GPCRs and fibroblast heterogeneity in fibroblast-associated diseases.

G protein-coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of "most targeted receptors". About one-third of the commercially available drugs for various diseases target the GPCRs. Fibroblasts lay the architectural skeleton of the body, and play a key role in supporting the growth, maintenance, and repair of almost all tissues by responding to the cellular cues via diverse and intricate GPCR signaling pathways. This review discusses the dynamic architecture of the GPCRs and their intertwined signaling in pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer as opposed to the GPCR signaling of fibroblasts in physiological conditions. Understanding the dynamics of GPCR signaling in fibroblasts with disease progression can help in the recognition of the complex interplay of different GPCR subtypes in fibroblast-mediated diseases. This review highlights the importance of designing and adaptation of next-generation strategies such as GPCR-omics, focused target identification, polypharmacology, and effective personalized medicine approaches to achieve better therapeutic outcomes for fibrosis and fibrosis associated malignancies.

MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS: A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS: Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.

A retrospective analysis of immune checkpoint inhibitors in patients with preexisting organ dysfunction.

BACKGROUND: There are limited to no data regarding the use of immune checkpoint inhibitors (ICIs) in patients who have preexisting organ dysfunction because these patients are frequently excluded from clinical trials. The authors' objective was to evaluate the effects of ICIs in patients with chronic kidney disease (CKD), cirrhosis, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF). METHODS: Data were obtained retrospectively for patients older than 18 years with solid organ malignancies who received at least one dose of an ICI between January 1, 2015, and January 1, 2021, and had either CKD (n = 90), cirrhosis (n = 20), COPD (n = 142), or CHF (n = 82) before ICI initiation at the authors' institution. Descriptive statistics were used to summarize patient characteristics, treatment characteristics, immune-related adverse events (IrAEs), and outcomes. An independent samples t-test or the Wilcoxon rank-sum test was used to assess differences in continuous variables; the χ2 test or the Fisher exact test was used to assess differences in categorical variables between patients with and without IrAEs. Progression-free survival (PFS) was assessed using Kaplan-Meier curves, and the log-rank test was used to assess differences in PFS. RESULTS: In all four cohorts, there were no statistically significant differences in patient characteristics, treatment characteristics, or outcomes, such as the number of hospitalizations and PFS, among those who experienced IrAEs compared with those who did not. In the CKD cohort, patients with IrAEs were significantly less likely to die than those without IrAEs (52% vs. 81% [p = .009] for all patients; 53% vs. 83% [p = .008] for patients with stage II/III disease who received no definitive local treatment and patients with stage IV disease); this difference was not observed in the cirrhosis, COPD, or CHF cohorts. There was no statistically significant difference in the number of heart failure and COPD exacerbations during the receipt of ICIs in the CHF and COPD cohorts, respectively. The incidence and time to onset of IrAEs in this study appeared to be similar to those reported previously in clinical trials that excluded patients with significant comorbidities. CONCLUSIONS: The current results demonstrate that ICIs are well tolerated by patients who have preexisting organ dysfunction.

The role of targeted therapy in thymic carcinoma.

Thymic carcinoma is a rare entity and can be distinguished from benign thymomas by their aggressive nature and poor prognosis. The National Comprehensive Cancer Network guidelines recommend resection followed by adjuvant platinum-based chemotherapy for resectable tumors. However, the outcomes for metastatic or relapsed thymic carcinomas are poor with no regimen showing a consistent benefit. Moreover, the relative rarity of these tumors makes clinical trials difficult. Molecular analysis of thymomas shows a high incidence of genetic mutations and targeted therapy holds promise. We will briefly outline and review the current role of targeted therapy in thymic cancer.

Activity of single-agent decitabine in atypical chronic myeloid leukemia.

Atypical chronic myeloid leukemia is a rare entity that presents diagnostic and therapeutic challenges. Traditionally utilized therapeutic agents such as hydroxyurea or interferon result in a median survival of approximately two years, thus warranting identification of better options. We report a 49-year-old Caucasian female, who presented with extreme leukocytosis (white blood cells of 148,300/µL) with left shift, severe anemia, and thrombocytopenia. Following a diagnosis of atypical chronic myeloid leukemia, she was started on intravenous decitabine. She subsequently developed paraneoplastic vasculitis of large arteries, which responded to high-dose glucocorticoid. Decitabine therapy resulted in an excellent hematologic response, transfusion independence, and successful transition to an allogeneic peripheral stem cell transplantation. However, the patient subsequently succumbed to the complications of acute graft-versus-host-disease. This case illustrates an association between atypical chronic myeloid leukemia and steroid-responsive paraneoplastic vasculitis and highlights the single-agent disease activity of decitabine in atypical chronic myeloid leukemia, which may be utilized as a bridging therapy to allogeneic stem cell transplantation.

Coping with an Advanced Stage Lung Cancer Diagnosis: Patient, Caregiver, and Provider Perspectives on the Role of the Health Care System.

Although lung cancer is the leading cause of cancer death in the USA, there have been few studies on patient-centered advanced lung cancer treatment practices. As part of a larger research study on how to use a patient-inclusive approach in late-stage lung cancer treatment, this present study describes patient, caregiver, and provider perspectives on the role of the health care system in helping patients cope with an advanced stage lung cancer diagnosis. Four focus group sessions were conducted with six to eleven participants per group for a total of 36 participants. Two focus groups were held with patients and family members/caregivers and two with physicians and nurses. A major theme that emerged concerned coping with an advanced lung cancer diagnosis, which is the subject of this paper. The patients, caregivers, and providers spoke passionately about interactions with the health care system and volunteered examples of supportive and non-supportive relationships between patients and clinicians. They advocated for better patient-provider communication practices as well as the expanded use of patient navigation and new patient orientation programs. This study contributes additional knowledge by including the perspectives of caregivers and providers who live and work closely with patients with advanced lung cancer. The findings can inform the development of comprehensive patient-centered care plans for patients living with an advanced lung cancer diagnosis.

Use and impact of adjuvant chemotherapy in patients with resected non-small cell lung cancer.

BACKGROUND: Despite clinical trials demonstrating improved survival with adjuvant chemotherapy (AC) for patients with American Joint Committee on Cancer stages I to III non-small cell lung cancer (NSCLC), it is unclear whether this survival benefit extends to broader populations. The current study evaluated patterns of AC use and examined the impact of AC on survival. METHODS: A retrospective analysis was conducted of patients in the Veterans Affairs Central Cancer Registry diagnosed with stages IB to IIIA NSCLC between 2001 and 2008. Descriptive statistics were used to examine patterns of AC use over an 8-year time period. Cox proportional hazards regression analyses were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CIs) to compare mortality risk among patients treated with and without AC. RESULTS: Among 14,306 patients with stages IB to IIIA NSCLC, 4929 underwent surgery and 22% of these received AC. The percentages of patients diagnosed in 2001 through 2003, 2004 through 2005, and 2006 through 2008 receiving AC were 7.0%, 29.8%, and 29.5%, respectively. There was no survival benefit with AC noted for patients diagnosed between 2001 and 2003, but AC was associated with improved survival for the period between 2004 and 2005 (HR, 0.78; 95% CI, 0.67-0.91) and 2006 through 2008 (HR, 0.79; 95% CI, 0.69-0.91). Of those patients receiving AC, 89% received platinum-doublet chemotherapy. Carboplatin remained the most common agent, although cisplatin use reached 43% in the period between 2006 and 2008. The HR for cisplatin relative to carboplatin was 0.96 (95% CI, 0.80-1.15). CONCLUSIONS: There was a significant increase in the use of AC between 2001 and 2008 and AC was associated with an improvement in overall survival.

Engaging patients and caregivers in patient-centered outcomes research on advanced stage lung cancer: insights from patients, caregivers, and providers.

Participatory and patient-centered approaches to cancer research have been highlighted as the most appropriate means of engaging patients in the conduct of clinical research. However, there is a paucity of patient-centered outcomes research (PCOR) on lung cancer. Previous studies seeking to define lung cancer treatment success have generally not included patients' and caregivers' perceptions and views in treatment decision-making. Additionally, little is known about effective strategies for the engagement of lung cancer patients in PCOR. We sought to gain insights into the perceptions of patients, caregivers, and providers on lung cancer treatment success, as well as on strategies for patient engagement in lung cancer PCOR. Four focus groups were conducted with provider, patient, and caregiver participants from four cancer centers in Nebraska and South Dakota. A total of 36 providers, patients, and caregivers participated in this study. Patients and caregivers confirmed that survival alone should not be the measure of lung cancer treatment success and that definitions of treatment success should emphasize factors such as effective clinical guidance throughout treatment, symptom management, functionality, and quality of life. Clinician participants noted that the definition of treatment success evolved over time and appeared to be linked to patients' experiences with chemotherapy. Participants identified barriers to and facilitators of research participation and suggested strategies for the recruitment and retention of research participants. Our study indicates that patients can successfully play active and engaged roles in clinical research, ranging from participant to partner. Judging from the enthusiasm of our focus group attendees, patients and caregivers want to participate and be engaged in clinical research.

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.

Targeting the EGFR signaling pathway in cancer therapy: What's new in 2023?

INTRODUCTION: Epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, and mutated in multiple cancers. In normal cell physiology, EGFR signaling controls cellular differentiation, proliferation, growth, and survival. During tumorigenesis, mutations in EGFR lead to increased kinase activity supporting survival, uncontrolled proliferation, and migratory functions of cancer cells. Molecular agents targeting the EGFR pathway have been discovered, and their efficacy has been demonstrated in clinical trials. To date, 14 EGFR-targeted agents have been approved for cancer treatments. AREAS COVERED: This review describes the newly identified pathways in EGFR signaling, the evolution of novel EGFR-acquired and innate resistance mechanisms, mutations, and adverse side effects of EGFR signaling inhibitors. Subsequently, the latest EGFR/panEGFR inhibitors in preclinical and clinical studies have been summarized. Finally, the consequences of combining immune checkpoint inhibitors and EGFR inhibitors have also been discussed. EXPERT OPINION: As new mutations are threatened against EGFR-tyrosine kinase inhibitors (TKIs), we suggest the development of new compounds targeting specific mutations without inducing new mutations. We discuss potential future research on developing EGFR-TKIs specific for exact allosteric sites to overcome acquired resistance and reduce adverse events. The rising trend of EGFR inhibitors in the pharma market and their economic impact on real-world clinical practice are discussed.

Mucins as Potential Biomarkers for Early Detection of Cancer.

Early detection significantly correlates with improved survival in cancer patients. So far, a limited number of biomarkers have been validated to diagnose cancers at an early stage. Considering the leading cancer types that contribute to more than 50% of deaths in the USA, we discuss the ongoing endeavors toward early detection of lung, breast, ovarian, colon, prostate, liver, and pancreatic cancers to highlight the significance of mucin glycoproteins in cancer diagnosis. As mucin deregulation is one of the earliest events in most epithelial malignancies following oncogenic transformation, these high-molecular-weight glycoproteins are considered potential candidates for biomarker development. The diagnostic potential of mucins is mainly attributed to their deregulated expression, altered glycosylation, splicing, and ability to induce autoantibodies. Secretory and shed mucins are commonly detected in patients' sera, body fluids, and tumor biopsies. For instance, CA125, also called MUC16, is one of the biomarkers implemented for the diagnosis of ovarian cancer and is currently being investigated for other malignancies. Similarly, MUC5AC, a secretory mucin, is a potential biomarker for pancreatic cancer. Moreover, anti-mucin autoantibodies and mucin-packaged exosomes have opened new avenues of biomarker development for early cancer diagnosis. In this review, we discuss the diagnostic potential of mucins in epithelial cancers and provide evidence and a rationale for developing a mucin-based biomarker panel for early cancer detection.

Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with lung cancer and ERBB2 mutation or amplification treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients had advanced lung cancer of any histology, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2 mutation or amplification. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) per RECIST v. 1.1 or stable disease (SD) of at least 16 weeks duration (SD16+). Secondary end points included safety, duration of response, duration of SD, progression-free survival, and overall survival. RESULTS: Twenty-eight patients with lung cancer (27 non-small-cell, 1 small-cell) and ERBB2 mutation (n = 15), ERBB2 amplification (n = 12), or both (n = 1) were enrolled from November 2016 to July 2020. All patients were evaluable for efficacy and toxicity. Three patients with partial response (two ERBB2 mutation; one both mutation and amplification) and seven patients with SD16+ (five ERBB2 mutation; two amplification) were observed for a DC rate of 37% (95% CI, 21 to 50; P = .005) and OR rate of 11% (95% CI, 2 to 28). Five patients had one or more grade 3 or 4 adverse or serious adverse events at least possibly related to P + T. CONCLUSION: Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non-small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations.

Assessment of prognostic factors after primary tumor resection in metastatic colon cancer patients: a Veteran's Affairs Central Cancer Registry (VACCR) analysis, 1995-2008.

BACKGROUND: Resection of the primary tumor in metastatic colon cancer may occur for palliation of bleeding or obstruction despite distant metastases. This study evaluates clinicopathologic features that serve as prognostic markers in those patients with stage IV colon cancer who undergo resection of their primary tumor. METHODS: Retrospective analysis of stage IV colon cancer patients who underwent surgical resection of the primary tumor from 1995 to 2008 was done via the Veteran's Affairs Central Cancer Registry. Age, Charlson co-morbidity index score, extent of metastases, sex, number of lymph nodes examined, lymph node ratio (LNR), type of surgery, use of adjuvant chemotherapy, primary tumor site, and grade were studied with respect to overall survival by using log-rank and Kaplan-Meier analysis. RESULTS: There were 2,625 patients with stage IV colon cancer who had primary tumor resection. Age at diagnosis, Charlson co-morbidity index score, lymph node ratio, and use of chemotherapy were found to be independent predictors of survival by multivariate analysis. CONCLUSION: Clinicopathologic factors such as LNR, use of chemotherapy, age, co-morbidities, site of primary colon tumor, and number of sites of metastasis are all independent predictors of overall survival in patients who undergo primary colon tumor resection in the metastatic setting.

Hemodynamic collapse following bilateral knee arthroplasty: a mysterious case.

Severe hemodynamic collapse after knee surgery from bilateral adrenal hemorrhages is rare. Even rarer is it occurring from adrenal hemorrhage as a complication of heparin induced thrombocytopenia. Due to lack of awareness of this rare complication and associated complex scenario in critically ill patients, diagnosis is often made post mortem. A diagnosis of bilateral adrenal hemorrhage should be considered in any patient presenting with non-specific symptoms of fever, abdominal pain, confusion and rapid hemodynamic collapse not responding to standard therapy. This is crucial especially in the setting of heparin induced thrombocytopenia as thrombosis and not hemorrhage is often the most feared complication of this syndrome.

Clinicopathologic factors associated with lymph node retrieval in resectable colon cancer: a Veterans' Affairs Central Cancer Registry (VACCR) database analysis.

BACKGROUND: A long-term determinant of survival in resectable colon cancer is the involvement of regional lymph nodes. We evaluated the clinicopathologic factors associated with lymph node retrieval. METHODS: We conducted a retrospective analysis of patients with resected stage I-III colon cancer in the Veteran's Affairs Central Cancer Registry between 1995 and 2008. One-way ANOVA compared the differences between various groups. Multivariate logistic regression analysis was performed to determine the factors associated with the harvest of 12 or more lymph nodes for pathologic examination. RESULTS: There were 19,240 patients with resectable colon cancer included in our analysis. Mean number of lymph nodes retrieved increased with later year of diagnosis, higher overall stage, higher T descriptor, age <65 years, poorer differentiation and right-sided tumors (P < 0.01 for all covariates). These aforementioned factors are also associated with an increased probability of retrieving 12 or more lymph nodes after surgical resection (P < 0.01 for all covariates). CONCLUSIONS: Later year of diagnosis, younger patients, right-sided tumors, poorer differentiation, higher T descriptor and overall stage are associated with increased number of lymph nodes retrieved. These may indicate the presence of an immunological response of tumor versus host affecting lymph node retrieval.

Differential mutation spectrum and immune landscape in African Americans versus Whites: A possible determinant to health disparity in head and neck cancer.

African Americans (AA) with Head and Neck Squamous Cell Carcinoma (HNSCC) have a worse disease prognosis than White patients despite adjusting for socio-economic factors, suggesting the potential biological contribution. Therefore, we investigated the genomic and immunological components that drive the differential tumor biology among race. We utilized the cancer genome atlas and cancer digital archive of HNSCC patients (1992-2013) for our study. We found that AA patients with HNSCC had a higher frequency of mutation compared to Whites in the key driver genes-P53, FAT1, CASP8 and HRAS. AA tumors also exhibited lower intratumoral infiltration of effector immune cells (CD8+, γδT, resting memory CD4+ and activated memory CD4+ T cells) with shorter survival than Whites. Unsupervised hierarchical clustering of differentially expressed genes demonstrated distinct gene clusters between AA and White patients with unique signaling pathway enrichments. Connectivity map analysis identified drugs (Neratinib and Selumetinib) that target aberrant PI3K/RAS/MEK signaling and may reduce racial disparity in therapy response.

Daily Lisinopril vs Placebo for Prevention of Chemoradiation-Induced Pulmonary Distress in Patients With Lung Cancer (Alliance MC1221): A Pilot Double-Blind Randomized Trial.

PURPOSE: Chemoradiation (CRT) is an integral treatment modality for patients with locally advanced lung cancer. It has been hypothesized that current use of an angiotensin-converting enzyme inhibitor during CRT may be protective for treatment-related lung damage and pneumonitis. METHODS AND MATERIALS: We conducted a pilot, double-blind, placebo-controlled, randomized trial. Study-eligible patients receiving curative thoracic radiation therapy (RT) were randomly assigned to 20 mg of lisinopril or placebo once daily during and up to 3 months after RT. All patients received concurrent chemotherapy. The primary endpoint was adverse event profiling. Multiple patient-reported outcome (PRO) surveys, including the Lung Cancer Symptom Scale, Function Assessment of Cancer Therapy-Lung, and the European Organisation for Research and Treatment of Cancer Lung Cancer Questionnaire, were applied with a symptom experience questionnaire. Exploratory comparative statistics were used to detect differences between arms with χ2 and Kruskal-Wallis testing. RESULTS: Five institutions enrolled 23 patients. However, accrual was less than expected. Eleven and 12 patients were in the placebo and lisinopril arms, respectively (mean age, 63.5 years; male, 62%). Baseline characteristics were balanced. Eighteen patients (86%) were former or current smokers. The primary endpoint was met; neither arm had grade 3 or higher hypotension, acute kidney injury, allergic reaction (medication-induced cough), or anaphylaxis (medication-related angioedema). Few PRO measures suggested that compared with the placebo arm, patients receiving lisinopril had less cough, less shortness of breath, fewer symptoms from lung cancer, less dyspnea with both walking and climbing stairs, and better overall quality of life (for all, P < .05). CONCLUSIONS: Although underpowered because of low accrual, our results suggest that there was a clinical signal for safety-and possibly beneficial by limited PRO measures-in concurrently administering lisinopril during thoracic CRT to mitigate or prevent RT-induced pulmonary distress. Our results showed that a definitive, larger-scale, randomized phase 3 trial is needed in the future.

Safety of long-term anticoagulation in patients with brain metastases.

Anticoagulation is thought to be associated with the risk of intracranial hemorrhage (ICH) in patients with brain metastases; however, the data on this topic are limited. This study was conducted to determine the incidence of ICH associated with anticoagulant use in adult patients with brain metastases. Consecutive patients with brain metastases occurring from 2006 to 2014 were identified from a single-institution database. Long-term anticoagulant therapy was defined as outpatient anticoagulation therapy of > 1 month. Chi-square tests and Fisher's exact test were used to compare rates of ICH by groups. This cohort included 125 patients with brain metastases. Of these, 64 had primary of non-small cell lung cancer (51.2%). Of these patients, 12/125 (9.6%) patients developed ICH. Neither the primary tumor site nor the number of brain metastases was associated with the development of ICH. ICH incidence was not associated with the use of anticoagulant therapy, with 8/67 (11.94%) patients on outpatient anticoagulation and 4/58 (6.9%) not on anticoagulation experiencing ICH (p = 0.33). The type of treatment did not significantly influence ICH, although those having combined WBRT and SRS were numerically more likely to experience ICH (4/15; 26.67%) of this cohort. In patients on enoxaparin, there was no difference in the incidence of ICH for daily versus twice-daily dosing (p = 1.0). Long-term anticoagulant use is not associated with an increased incidence of ICH in patients with intracranial metastases.

Advanced pancreatic cancer: a meta-analysis of clinical trials over thirty years.

BACKGROUND: In contrast to other cancers, survival rates for pancreatic ductal adenocarcinoma (PDAC) patients have improved but minimally over the past thirty years. The aim of this study was to perform a meta-analysis of clinical trials published since 1986 to determine trends in median overall survival in primarily metastatic PDAC. MATERIALS AND METHODS: All Phase 2-4 clinical trials published during or after 1986 investigating first-line systemic chemotherapy in metastatic PDAC were included in the meta-analysis. Publications obtained through PubMed and www.ClinicalTrials.gov were cross-referenced to identify additional trials. Trials enrolling fewer than 50% of study participants with metastatic disease were excluded. RESULTS: Of 19,488 patients enrolled in 151 clinical trials, 84% had metastatic disease and 16% had locally advanced pancreatic cancer. In clinical trials published from 1986 to 2016, the weighted median overall survival (wMOS) increased by 3.0 months. The median wMOS was higher in combination therapy (7.31 months, IQR 5.4 to 8.5) compared to non-gemcitabine, single-agent therapy (4.76 months, IQR 3.5 to 6.0), gemcitabine monotherapy (6.48 months, IQR 5.9 to 7.2), and gemcitabine plus single-agent therapy (7.09 months, IQR 6.3 to 8.2). Of all regimens used in more than one study arm, FOLFIRINOX had the highest wMOS (10.9 months). CONCLUSIONS: Regardless of treatment regimen, survival rates in PDAC have minimally improved over time. Of drugs used in two or more study arms, only FOLFIRINOX has a wMOS greater than ten months. Emphasis should, therefore, be placed on identification of novel targets that promote early diagnosis and intervention. FUNDING: The authors on this manuscript are in parts, supported by grants from the National Institutes of Health (EDRN U01 CA200466, SPORE P50 CA127297, R01 CA183459, R21 AA026428 and R01 CA 195586).

Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells.

The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo. Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated γH2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication.