ABSTRACT
The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Research Design , Urologic Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor , Cisplatin/administration & dosage , Humans , Interleukin-2/administration & dosage , Interleukin-2/analogs & derivatives , Molecular Targeted Therapy , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Nivolumab/administration & dosage , Polyethylene Glycols/administration & dosage , Prognosis , Urologic Neoplasms/diagnosis , Urologic Neoplasms/etiology , Urologic Neoplasms/mortalityABSTRACT
INTRODUCTION: COVID-19 has caused 4 million deaths as of 24 August 2021. A significant number of patients were admitted to undesignated ICU areas before transfer to a desig-nated ICU owing to the unavailability of ICU beds. We aim to compare the mortality and length of stay of patients in these 2 areas. MATERIAL AND METHODS: We retrospectively studied all critically ill patients with COVID-19 pneumonia who were admitted to Dubai hospital between 1 January 2020 and 30 June 2020. Patients who transferred to wards other than designated ICU constitute cases, while those who were admitted directly to designated ICUs constitute controls. The demographics, clinical parameters, and treatment profile of these patients were recorded and compared. Mortality and length of stay were calculated. RESULTS: The sample includes 239 subjects (admitted to an undesignated ICU ward [n = 107] and directly admitted to a designated ICU ward [n = 132]). Patients admitted to an undesignated ICU had extra transfers between wards and had more days on MV (median [IQR] 18 (19) vs. 11 (14); P = 0.001), greater length of stay in the ICU (median [IQR]) 21.5 (19) vs. 15 (14); P = 0.001), and greater length of stay in hospital (median [IQR] 32 (28) vs. 21 (26); P = 0.001). Multiple logistic regression analysis showed that patients treated at an undesignated ICU have better survival (odds of death for patients cared for at an undesignated ICU was 0.347 with CI 0.178-0.676; P = 0.002). Multiple linear regression analysis also showed that patients treated at an undesignated ICU had longer stay - 4.2 days, CI 1.3-7.13, P = 0.004). CONCLUSIONS: Admission to an undesignated ICU impacts mortality and length of ICU and hospital stay.
Subject(s)
COVID-19 , Respiratory Distress Syndrome , Humans , Length of Stay , COVID-19/therapy , Retrospective Studies , Critical Illness/therapy , Intensive Care Units , Hospital MortalityABSTRACT
The RECOVERY study documented lower 28-day mortality with the use of dexamethasone in hospitalized patients on invasive mechanical ventilation or oxygen with COVID-19 Pneumonia. We aimed to examine the practice patterns of steroids use, and their impact on mortality and length of stay in ICU. We retrospectively examined records of all patients with confirmed Covid 19 pneumonia admitted to the ICU of Dubai hospital from January 1st, 2020 - June 30th, 2020. We assigned patients to four groups (No steroids, low dose, medium dose, and high dose steroids). The primary clinical variable of interest was doses of steroids. Secondary outcomes were 28-day mortality and length of stay in ICU". We found variability in doses of steroid treatment. The most frequently used dose was the high dose. Patients who survived were on significantly higher doses of steroids and had significantly longer stays in ICU. The prescription of steroids in Covid-19 ARDS is variable. The dose of steroids impacts mortality rate and length of stay in ICU, although patients treated with high dose steroids seem to stay more days in ICU.
ABSTRACT
PURPOSE: Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS: Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0. RESULTS: Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 (P = .3 for association between PD-L1 and < pT2N0). CONCLUSION: Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Neoadjuvant Therapy , Urinary Bladder Neoplasms , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/therapeutic use , Cisplatin/therapeutic use , Cystectomy , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Female , Humans , Male , Muscles , Neoadjuvant Therapy/adverse effects , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapy , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgery , GemcitabineABSTRACT
PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents, Immunological/therapeutic use , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Molecular Targeted Therapy , Mutation , Neoplasm Metastasis , Registries , Tumor BurdenABSTRACT
AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.
Subject(s)
Adenocarcinoma/therapy , Chemoradiotherapy, Adjuvant , Esophageal Neoplasms/therapy , Esophagectomy , Induction Chemotherapy , Neoadjuvant Therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Cell Differentiation , Chemoradiotherapy, Adjuvant/adverse effects , Chemoradiotherapy, Adjuvant/mortality , Disease-Free Survival , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophagectomy/adverse effects , Esophagectomy/mortality , Female , Humans , Induction Chemotherapy/adverse effects , Induction Chemotherapy/mortality , Male , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoadjuvant Therapy/mortality , Time Factors , United StatesABSTRACT
BACKGROUND: Pancreatic adenocarcinoma (PDAC) is now the third leading cause of cancer mortality in the United States. More than 80% of patients present with distant metastasis precluding surgical eligibility. Even among patients with localized disease deemed eligible for surgical resection, the median survival is only 22.8 months due to high recurrence rates. Identification of a biomarker correlated with patient specific prognosis upon initial diagnosis can serve as a way to individualize treatment options. METHODS: We performed a retrospective cohort study analyzing pathology of patients who underwent curative intent surgery for PDAC at Geisinger Medical Center from 1998-2011 to identify whether the expression of KOC can be predictive of patient specific prognosis. Tissue microarrays of specimens were assessed by immunohistochemistry. RESULTS: A total of 62 patients are included. Comparisons between groups on overall survival (OS) and progression free survival (PFS) are estimated using the Kaplan-Meier method and the log-rank test. Each biomarker was represented as low and high expression by categorizing the expression score at <4+ or >4+, based on intensity and extent of cells stained. 40 deaths occurred in the sample. Distant metastasis and differentiation (well/moderate vs. poor) were related to OS (P=0.0120, P=0.0086). Twenty-nine patients progressed in their disease. High/low KOC expression were significantly related to PFS (P=0.0556). Patients with a high KOC expression were more than 2 times more likely to progress compared to those with a low KOC expression (HR =2.04; 95% CI: 0.97, 4.29). CONCLUSIONS: Our data is suggestive of KOC being a useful prognostic biomarker for identifying those patients with PDAC who have a high risk for early progression and distant metastasis. Larger studies are needed to determine whether KOC can be a therapeutic target in the treatment of pancreatic cancer. Furthermore, considering high KOC expressers had a worse PFS than their counterparts, investigation regarding the use of KOC expression as a biomarker to preselect patients who may benefit most from neoadjuvant chemotherapy is warranted.
ABSTRACT
Atherosclerosis is distinguished by the accumulation of lipoprotein lipid within the arterial wall. An ionic interaction of positively charged regions of apolipoprotein (apo) B with matrix proteins, including proteoglycans, collagen, and fibronectin, is thought to initiate this process. Proteoglycans are complex glycoproteins containing highly negatively charged carbohydrate chains. These proteins are abundant in atherosclerosis lesions, and they associate with apoB-containing lipoproteins. Several specific regions of apoB may mediate this process. Other lipoprotein-associated proteins, including apoE and lipases, might also participate in this process. In addition, retention may occur via lipoprotein association with other matrix molecules or as a consequence of intra-arterial lipoprotein aggregation.
Subject(s)
Arteriosclerosis/metabolism , Lipoproteins/metabolism , Animals , HumansSubject(s)
Carcinoma, Hepatocellular/pathology , Head and Neck Neoplasms/pathology , Liver Neoplasms/pathology , Black or African American , Aged, 80 and over , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/therapy , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/secondary , Head and Neck Neoplasms/therapy , Humans , Liver/diagnostic imaging , Liver/pathology , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/pathology , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Male , RadiographyABSTRACT
Angiosarcomas represent 1-2% of soft tissue sarcomas and most frequently occur in the subcutis. They may affect internal organs, such as the heart, liver, and spleen, and only rarely do they emerge in the gastrointestinal tract. The association between angiosarcomas and certain toxic chemical substances or previous external-beam radiation therapy is well documented.