Biomedical subjects

N Ramnath

Publications and source records attributed to N Ramnath.

6 recordsLinked to original sources

PubMed2005

Is downregulation of MHC class I antigen expression in human non-small cell lung cancer associated with prolonged survival?

PURPOSE: To characterize HLA class I antigen expression in non-small cell lung cancer (NSCLC) lesions, and to assess the clinical significance of these molecules' downregulation. METHODS: One hundred and ninety primary formalin fixed, paraffin embedded NSCLC lesions were stained with HLA class I heavy chain-specific mAb HC-10. Results were scored as percentage of stained tumor cells and categorized into three groups: 0-24% (negative), 25-75% (heterogeneous) and >75% (positive). HLA class I antigen expression was correlated with clinical and pathologic predictors of time to progression and survival and analyzed using the chi-square test. Association between HLA class I antigen expression and survival was assessed using Cox regression models, while controlling for confounders. RESULTS: HLA class I antigen expression was negative, heterogeneous and positive in 153, 25 and 12 primary NSCLC lesions, respectively. Independent variables significantly associated with survival included tumor stage, PS and weight loss. The median survival times were 40.6, 44.0 and 17.9 months for patients with a HLA class I antigen expression scored as negative, heterogeneous and positive, respectively. CONCLUSION: HLA class I antigen defects were found with high frequency (93.6%) in NSCLC lesions. HLA class I antigen downregulation was associated with improved survival, although this association was not statistically significant. These results, which parallel similar findings in uveal melanoma and in breast carcinoma, raise the possibility that NK cells may play a role in the control of NSCLC tumors.

Adult↗

PubMed2005

S-phase modulation by irinotecan: pilot studies in advanced solid tumors.

Two studies of irinotecan (CPT-11) followed 24 h later by an antimetabolite were conducted. The objectives of the studies were: (1) to determine whether the increase in S-phase in tumor cells seen 24 h after CPT-11 administration in animal studies is seen in advanced solid tumors in patients, (2) to determine the dose of CPT-11 required to produce this effect, (3) to compare two methods (immunohistochemistry, IHC, for cyclin A, and DNA flow cytometry, FC) for evaluating S-phase in tumor biopsies from patients, and (4) to establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of CPT-11, given 24 h before gemcitabine (GEM, 1000 mg/m(2)). In one study CPT-11 was followed 24 h later by 5-fluorouracil (5-FU), 400 mg/m(2) per week for 4 weeks every 6 weeks. Tumor biopsies were obtained before and 24 h after CPT-11 administration before administration of 5-FU and assayed for S-phase by IHC for cyclin A and by FC. The starting dose of CPT-11 was 80 mg/m(2) per week with subsequent exploration of 40 and 60 mg/m(2) per week to establish the dose-effect relationship of the increase in tumor cells in S-phase. In the second study, CPT-11 was given 24 h before GEM 1000 mg/m(2) per week for 2 weeks every 3 weeks. Doses of 20-80 mg/m(2) were explored to establish the MTD and DLT and to study tumor cell S-phase in selected patients. CPT-11 80 mg/m(2) produced a mean increase in S-phase by IHC for cyclin A of 137%. Lesser increases were seen with 40 and 60 mg/m(2). CPT-11 followed 24 h later by 5-FU 400 mg/m(2) per week for 4 weeks was well tolerated. In the study of CPT-11 followed by GEM 1000 mg/m(2), 60 mg/m(2) of CPT-11 was the MTD.

Adenocarcinoma↗

PubMed2004

A phase I and pharmacokinetic study of BAY59: a novel taxane.

PURPOSE: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLT) and the pharmacokinetics of BAY59, a novel taxane given as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: Initially, 15 patients with previously treated (median of 4 prior chemotherapy regimens) refractory cancers, but with normal marrow, hepatic and renal function were treated with BAY59 at doses of 15, 30, 50, 75 and 100 mg/m2 using a standard dose escalation design. Subsequently, 11 patients were treated, 5 at 90 mg/m2 and 6 who had had prior oxaliplatin at 75 mg/m2. RESULTS: At 75 mg/m2, grade 4 neutropenia was noted in 2/6 patients, of whom 1 had grade 4 neutropenia lasting more than 5 days (DLT). At 100 mg/m2, 2/2 patients had febrile neutropenia, with 1 fatality. At 90 mg/m2, 2/5 patients had DLTs, including grade 3 neuropathy, severe lower extremity pain, dehydration and grade 4 neutropenia. The MTD was determined to be 75 mg/m2. A cohort of 6 patients, previously exposed to oxaliplatin, were enrolled at the MTD to evaluate the incidence of neurotoxicity. While DLTs (grade 3 arthralgia, grade 4 neutropenia) were noted in 3/6 patients, there was no increase in the incidence of neurotoxicity. There were no responses. Pharmacokinetics of BAY59 was linear over the doses studied, with a median terminal half-life of 21 h. CONCLUSIONS: The recommended phase II dose for BAY59 is 75 mg/m2.

Adult↗

PubMed2001

MCM2 is an independent predictor of survival in patients with non-small-cell lung cancer.

PURPOSE: Minichromosome maintenance protein 2 (MCM2) is a component of the prereplicative complex. It is essential for eukaryotic DNA replication and is only expressed in proliferating cells. The prognostic utility of MCM2 compared with Ki-67, another marker of proliferating cells, on survival of patients with non-small-cell lung cancer (NSCLC) was studied. PATIENTS AND METHODS: We examined the immunohistochemical expression of MCM2 and Ki-67 in primary pathologic tumor specimens from 221 NSCLC patients. For each marker, the fraction of tumor cells with positive staining was assessed as a percentage and categorized into four groups: 0% to 24%, 25% to 49%, 50% to 74%, and > or = 75%. MCM2 and Ki-67 immunoreactivities were compared with each other, and associations with pathologic and clinical parameters predictive of survival were analyzed with the chi(2) test. Cox regression models were used to assess associations between MCM2 and Ki-67 and survival while controlling for confounders. RESULTS: Independent variables significantly associated with survival were tumor stage, performance status, and staining category. Patients with less than 25% MCM2 immunoreactivity had a longer median survival time than patients with > or = 25% MCM2 immunoreactivity (46 v 31 months; P =.039) and a lower relative risk (RR) of death (RR, 0.55, 95% confidence interval, 0.34 to 0.88). There was no significant association between survival and Ki-67 expression. CONCLUSION: Immunostaining of tumor cells for MCM2 is an independent prognostic parameter of survival for patients with NSCLC. Interpretable results can be obtained on more than 96% of paraffin-embedded specimens, and approximately 35% will be in the favorable subgroup, with less than 25% positively stained tumor cells. Whether MCM2 is predictive of response to therapy needs to be studied.

Adenocarcinoma↗

PubMed1997

Phase II evaluation of cisplatin and WR2721 for refractory metastatic breast cancer.

Cisplatin, as second-line therapy for metastatic breast cancer (MBC), has at best shown only modest response rates. At high doses, the toxicity profile of this drug may outweigh any potential benefits for MBC patients. We performed a phase II study to determine whether the investigational agent WR2721 would mitigate the toxicity of cisplatin in patients with MBC and to assess the antitumor response of cisplatin as salvage therapy. Thirteen women were enrolled in the study. Cisplatin was administered at a dose of 120 mg/m2 together with WR2721 at a dose of 910 mg/m2 intravenously every 21 days. Response was assessed at the end of two cycles, and toxicity was evaluated after each treatment cycle. No objective antitumor responses were noted. Three patients exhibited toxicity from cisplatin in the form of ototoxicity, nephrotoxicity, myelotoxicity, and persistent delayed nausea and vomiting necessitating discontinuation from the study. There was one death from renal failure. WR2721 itself caused significant but transient hypotension in 46% of the patients. In our experience, salvage chemotherapy with cisplatin in pretreated patients with MBC produced no objective responses. WR2721 did not prevent the occurrence of organ toxicity.

Adult↗

PubMedDate not supplied

Activity of 9-cis-retinoic acid and receptor-selective retinoids in small cell lung cancer cell lines.

Dysregulation of retinoid signaling pathways appears to be an early event in the pathogenesis of small cell lung cancer (SCLC). We evaluated the activity of 9-cis-retinoic acid (9cRA), a pan- receptor agonist, and two synthetic retinoids, TTNPB and LG100153, which are RAR- and RXR- selective, respectively, against a panel of SCLC cell lines. LG100153 was the most potent agent with an IC50 < 1.0 microM in three cell lines. TTNPB had an IC50 < 1.0 microM in two lines, and 9cRA an IC50 < 1.0 microM in only one. By fluorescent microscopy, LG100153, TTNPB and 9cRA also induced morphologic evidence of apoptosis in three, two and one cell lines, respectively. Although the expression of RARs and RXRs varied widely between cell lines, there was no clear correlation between the level or pattern of receptor expression and retinoid activity. These data suggest that novel retinoids, especially RXR-selective agents, deserve further evaluation in the treatment of SCLC.

Alitretinoin↗