Purpose The antisense oligonucleotide, LY2275796, blocks expression of eIF-4E, an mRNA translation regulator upregulated in tumors. This Phase I study sought an appropriate LY2275796 dose in patients with advanced tumors. Experimental Design A 3-day loading dose, then weekly maintenance doses, were given to 1–3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations; tumor biopsies, to quantify eIF-4E mRNA/protein. Results Thirty patients with Stage 4 disease received ≥1 LY2275796 dose. A dose-limiting toxicity was observed at 1200 mg, with 1000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1–2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and post-dose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and seven patients achieved stable disease (minimum of 6 weeks) as best response, with two patients on therapy >3 months (one with melanoma, one with cystadenocarcinoma of the head/neck). Conclusions LY2275796 was well tolerated up to 1000 mg. Since tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.

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BACKGROUND: The staging system for non–small cell lung cancer (NSCLC) does not consider tumor burden or number of metastatic sites, although oligometastases are more favorable. METHODS: Using log‐rank testing, the authors analyzed overall survival (OS) in 1284 patients newly presenting with metastatic NSCLC by number of metastatic organ sites and the presence of brain metastases. RESULTS: OS for patients without brain metastases was found to be correlated with the number of metastatic sites (P = .0009). Brain metastases conferred an inferior OS (median of 7 months vs 9 months; 95% confidence interval, 7‐8 months vs 8‐10 months [P = .00,002]). To evaluate the influence of tumor burden on OS, the authors considered subsets of patients in whom the brain (n = 135) or lung (n = 137) was the solitary metastatic organ site. In patients with brain metastases, OS was found to be correlated inversely with the volume of all metastases or the largest lesion (hazards ratio, 1.04 or 1.03, respectively; P = .01). For patients with lung metastases, OS was better for those with a maximum tumor size below the median of 40 mm (P = .0004). CONCLUSIONS: Staging of NSCLC and clinical trial patient stratification should include quantitation of tumor burden. The prognostic impact of brain metastases is small and partly dependent on tumor volume, which indicates the need for aggressive therapy for patients with NSCLC brain metastasis and their inclusion in clinical trials. Cancer 2009. © 2009 American Cancer Society.

BACKGROUNDThe primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed‐carboplatin combination as first‐line therapy in patients with advanced nonsmall cell lung cancer.METHODSEligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration–time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis.RESULTSFifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety‐six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1‐year survival 56.0%, and median survival 13.5 months.CONCLUSIONSThis is an active, very well‐tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted. Cancer 2005. © 2005 American Cancer Society.

Autophagy appears to play an important role in the normal development and maintenance of homeostasis in a variety of tissues, including the female reproductive tract. However, the role of autophagy and the association between autophagy and apoptosis in cyclic remodeling of the human endometrium have not been described. Therefore, we investigated the involvement of autophagy during the human endometrial cycle and its association with apoptosis. Endometrial samples were obtained from 15 premenopausal, nonpregnant women who underwent hysterectomies for benign gynecological reasons. The autophagy-associated protein, microtubule-associated protein 1 light chain 3 alpha (MAP1LC3A), was immunolocalized, and its expression level was measured by Western blot analysis. Apoptosis was evaluated by measuring the expression level of cleaved caspase 3 protein. MAP1LC3A protein was primarily expressed within the endometrial glandular cells and increased during the secretory phase. The expression level of the membrane-bound form of MAP1LC3A (MAP1LC3A-II) also increased as the menstrual cycle progressed, reaching a maximum level during the late secretory phase. This pattern coincided with the expression of cleaved caspase 3. Furthermore, expression of MAP1LC3A-II and cleaved caspase 3 increased in the in vitro-cultured endometrial cancer cells when estrogen and/or progesterone were withdrawn from the culture media to mimic physiological hormonal changes. These findings suggest that endometrial cell autophagy is directly involved in the cyclic remodeling of the human endometrium and is correlated with apoptosis. In addition, we inhibited autophagic processes using 3-methyladenine (3-MA) or bafilomycin A1 (Baf A1) to evaluate the role of autophagy in apoptosis induction in endometrial cancer cells. While the inhibition of autophagosome formation using 3-MA did not decrease apoptosis or cell death, the inhibition of autophagosome degradation by fusion with lysosomes using Baf A1 increased apoptosis and cell death, suggesting that the accumulation of autophagosomes induces apoptosis. Furthermore, Baf A1-induced apoptotic cell death was decreased by the apoptosis inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK). In conclusion, these results indicate that autophagy is involved in the endometrial cell cycle affecting apoptosis and is most prominent during the late secretory phase.

Our results indicate that CD4(+) CD25(+) regulatory T cells as well as Foxp3 may play a crucial role in immunological imbalance of AR. These findings suggest that increasing Foxp3 and CD4(+)CD25(+) T cells have the potential to be new therapeutic targets for the treatment of AR.

Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for >or= 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.

Loss of heterozygosity (LOH) at chromosome 10q23-q25 is frequent in small cell lung cancer (SCLC), indicating the presence of putative tumor suppressor genes. PTEN/ MMAC1, a newly cloned candidate tumor suppressor gene at 10q23, was mutated in multiple human cancers. We investigated whether mutations of PTEN/MMAC1 play an important role in SCLC tumorigenesis. We examined 16 SCLC cell lines for PTEN/MMAC1 mRNA expression by reverse-transcriptase polymerase chain reaction (RT ± PCR) and potential mutations by sequencing analysis of the PTEN/MMAC1 coding region. No mutation was observed in PTEN/MMAC1 cDNAs in 15 cell lines expressing PTEN/MMAC1. One SCLC cell line, DMS79, did not have detectable PTEN/ MMAC1 expression. Importantly, we identi®ed a novel homologue of PTEN/MMAC1, termed PTH2, localized to chromosome 9p21-q13 and containing only ten amino acid substitutions compared with the PTEN/MMAC1 coding region. However, because the putative initiation codon for PTEN/MMAC1 gene was changed to arginine in PTH2, the translational initiation site of PTH2 is very likely to di er from that of the PTEN/MMAC1. PTH2 was expressed in two normal lung tissues and two normal colon tissues, but in only four of 16 SCLC cell lines. A missense mutation in PTH2 was identi®ed in a SCLC cell line that did not express PTEN/MMAC1 mRNA. Our data suggest that inactivation of PTEN/ MMAC1 is a rare event in SCLC tumorigenesis. However, the PTEN/MMAC1 homologue PTH2 may play a role in SCLC tumorigenesis.