Sex-dependent Prognosis of Patients with Advanced Soft Tissue Sarcoma.

PURPOSE: To examine whether overall survival (OS) differs for male and female patients with advanced soft-tissue sarcoma (STS). EXPERIMENTAL DESIGN: The study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 and 3 locally advanced or metastatic STS whose tumor underwent next-generation sequencing. We used Cox regression modeling to examine association of sex and OS adjusting for other important factors. RESULTS: Among 388 eligible patients, 174 had leiomyosarcoma (LMS), 136 had undifferentiated pleomorphic sarcoma (UPS), and 78 had liposarcoma. OS for male versus female patients appeared to be slightly better among the full cohort [HR = 0.89; 95% confidence interval (CI), 0.66-1.20]; this association appeared to be stronger among the subsets of patients with LMS (HR = 0.76; 95% CI, 0.39-1.49) or liposarcoma (HR = 0.74; 95% CI, 0.32-1.70). Better OS for male versus female patients was also observed among all molecular subgroups except mutRB1 and mutATRX, especially among patients whose tumor retained wtTP53 (HR = 0.73; 95% CI, 0.44-1.18), wtCDKN2A (HR = 0.85; 95% CI, 0.59-1.23), wtRB1 (HR = 0.73; 95% CI, 0.51-1.04), and among patients whose tumor had mutPTEN (HR = 0.37; 95% CI, 0.09-1.62). OS also appeared to be better for males in the MSK-IMPACT and TCGA datasets. CONCLUSIONS: A fairly consistent pattern of apparent better OS for males across histologic and molecular subgroups of STS was observed. If confirmed, our results could have implications for clinical practice for prognostic stratification and possibly treatment tailoring as well as for future clinical trials design.

KRAS Sequence Variation as Prognostic Marker in Patients With Young- vs Late-Onset Colorectal Cancer.

Importance: The understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time. Objective: To characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC. Design, Setting, and Participants: This cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023. Main Outcomes and Measures: CRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs. Results: Among 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer. Conclusions and Relevance: In this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS-associated mortality risk was higher in distal tumors than proximal tumors.

Toward Precision Perioperative Therapy in GI Malignancies.

PURPOSE: The term precision oncology typically refers to molecularly guided therapies against cancer. Less appreciated but also critically important is molecular identification of patients with resectable disease who are most likely to benefit from perioperative drugs, and tailored selection of such drugs. We call this idea precision perioperative therapy. Over the past several years, use of precision perioperative approaches for patients with localized GI cancers has expanded in clinical trials and practice. Here, we summarize the status of the field and highlight areas of future innovation. METHODS: Using PubMed, we reviewed articles published from 2017 to 2023 in English. We used search terms "adjuvant," "perioperative," "neoadjuvant," and "precision medicine" for various types of GI malignancies. Information about ongoing clinical trials was accessed through ClinicalTrials.gov, accessed January 2023. RESULTS: Paradigms such as minimal residual disease detection via circulating tumor DNA and perioperative immunotherapy in lieu of chemotherapy for mismatch repair-deficient disease may lead to reduced toxicity and improved long-term outcomes in select populations. Molecularly targeted drugs that have shown activity against metastatic disease may also hold promise in the curable setting. CONCLUSION: The field is very much in development, but emerging data demonstrate early promise. We are optimistic that ongoing research efforts will increasingly bring precision perioperative therapy to patients with resectable GI malignancies.

Trends in Epidemiology of Esophageal Cancer in the US, 1975-2018.

Importance: Esophageal cancer (EC) is the 7th most common cancer worldwide and 14th in the US. More data are needed to study the changing incidence patterns of its 2 primary histologic subtypes, squamous cell carcinoma of the esophagus (SCE) and adenocarcinoma of the esophagus (ACE). Objective: To examine temporal trends in incidence rates of EC, ACE, and SCE from 1975 through 2018. Design, Setting, and Participants: In this population-based cross-sectional study, data were derived from 9 Surveillance, Epidemiology, and End Results (SEER) registries from January 1975 through December 2018 and from all 21 registries for January 2000 through December 2018 for patients with a diagnosis of EC from 1975 through 2018 (International Classification of Disease-Oncology, Third Edition codes). Age-adjusted incidence rates (AAIRs) of EC, ACE, and SCE were calculated. The timing and magnitude of the annual percentage change (APC) in incidence were examined using Joinpoint regression analyses. Data analysis was started in 2021 and updated and completed in 2023. Main Outcome and Measures: The APC for age-adjusted EC incidence rates as stratified by histology, anatomical location, stage, sex, age, race and ethnicity, and geographic region. Results: A total of 47 648 patients with a diagnosis of EC were retained for analysis. These included 22 419 (47.1%) with a diagnosis of SCE, 22 217 (46.6%) with ACE, and 3012 (6.3%) with other subtypes. The AAIR for EC changed from 4.14 per 100 000 population in 1975 to 4.18 in 2018, AAIRs of SCE declined from 3.06 in 1975 to 1.15 in 2018 as well as for ACE, and AAIRs increased from 0.42 in 1975 to 2.78 in 2018. From 1975 through 2004, EC incidence significantly increased (APC, 0.53; 95% CI, 0.4 to 0.7) but significantly decreased (APC, -1.03; 95% CI, -1.3 to -0.7) from then until 2018. The APC of SCE significantly continued to decline (-2.80, 95% CI, -3.0 to -2.6), and ACE increased from 2000 to 2006 (APC, 2.51; 95% CI, 1.0 to 4.0) but has since stabilized from 2006 to 2018. Conclusions and Relevance: The results of this cross-sectional study suggest that the incidence of EC modestly declined since 2004 and that the incidence of SCE continued to decline while the incidence rate of ACE plateaued for more than a decade. Understanding factors associated with plateaued rates of ACE may help inform public health interventions.

Immunotherapy in the Management of Esophagogastric Cancer: A Practical Review.

Recent data support incorporation of immune checkpoint inhibitors into the treatment armamentarium for esophageal, gastroesophageal junction, and gastric (esophagogastric) cancer. This practical review focuses on clinical trials that influenced US Food and Drug Administration approvals and treatment guidelines in esophagogastric cancer, including the impact of location, stage, histology, human epidermal growth factor receptor 2 status, and PD-(L)1 expression on these guidelines. The role of immunotherapy in the locally advanced and metastatic setting is constantly expanding. Over the next few years, the many ongoing trials exploring immunotherapy are anticipated to bring new treatment regimens into the frontline setting with the potential to improve survival in patients with advanced disease.

A microdosing framework for absolute bioavailability assessment of poorly soluble drugs: A case study on cold-labeled venetoclax, from chemistry to the clinic.

This work presents an end-to-end approach for assessing the absolute bioavailability of highly hydrophobic, poorly water-soluble compounds that exhibit high nonspecific binding using venetoclax as a model drug. The approach utilizes a stable labeled i.v. microdose and requires fewer resources compared with traditional approaches that use radioactive 14 C-labeled compounds. The stable labeled venetoclax and internal standard were synthesized, then an i.v. formulation was developed. In the clinical study, female subjects received a single oral dose of venetoclax 100 mg followed by a 100-µg i.v. dose of cold-labeled 13 C-venetoclax at the oral time of maximum concentration (Tmax ). The i.v. microdose was prepared as an extemporaneous, sterile compounded solution on the dosing day by pharmacists at the clinical site. Several measures were taken to ensure the sterility and safety of the i.v. preparation. A sensitive liquid chromatography-tandem mass spectrometry method was developed to allow the detection of plasma levels from the i.v. microdose. Plasma samples were collected through 72 h, and pharmacokinetic parameters were estimated using noncompartmental methods. Postdosing sample analysis demonstrated the consistency of the preparations and allowed the precise calculation of the pharmacokinetic parameters based on the actual injected dose. The absolute bioavailability of venetoclax was estimated at 5.4% under fasting conditions. Venetoclax extraction ratio was estimated to be 0.06 suggesting that the fraction transferred from the enterocytes into the liver is limiting venetoclax bioavailability. The proposed framework can be applied to other highly hydrophobic, poorly water-soluble compounds that exhibit high nonspecific binding to support the understanding of their absorption and disposition mechanisms and guide formulation development.

Frequency of Medical Reversal Among Published Randomized Controlled Trials Assessing Cardiopulmonary Resuscitation (CPR).

OBJECTIVE: To characterize what proportion of all randomized controlled trials (RCTs) among patients experiencing cardiac arrest find that an established practice is ineffective or harmful, that is, a medical reversal. METHODS: We reviewed a database of all published RCTs of cardiac arrest patient populations between 1995 and 2014. Articles were classified on the basis of whether they tested a new or existing therapy and whether results were positive or negative. A reversal was defined as a negative RCT of an established practice. Further review and categorization were performed to confirm that reversals were supported by subsequent systematic review, as well as to identify the type of medical practice studied in each reversal. This study was conducted from October 2017 to June 17, 2019. RESULTS: We reviewed 92 original articles, 76 of which could be conclusively categorized. Of these, 18 (24%) articles examined a new medical practice, whereas 58 (76%) tested an established practice. A total of 18 (24%) studies had positive findings, whereas 58 (76%) reached a negative conclusion. Of the 58 articles testing existing standard of care, 44 (76%) reversed that practice, whereas 14 (24%) reaffirmed it. CONCLUSION: Reversal of cardiopulmonary resuscitation practices is widespread. This investigation sheds new light on low-value practices and patterns of medical research and suggests that novel resuscitation practices have low pretest probability and should be empirically tested with rigorous trials before implementation.

A way forward for cancer prevention therapy: personalized risk assessment.

Cancer is characterized by genetic and molecular aberrations whose number and complexity increase dramatically as cells progress along the spectrum of carcinogenesis. The pharmacologic application of agents in the context of a lower burden of dysregulated cellular processes constitutes an efficient strategy to enhance therapeutic efficacy, and underlies the rationale for using cancer prevention agents in high-risk populations. A longstanding barrier to implementing this strategy is that the risk in the general population is low for any given cancer, many people would have to be treated in order to benefit a few. Therefore, identifying and treating high-risk individuals will improve the risk: benefit ratio. Currently, risk is defined by considering a relatively low number of factors. A strategy that considers multiple factors has the ability to define a much-higher-risk cohort than the general population. This article will review the rationale for evaluating multiple risk factors so as to identify individuals at highest risk. It will use breast and lung cancer as examples, will describe currently available risk assessment tools, and will discuss ongoing efforts to expand the impact of this approach. The high potential of this strategy to provide a way forward for developing cancer prevention therapy will be highlighted.

The efficacy and safety of a catheter removal only strategy for the treatment of PICC line thrombosis versus standard of care anticoagulation: a retrospective review.

Peripherally-inserted central catheters (PICCs) are commonly used during hospitalization. Unfortunately, their use can be complicated by catheter-related thrombosis (CRT). Current guidelines recommend 3-6 months of anticoagulation for patients with CRT after catheter removal. This recommendation is based on extrapolation of data on lower extremity thrombosis, as data is lacking regarding the efficacy and safety of more specific management strategies. Many providers feel catheter removal alone is a reasonable treatment option, particularly for patients at risk for bleeding. We performed a retrospective analysis of hospitalized adult patients diagnosed with CRT at our center. We determined rates of progressive thrombosis and bleeding in cohorts of patients who underwent catheter removal vs those who had catheters removed and received anticoagulation. Among 83 total patients, 62 were treated with PICC removal alone, while 21 underwent PICC removal followed by therapeutic anticoagulation. Patients treated with PICC removal alone were more likely to have hematologic malignancy, receive chemotherapy, develop thrombocytopenia, and have brachial vein thrombosis. No patients in the PICC removal plus anticoagulation arm developed progressive thrombosis, while 6.4% of patients treated with catheter removal alone developed a secondary VTE event, including one PE, three DVTs, and five patients (8%) who developed progressive symptoms leading to initiation of anticoagulation. Major bleeding was significantly more common in the PICC removal + anticoagulation arm (28.5% vs. 4.8% p = 0.007). Catheter-removal alone results in significantly reduced major bleeding compared with catheter-removal plus anticoagulation. In select patients, catheter removal alone may be an option for CRT.

The ERM protein, ezrin, regulates neutrophil transmigration by modulating the apical localization of MRP2 in response to the SipA effector protein during Salmonella Typhimurium infection.

In human disease induced by Salmonella enterica serovar Typhimurium (S. Typhimurium), transepithelial migration of neutrophils rapidly follows attachment of the bacteria to the epithelial apical membrane. We have previously shown that during S. Typhimurium infection the multidrug resistance-associated protein 2 (MRP2) is highly expressed at the apical surface of the intestinal epithelia, and that it functions as an efflux pump for the potent neutrophil chemoattractant hepoxilin A(3) . However, the molecular mechanisms regulating its apical localization during active states of inflammation remain unknown. Thus, our objective was to determine the mechanistic basis for the translocation of MRP2 to the apical surface of intestinal epithelial cells during S. Typhimurium infection. We show that suppression of ezrin, through either RNAi or truncation of the C-terminus, results not only in a decrease in S. Typhimurium-induced neutrophil transmigration but also significantly attenuates the apical membrane expression of MRP2 during Salmonella infection. In addition, we determined that S. Typhimurium induces the activation of ezrin via a PKC-α-dependent pathway and that ezrin activation is coupled to apical localization of MRP2. Based on these results we propose that activation of ezrin is required for the apical localization of MRP2 during S. Typhimurium infection.

Multidrug resistance-associated transporter 2 regulates mucosal inflammation by facilitating the synthesis of hepoxilin A3.

Neutrophil transmigration across mucosal surfaces contributes to dysfunction of epithelial barrier properties, a characteristic underlying many mucosal inflammatory diseases. Thus, insight into the directional movement of neutrophils across epithelial barriers will provide important information relating to the mechanisms of such inflammatory disorders. The eicosanoid hepoxilin A(3), an endogenous product of 12-lipoxygenase activity, is secreted from the apical surface of the epithelial barrier and establishes a chemotactic gradient to guide neutrophils from the submucosa across epithelia to the luminal site of an inflammatory stimulus, the final step in neutrophil recruitment. Currently, little is known regarding how hepoxilin A(3) is secreted from the intestinal epithelium during an inflammatory insult. In this study, we reveal that hepoxilin A(3) is a substrate for the apical efflux ATP-binding protein transporter multidrug resistance-associated protein 2 (MRP2). Moreover, using multiple in vitro and in vivo models, we show that induction of intestinal inflammation profoundly up-regulates apical expression of MRP2, and that interfering with hepoxilin A(3) synthesis and/or inhibition of MRP2 function results in a marked reduction in inflammation and severity of disease. Lastly, examination of inflamed intestinal epithelia in human biopsies revealed up-regulation of MRP2. Thus, blocking hepoxilin A(3) synthesis and/or inhibiting MRP2 may lead to the development of new therapeutic strategies for the treatment of epithelial-associated inflammatory conditions.

Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils.

Salmonella spp. and Shigella spp. are responsible for millions of cases of enteric disease each year worldwide. While these pathogens have evolved distinct strategies for interacting with the human intestinal epithelium, they both induce significant proinflammatory responses that result in massive transepithelial migration of neutrophils across the intestinal mucosa. It has previously been shown with Salmonella enterica serotype Typhimurium that the process of neutrophil transmigration is mediated in part by the secretion of hepoxilin A(3) (HXA(3); 8-hydroxy-11,12-epoxy-eicosatetraenoic acid), a potent neutrophil chemoattractant, from the apical surface of infected model intestinal epithelium. This study confirms that HXA(3) is also secreted in response to infection by Shigella flexneri, that it is produced by a pathway involving 12/15-lipoxygenase (12/15-LOX), and that S. enterica serovar Typhimurium and S. flexneri share certain elements in the mechanism(s) that underlies the otherwise separate signal transduction pathways that are engaged to induce polymorphonuclear leukocyte (PMN) transepithelial migration (protein kinase C and extracellular signal-regulated kinases 1 and 2, respectively). PMN transepithelial migration in response to infection with S. flexneri was dependent on 12/15-LOX activity, the enzyme responsible for the initial metabolism of arachidonic acid to HXA(3). Probing further into this pathway, we also found that S. enterica serovar Typhimurium and S. flexneri activate different subtypes of phospholipase A(2), a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. Thus, although S. enterica serovar Typhimurium and S. flexneri utilize different mechanisms for triggering the induction of PMN transepithelial migration, we found that their reliance on 12/15-LOX is conserved, suggesting that enteric pathogens may ultimately stimulate similar pathways for the synthesis and release of HXA(3).

Salmonella enterica serovar Typhimurium modulates P-glycoprotein in the intestinal epithelium.

Studies over the last decade have shown that Salmonella enterica serovar Typhimurium (S. typhimurium) is able to preferentially locate to sites of tumor growth and modulate (shrink) the growth of many cancers. Given this unique association between S. typhimurium and cancer cells, the objective of this study was to investigate the capacity of this microorganism to modulate the plasma membrane multidrug resistance (MDR) protein P-glycoprotein (P-gp), an ATP-binding cassette transporter responsible for effluxing many cancer drugs. Using an in vitro model of S. typhimurium infection of polarized human cancer intestinal cell lines, we have found that this enteric pathogen functionally downregulates the efflux capabilities of P-gp. Specifically, we show that S. typhimurium infection of human intestinal cancer cells results in the enhanced intracellular accumulation of a number of P-gp substrates that corresponds to the posttranscriptional downregulation of P-gp expression. Furthermore, cells expressing small interfering RNAs against MDR1, the gene encoding P-gp, were significantly more susceptible to the cytotoxic effects of bacterial infection. This result is consistent with our observation that S. typhimurium was significantly less able to invade cells overexpressing MDR1. Taken together, these results reveal a novel role for P-gp in the maintenance of homeostasis in the gastrointestinal tract in regard to bacterial infection. Thus the regulation of P-gp by S. typhimurium has important implications not only for the development of new cancer therapeutics aimed at reversing drug resistance but also in the understanding of how microbes have evolved diverse strategies to interact with their host.