A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy.

BACKGROUND: Up to 40% of patients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) present with disease progression in the central nervous system (CNS), either as brain metastases (BM) or leptomeningeal metastases (LM). Osimertinib (80 mg), a third-generation, irreversible, oral EGFR TKI, has shown efficacy in active CNS metastases. However, efficacy of osimertinib 160 mg in BM or LM is unclear. PATIENTS AND METHODS: This prospective, single-arm, two cohort study evaluated the efficacy of osimertinib 160 mg in T790M-positive BM or LM NSCLC patients who progressed on prior EGFR TKI (NCT03257124) treatment. The primary end points were objective response rate (ORR) (H1 = 30%) for the BM cohort and overall survival (OS) (H1 = 5 months) for the LM cohort. RESULTS: The median follow-up duration was 10.1 months and 9.6 months for the BM and LM cohorts, respectively. In the BM cohort, intracranial ORR and disease control rate were 55.0% and 77.5%, respectively. The median progression-free survival (PFS) was 7.6 months [95% confidence interval (CI) 5.0-16.6]; the median OS was 16.9 months [95% CI 7.9-not reached (NR)]. In the LM cohort, intracranial disease control rate was 92.5% and complete response rate was 12.5%. The median OS was 13.3 months (95% CI 9.1-NR); the median PFS was 8.0 months (95% CI 7.2-NR). Subgroup analyses based on previous exposure to T790M-targeting agents, including osimertinib 80 mg or other third-generation EGFR TKIs, showed no difference in PFS in both the BM (n = 18, P = 0.39) and LM (n = 17, P = 0.85) cohorts. Previous radiotherapy favored PFS in the BM cohort (hazard ratio 0.42, P = 0.04). The most common adverse events were decreased appetite, diarrhea, and skin rash; however, most were grade 1-2. CONCLUSION: Thus, osimertinib 160 mg demonstrated promising ORR and survival benefit with a tolerable safety profile in EGFR T790M-positive NSCLC patients with CNS metastasis who progressed on prior EGFR TKIs.

Prognostic significance of cachexia score assessed by CT in male patients with small cell lung cancer.

To determine the prognostic significance of CT-determined cachexia scores (CSs) in 127 consecutive male small cell lung cancer (SCLC) patients, cross-sectional areas of muscle and fat tissues at the third lumbar vertebra (L3) were retrospectively measured on baseline CT images. CSs were determined based on the presence of sarcopenia and/or adipopenia. According to the presence of sarcopenia (L3 muscle index <55 cm2 /m2 , 86.8%) and adipopenia (L3 fat index <22 cm2 /m2 , 11.8%), CSs were defined as follows: CS2 (sarcopenia and adipopenia, 11.8%), CS1 (sarcopenia only, 74.8%) and CS0 (13.4%). CS2 was significantly related to lower body mass index (p < .001) and poor performance status (p = .002), and patients with CS2 had shorter OS than patients with CS1 or CS0 (median OS, 5.0 months vs. 8.9 months vs. 18.3 months; p = .007). Multivariable analysis revealed that CS was an independent prognostic factor of poor survival (HR, 1.99 for CS1 and 2.59 for CS2, p = .036 and .023, CS0 as a reference), along with extensive stage (p < .001), supportive care only (p < .001) and an elevated lactate dehydrogenase (p = .005). CT-determined CSs, based on the presence of sarcopenia and/or adipopenia, could be used to predict prognosis in male SCLC.

Randomized phase II study of irinotecan, leucovorin and 5-fluorouracil (ILF) versus cisplatin plus ILF (PILF) combination chemotherapy for advanced gastric cancer.

BACKGROUND: Irinotecan, in combination with 5-fluorouracil (5-FU) or cisplatin, has demonstrated efficacy against advanced gastric cancer (AGC). PATIENTS AND METHODS: Chemotherapy-naive AGC patients were randomly assigned to receive irinotecan 150 mg/m(2) on day 1, leucovorin 20 mg/m(2) and a 22-h infusion of 5-FU 1000 mg/m(2) on days 1 and 2 (ILF) or ILF plus cisplatin 30 mg/m(2) on day 2 (PILF). Treatment was repeated every 2 weeks. RESULTS: Of 91 registered patients, 45 patients were treated with ILF and 45 with PILF. For both arms, 687 chemotherapy cycles were delivered (median = 7 for ILF and 8 for PILF). Both ILF and PILF were generally well tolerated and there was no relevant difference in the occurrence of overall grade 3/4 toxic effects between the two arms. Four patients died during treatment: one in the ILF and three in the PILF arm. The objective response rate was 42% for both arms. There was no significant difference in therapeutic efficacy between ILF and PILF with respect to progression-free survival (4.8 versus 6.2 months; P = 0.523) and overall survival (10.7 versus 10.5 months; P = 0.850). CONCLUSION: Both ILF and PILF are active as first-line chemotherapy for AGC. The addition of cisplatin, however, has no clear advantage over ILF.

Array-based comparative genomic hybridization and copy number variation in cancer research.

Array-based comparative genomic hybridization (aCGH) is a molecular cytogenetic technique used in detecting and mapping DNA copy number alterations. aCGH is able to interrogate the entire genome at a previously unattainable, high resolution and has directly led to the recent appreciation of a novel class of genomic variation: copy number variation (CNV) in mammalian genomes. All forms of DNA variation/polymorphism are important for studying the basis of phenotypic diversity among individuals. CNV research is still at its infancy, requiring careful collation and annotation of accumulating CNV data that will undoubtedly be useful for accurate interpretation of genomic imbalances identified during cancer research.

Locoregional response and increased natural killer activity after intratumoral injection of HLA-B7/beta2-microglobulin gene in patients with cancer.

The purpose of this study was to assess the therapeutic potential of injecting the gene for HLA-B7/beta2-microglobulin into the subcutaneous metastatic nodules of patients who are refractory to conventional treatments. The nine patients evaluated were divided into three groups and given escalating doses of DNA (20, 40, and 100 microg of the HLA-B7 plasmid DNA/lipid complex for each group) every 2 weeks. Biopsy specimens from the treated tumor nodules of all nine patients were positive for the presence of DNA and for HLA-B7 mRNA expression. Moreover, in six of the nine patients, immunohistology of tumor biopsy samples revealed the expression of recombinant HLA-B7 protein. Also, all nine patients showed an increase in NK activity in their circulating peripheral blood lymphocytes. In two lung cancer patients, one partial and one mixed response was observed after gene transfer. These responses were confined to the treated nodules and the untreated locoregional lymph nodes; the lung masses showed no regression. Remission durations were 14 and 6 weeks, respectively, and in a total of 35 cycles no significant toxicities were observed. Immunohistologic analysis revealed an increased infiltration of CD4+ T cells, macrophages, and NK cells after therapy. In two responding cases, direct intratumoral injection of an allogeneic class I gene could elicit an antitumor response in locoregional areas, possibly through the activation of NK cells.

COMT genotype and effectiveness of entacapone in patients with fluctuating Parkinson's disease.

OBJECTIVE: To investigate the relationship between the catechol-O-methyltransferase (COMT) genotype and the therapeutic efficacy of entacapone. METHODS: The efficacy of 2 months of entacapone treatment in 65 patients with PD with end-of-dose deterioration was studied. The efficacy of entacapone was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) score, the daily levodopa dosage, and the patients' diary card. RESULTS: Thirty-six patients (55.4%) had a high-activity COMT gene (COMT(HH)), 22 (33.8%) had an intermediate-activity COMT gene (COMT(HL)), and 7 patients (10.8%) had a low-activity COMT gene (COMT(LL)). Two months of entacapone treatment resulted in a significant increase in "on" time, a reduction in "off" time, and a reduction in the total UPDRS score, but these results were independent of the COMT genotype of the patient. There was no significant difference in the frequency or severity of dyskinesias between the patients with different COMT genotypes. CONCLUSION: The COMT genotype seems to be a minor factor in judging the beneficial effects of entacapone administration.

Ramosetron for the prevention of cisplatin-induced acute emesis: a prospective randomized comparison with granisetron.

Control of nausea and vomiting is very important in determining patient compliance with cisplatin chemotherapy. A multicentre, randomized, single-blind study was conducted to compare the tolerability and efficacy of ramosetron with those of granisetron over 24 h following cisplatin administration to cancer patients. In eight study centres, a total of 194 adult patients were randomly assigned to receive either intravenous ramosetron 0.3 mg or intravenous granisetron 3.0 mg. The anti-emetic effect of ramosetron determined from the no-vomiting rate lasted longer, but there was no significant difference in the number of acute vomiting episodes or the severity of nausea between the two groups. In the tolerability evaluation, there were no statistically significant differences between the two groups, except for a higher incidence of dull headache in the granisetron group. Ramosetron and granisetron appear to have equivalent efficacy and tolerability profiles, but the effects of ramosetron on the prevention of acute vomiting in patients undergoing cisplatin chemotherapy were longer lasting.

In vitro immunohistochemical localization of S-phase cells by a monoclonal antibody to bromodeoxyuridine.

Bromodeoxyuridine, an analogue of thymidine, can be detected by means of monoclonal antibodies and utilized as a marker of the S-phase of the cell cycle. In vitro immunohistochemical application of the BrdU/anti-BrdU-MAb method permits a quantitative assessment of the proliferative activity of a tissue as well as the direct location of the actively replicating cells in histological sections. In this paper, a method for the detection of the labeling index of S-phase cells in normal and neoplastic tissues with in vitro BrdU labeling and standard immunohistochemical techniques using anti-BrdU-MAb and avidin-biotin peroxidase complex is described. We have employed this method in 47 human solid tumor samples, including squamous cell carcinomas of head and neck and cervix uteri, adenocarcinomas and malignant lymphomas, and also evaluated the possible application of the BrdU labeling index to estimate the cycling S-phase cells in neoplastic cell populations. In our data, the in vitro labeling index varied greatly in an individual case (3.56-29.2%) and from an area to an area within the same case. Squamous cell carcinomas of the head and neck showed higher LI than those of the cervix uteri. A case of metastatic carcinoma to the lung from ductal carcinoma of the breast had the highest LI (29.2%), in contrast to the low LI (3.6%) in the primary ductal carcinoma of breast.

Ontogeny of natural killer cells and T cells by analysis of BCR-ABL rearrangement from patients with chronic myelogenous leukaemia.

Chronic myelogenous leukaemia (CML) is a haematological malignant disorder characterized by the Philadelphia chromosome (Ph) and BCR-ABL gene rearrangement. This abnormal fusion gene can be considered to serve as a marker for the transformed cell clone in CML and is found in all cells arising from the same malignant precursor cell. It has been detected in CML cells of the myeloid, monocytic, erythroid and B-lymphocytic lineages. However, it is still arguable as to whether T lymphocytes or natural killer (NK) cells carry this marker. Answering this question would clarify the ontogenic relationship between NK cells and T cells. We examined 12 CML patients and studied the expression of BCR-ABL rearrangement by fluorescence in situ hybridization (FISH) in both NK cells and T cells sorted by flow cytometry. The purity of T cells was 95.6-99.8% and that of NK cells was 95.3-99.3% after sorting. Neither NK cells nor T cells showed any positive BCR-ABL signal with the exception of one patient who recovered from a lymphoid blastic crisis. We speculate that T cells and NK cells originate from BCR-ABL-negative stem cells.

Phase II clinical trial of SKI-2053R, a new platinum analog, in the treatment of patients with advanced gastric adenocarcinoma.

BACKGROUND: SKI-2053R (SK Chemicals, Kyungki-Do, South Korea) is a new platinum derivative with antitumor activity against various cell lines, including cisplatin-resistant tumor cell lines. Preclinical studies have suggested that it is less nephrotoxic than cisplatin. This study evaluated the efficacy and toxicity of SKI-2053R in the treatment of patients with advanced gastric adenocarcinoma. METHODS: Thirty-seven patients with advanced gastric adenocarcinoma that was unresectable or metastatic were treated. No prior chemotherapy or radiotherapy was allowed. Patients received SKI-2053R 360 mg/m(2) by 1-hour infusion on Day 1. After the first cycle, subsequent doses were adjusted according to the toxicity. Courses were repeated every 28 days. RESULTS: Thirty-five patients were evaluable for response and toxicity. Six patients achieved a major response (17%; 95% confidence interval, 8-33%); 2 were complete and 4 were partial responses. The median duration of response was 7.2 months, with a range of 1-20 months. Patients could tolerate the treatment without significant toxicity. No patients had Grade 3 or 4 toxicity. The most frequent toxicity was Grade 1 or 2 proteinuria (26% of cycles), but it was mild and transient. Leukopenia, thrombocytopenia, azotemia, nausea and vomiting, and neurotoxicity were not frequent. These low toxicity profiles indicated that the dose of SKI-2053R could be increased in future studies. CONCLUSIONS: SKI-2053R was active in the treatment of patients with gastric adenocarcinoma and had favorable toxicity profiles.

Combination Chemotherapy of Oxaliplatin, 5-Fluorouracil, and Leucovorin in 5-Fluorouracil-Pretreated Patients with Metastatic Colorectal Cancer.

PURPOSE: To evaluate the efficacy and toxicity of oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer who previously treated with 5-FU-based chemotherapy. MATERIALS AND METHODS: Between April 1999 and January 2001, thirty-two patients were enrolled in this study. Oxaliplatin 130 mg/m2 was given intravenously (IV) on day 1 as was 5-FU 500 mg/m2 IV followed by continuous infusion of 5-FU 3,000 mg/m2 and LV 100 mg/m2 for 48 hours administered every 3 weeks. Six patients had received 5-FU as an adjuvant setting and 26 patients as a palliative regimen. RESULTS: The median age of the patients was 50 years (range; 19-69) and the dominant sites of metastasis were the liver, lung or both in 9, 5 and 2 patients respectively. In 30 evaluable patients, the overall response rate was 27% including 1 complete response and 7 partial responses. The median response duration was 28 weeks (95% confidence interval; 22~34 weeks) and the median progression free survival of all patients was 24 weeks (95% confidence interval; 15~33 weeks). A median 5 cycles (range; 2~9) and total 155 cycles were performed in 32 patients. 150 cycles were evaluable for toxicity. The most common hematologic toxicity was grade 1~2 anemia in 78 cycles (52%). Leukopenia (39%) and thrombocytopenia (23%) were fully reversible. The most common non-hematologic toxicity was nausea/vomiting (43/30%) followed by diarrhea (23%), hepatotoxicity (21%) and neurotoxicity (21%). One patient ceased therapy due to grade 4 diarrhea. No other severe toxicity interrupted this treatment. CONCLUSION: Oxaliplatin, 5-FU and LV in combination showed significant activity in previously treated metastatic colorectal cancer with favorable toxicity.