Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma

Background: Vorinostat has demonstrated activity in refractorycutaneous T-cell lymphoma. In a phase I trial, an encouragingactivity in diffuse large-B-cell lymphoma (DLBCL) was noted. Patients and methods: We carried out a phase II trial (NCT00097929 [ClinicalTrials.gov] )of oral vorinostat 300 mg b.i.d. (14 days/3 weeks or 3 days/week)in patients with measurable, relapsed DLBCL who had receivedtwo or more systemic therapies. Response rate and duration (DOR),time to progression (TTP) and safety were assessed. Results: Eighteen patients were enrolled (median age: 66 years;median prior therapies: 2). Seven received 300 mg b.i.d. 14days/3 weeks, but four had grade 3 or 4 toxicity (dose-limitingtoxicity, DLT). The schedule was amended to 300 mg b.i.d. 3days/week), and none had DLT. One achieved a complete response(TtR = 85 days; DOR = >468 days) and one had stable disease(301 days). Sixteen discontinued for progressive disease; medianTTP was 44 days. Median number of cycles was 2 (1 to >19).Common drug-related adverse experiences (AEs; mostly grade 1/2)were diarrhea, fatigue, nausea, anemia and vomiting. Three patientshad dose reduction; none discontinued for drug-related AEs.Drug-related AE grade 3 included thrombocytopenia (16.7%) andasthenia (11.1%). Conclusion: Vorinostat was well tolerated at 300 mg b.i.d. 3days/week or 200 mg b.i.d. 14 days/3 weeks but had limited activityagainst relapsed DLBCL. Key words: diffuse large-B-cell lymphoma, DLBCL, HDAC, histone deacetylase inhibitor, SAHA, suberoylanilide hydroxamic acid, vorinostat Received for publication January 9, 2008. Accepted for publication January 15, 2008.     

Infusion of β-FNA into the thalamus attenuates morphine-induced c-Fos induction in the rat caudate putamen

The medial thalamus contains μ opioid receptors and sends a glutamatergic projection to the caudate putamen (CPu) in rat. Morphine-induced c-Fos expression in the CPu has been shown to be blocked by pretreatment with antagonists to N-methyl- -aspartate receptors, indicating the involvement of glutamate in this morphine-induced response. The importance of the glutamatergic projections from the thalamus was assessed by infusing the μ opioid receptor antagonist, β-funaltrexamine (β-FNA), prior to systemic morphine injection. Infusion of β-FNA near specific medial thalamic nuclei attenuated morphine-induced c-Fos expression in the CPu.     

Local anesthesia for fine-needle aspiration biopsy of palpable breast masses: The effectiveness of a jet injection system

To determine the effectiveness of the Biojector® 2000 needle-free lidocaine injection system in achieving satisfactory local anesthesia for fine-needle aspiration (FNA) of palpable breast lesions, we studied 29 female patients. Each patient served as her own control and had two FNA biopsies performed on the lesion. The first FNA biopsy was preceded by either no anesthesia, ethyl chloride cold spray, or traditional needle lidocaine injection. The second FNA was preceded by the Biojector 2000. Twenty-four patients (83%) reported that they preferred the Biojector 2000 over either no anesthesia, ethyl chloride spray, or needle and syringe lidocaine injection. The Biojector 2000 needle-free injection system is an effective and useful method of local anesthesia for FNA of palpable breast masses. Diagn. Cytopathol. 1997;17:472–476. © 1997 Wiley-Liss, Inc.     

Multisystem Inflammatory Syndrome in Adults and Adolescents Associated with COVID-19 Infection: A Single-center Experience

How to cite this article: Arjun R, Niyas VKM, Thomas SM, Raman M, Thomas A, Aloysius W, et al. Multisystem Inflammatory Syndrome in Adults and Adolescents Associated with COVID-19 Infection: A Single-center Experience. Indian J Crit Care Med 2022;26(1):145–148.     

Do Micromorphometric Features of Metastatic Deposits Within Sentinel Nodes Predict Nonsentinel Lymph Node Involvement in Melanoma?

Introduction  Multiple attempts have been made to identify melanoma patients with a positive sentinel lymph node (SLN) who are unlikely to harbor residual disease in the nonsentinel lymph nodes (NSLN). We examined whether the size and location of the metastases within the SLN may help further stratify the risk of additional positive NSLN. Methods  A review of our Institutional Review Board (IRB)-approved melanoma database was undertaken to identify all SLN positive patients with SLN micromorphometric features. Univariate logistic regression techniques were used to assess potential significant associations. Decision tree analysis was used to identify which features best predicted patients at low risk for harboring additional disease. Results  The likelihood of finding additional disease on completion lymph node dissection was significantly associated with primary location on the head and neck or lower extremity (P = 0.01), Breslow thickness >4 mm (P = 0.001), the presence of angiolymphatic invasion (P < 0.0001), satellitosis (P = 0.004), extranodal extension (P = 0.0002), three or more positive SLN (P = 0.02) and tumor burden within the SLN >1% surface area (P = 0.004). Sex, age, mitotic rate, ulceration, Clark level, histologic subtype, regression, and number of SLN removed had no association with finding a positive NSLN. Location of the metastases (capsular, subcapsular or parenchymal) showed no correlation with a positive NSLN. Decision tree analysis incorporating size of the metastatic burden within the SLN along with Breslow thickness can identify melanoma patients with a positive SLN who have a very low risk of harboring additional disease with the NSLN. Conclusion  Size of the metastatic burden within the SLN, measured as a percentage of the surface area, helps stratify the risk of harboring residual disease in the nonsentinel lymph nodes (NSLN), and may allow for selective completion lymphadenectomy.     

A Differential MicroRNA Profile Distinguishes Cholangiocarcinoma from Pancreatic Adenocarcinoma

Background

Cancers of the bile duct and the pancreas are virtually indistinguishable using conventional histopathological and clinical characteristics. We sought to use microRNA (miR) profiling to differentiate these two cancers.

Methods

RNA was harvested from the tumors of patients undergoing curative resection for cholangiocarcinoma or pancreatic adenocarcinoma and compared with adjacent normal bile duct or pancreas, respectively. There were 31 pairs of cholangiocarcinoma with matched tumor and adjacent bile duct and nine pairs of pancreatic cancer with matched tumor and adjacent uninvolved pancreas that had sufficient quantity of RNA that were included in the final analysis. Differential microRNA expression profiles were determined using the nCounter System from nanoString Technologies (Seattle, WA,USA).

Results

A total of 41 differentially expressed miRs were identified in cholangiocarcinoma (25 overexpressed, 16 underexpressed) and 52 differentially expressed miRs were found in pancreatic adenocarcinoma (30 overexpressed, 22 underexpressed) relative to adjacent normal tissue. Of these two profiles, 15 miRs were commonly dysregulated between tumor types. Also, eight miRs were similarly overexpressed or underexpressed in cholangiocarcinoma and pancreatic adenocarcinoma, whereas the other seven miRs had inverse expression levels.

Conclusions

Cholangiocarcinoma has a distinct miR profile from pancreatic adenocarcinoma. Discrimination between these two tumor types may be possible with as few as seven miRs.     

Activity of high-dose toremifene plus cisplatin in platinum-treated non-small-cell lung cancer: a phase II California Cancer Consortium Trial

PURPOSE: Although cisplatin is an important agent in non-small-cell lung cancer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include the protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregulate PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifene potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view of these findings, we hypothesized that toremifene would reverse platinum resistance and that this interaction would be influenced by tumor estrogen receptor (ER) status. MATERIALS AND METHODS: A phase II trial of high-dose toremifene (600 mg orally daily on days 1-7) plus cisplatin (50 mg/m2 intravenously on days 4 and 11) every 28 days in NSCLC patients was conducted. A group of 30 patients with metastatic NSCLC who had been previously treated with platinum-based therapy were enrolled. RESULTS: All of the 30 patients were assessable for toxicity and 28 for tumor response. Therapy was well tolerated with minimal hematologic and non-hematologic toxicity. Common toxicity criteria grade 3 hematologic toxicity was seen in only three patients. Five patients achieved a partial response for an overall response rate of 18% (95% CI 6-37). Median overall survival was 8.1 months (95% CI 5.4-17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informative pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (alpha and epsilon) while c-Fos was overexpressed in three. None of the responding patient tumors exhibited c-FOS or PKC-epsilon overexpression. ER expression was found to be infrequent (8%), contrasting with previous reports in this tumor type. CONCLUSION: While this phase II study indicates that high-dose toremifene plus cisplatin is feasible, active, and well tolerated in NSCLC patients previously treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.     

Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design

IntroductionThere are currently no approved targeted therapies for lung squamous-cell carcinoma (LSCC) and KRAS-mutant lung adenocarcinoma (LUAD). About 30% of LSCC and 25% of KRAS-mutant LUAD exhibit hyperactive NRF2 pathway activation through mutations in NFE2L2 (the gene encoding NRF2) or its negative regulator, KEAP1. Preclinical data demonstrate that these tumors are uniquely sensitive to dual inhibition of glycolysis and glutaminolysis via mammalian target of rapamycin (mTOR) and glutaminase inhibitors. This phase 1 study was designed to assess safety and preliminary activity of the mTOR inhibitor MLN0128 (sapanisertib) in combination with the glutaminase inhibitor CB-839 HCl.MethodsPhase 1 dose finding will use the queue-based variation of the 3 + 3 dose escalation scheme with the primary endpoint of identifying the recommended expansion dose. To confirm the acceptable tolerability of the recommended expansion dose, patients will subsequently enroll onto 1 of 4 expansion cohorts (n = 14 per cohort): (1) LSCC harboring NFE2L2 or (2) KEAP1 mutations, or (3) LUAD harboring KRAS/(KEAP1 or NFE2L2) coalterations, or (4) LSCC wild type for NFE2L2 and KEAP1. The primary endpoint of the dose expansion is to determine the preliminary efficacy of MLN0128/CB-839 combination therapy.ConclusionThis phase 1 study will determine the recommended expansion dose and preliminary efficacy of MLN0128 and CB-839 in advanced non–small-cell lung cancer with a focus on subsets of LSCC and KRAS-mutant LUAD harboring NFE2L2 or KEAP1 mutations.