatment included receiving any drug (lactulose or rifaximin), or combination therapy. Treatment rates pre- vs. post-MMEI were compared using logistic regression. RESULTS: 471 patients were included. There were lower odds of receiving any drug post-MMEI (p = 0.03). There was no difference in receiving combination therapy pre- or post-MMEI (p = 0.32). Predictors of receiving any drug included alcohol-related or cryptogenic cirrhosis (p's < 0.001), and the presence of ascites (p = 0.005) and/or portal hypertension (p = 0.003). The only significant predictor of not receiving any drug treatment was having autoimmune cirrhosis (p < 0.001). Patients seen by internal medicine (p = 0.01) or who were intoxicated (p = 0.02) were less likely to receive rifaximin. Any treatment was associated with higher 30-day liver disease-specific readmission (p < 0.001). CONCLUSION: This MMEI did not increase HE treatment rates, suggesting that alternative strategies are needed to identify and address barriers to treatment.

Connectivity mapping-based identification of pharmacological inhibitor targeting HDAC6 in aggressive pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to limited therapeutic options and expensive/burdensome drug discovery processes. Utilizing genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting may improve pancreatic cancer (PC) patient outcomes. Initially, we mapped CMAP data to gene expression from 106 PC patients, identifying nine negatively connected drugs. These drugs were further narrowed down using a similar analysis for PC cell lines, human tumoroids, and patient-derived xenografts datasets, where ISOX emerged as the most potent agent to target PC. We used human and mouse syngeneic PC cells, human and mouse tumoroids, and in vivo mice to assess the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Global transcriptomic and pathway analysis of the ISOX-LINCS signature identified HDAC 6/cMyc as the target axis for ISOX. Specifically, we discovered that genetic and pharmacological targeting of HDAC 6 affected non-histone protein cMyc acetylation, leading to cMyc instability, thereby disrupting PC growth and metastasis by affecting cancer stemness. Finally, KrasG12D harboring tumoroids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a new drug to treat advanced PC patients without toxicity to normal cells. Our study supports the clinical utility of ISOX along with 5FU in future PC clinical trials.

Pancreatic Cysts Greater Than 1 cm Are Associated With an Increased Risk for Developing Pancreatic Cancer in Individuals From Pancreatic-Cancer Prone Kindreds Undergoing Surveillance.

BACKGROUND: The International Cancer of the Pancreas Screening Consortium recommended annual imaging for individuals at increased risk for developing a pancreatic ductal adenocarcinoma (PDAC) who did not have concerning pancreatic findings or a cyst <3 cm without worrisome features. We aimed to determine if 3-cm cyst size accurately predicted advanced precursor lesions in high-risk individuals undergoing surveillance. METHODS: Imaging for high-risk individuals (HRIs) undergoing PDAC surveillance from 2007 to 2021 was reviewed and pancreatic abnormalities were recorded including dominant cyst size and number of cysts. Subjects were excluded if they had the following: (1) no follow-up imaging after baseline, (2) solid lesion at baseline, or (3) development of solid lesion without having cyst on prior imaging. RESULTS: Five of the 77 HRIs found to have a cystic lesion on surveillance developed a PDAC: 3 with cystic lesion >1 cm as compared with only 2 of 67 HRIs with cystic lesions <1 cm (P < 0.05). None of these cysts developed worrisome findings and 4/5 PDACs did not arise from visualized cystic precursor lesion. CONCLUSIONS: Patients with a cyst ≥1 cm were at increased risk for developing PDAC compared with patients with cyst <1 cm. Pancreatic ductal adenocarcinoma usually did not arise from a recognized cystic lesion.

Durvalumab Outcomes in Stage III Non-small Cell Lung Cancer: A Single-institution Study.

BACKGROUND/AIM: The PACIFIC trial demonstrated improved survival in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with durvalumab following definitive concurrent chemoradiotherapy (CRT). This study sought to explore real-world outcomes with durvalumab consolidation therapy at our institution. PATIENTS AND METHODS: We retrospectively identified patients diagnosed with stage III NSCLC at our institution from January 2012 to January 2022. We created two cohorts: one who received durvalumab following definitive CRT and a historical one who did not. Primary outcomes of interest included median progression-free survival (PFS) and overall survival (OS). Additionally, we performed subgroup analysis on the durvalumab cohort to explore the associations between survival and time to durvalumab initiation, PD-L1 expression, and neutrophil-to-lymphocyte ratio (NLR). RESULTS: We identified 79 patients with locally advanced NSCLC who were not surgical candidates. Patients treated with durvalumab (n=44) had significantly improved survival compared to the historical cohort (n=35) including a median PFS of 17.4 months versus 8.0 months (p=0.0019) and a median OS of 37.0 months versus 17.0 months (log-rank p-value=0.07, Wilcoxon p-value=0.02). Within the durvalumab group, outcomes did not significantly differ between those who initiated therapy before or after 42 days of finishing CRT, between various PD-L1 expression levels, or between high or low NLR. CONCLUSION: Patients who received durvalumab as consolidation therapy following definitive CRT demonstrated significantly improved survival compared to a historical cohort who did not receive durvalumab. Furthermore, durvalumab appears to benefit patients regardless of time to initiation, PD-L1 expression, or NLR.

Integrative analysis of clinicopathological features defines novel prognostic models for mantle cell lymphoma in the immunochemotherapy era: a report from The North American Mantle Cell Lymphoma Consortium.

BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.

Radical nephrectomy performed by open, laparoscopy with or without hand-assistance or robotic methods by the same surgeon produces comparable perioperative results

PURPOSE: Radical nephrectomy can be performed using open or laparoscopic (with or without hand assistance) methods, and most recently using the da Vinci Surgical Robotic System. We evaluated the perioperative outcomes using a contemporary cohort of patients undergoing radical nephrectomy by one of the above 4 methods performed by the same surgeon. MATERIALS AND METHODS: The relevant clinical information on 57 consecutive patients undergoing radical nephrectomy from September 2000 until July 2004 by a single surgeon was entered in a Microsoft Access DatabaseTM and queried. Following appropriate statistical analysis, p values < 0.05 were considered significant. RESULTS: Of 57 patients, the open, robotic, laparoscopy with or without hand assistance radical nephrectomy were performed in 18, 6, 21, and 12 patients, respectively. The age, sex, body mass index (BMI), incidence of malignancy, specimen and tumor size, tumor stage, Fuhrman grade, hospital stay, change in postoperative creatinine, drop in hemoglobin, and perioperative complications were not significantly different between the methods. While the estimated median blood loss, postoperative narcotic use for pain control, and hospital stay were significantly higher in the open surgery method (p < 0.05), the median operative time was significantly shorter compared to the robotic method (p = 0.02). Operating room costs were significantly higher in the robotic and laparoscopic groups; however, there was no significant difference in total hospital costs between the 4 groups. CONCLUSIONS: The study demonstrates that radical nephrectomy can be safely performed either by open, robotic, or laparoscopic with or without hand assistance methods without significant difference in perioperative complication rates. A larger cohort and longer follow up are needed to validate our findings and establish oncological outcomes.