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Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation–positive non–small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR–TKIs contributes to EGFR–TKI-induced apoptosis in EGFR mutation–positive NSCLC cells. We have now investigated the role of survivin expression in EGFR–TKI resistance induced by PTEN loss. The EGFR–TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation–positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation–positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT–survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation–positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR–TKI resistance in EGFR mutation–positive NSCLC. Mol Cancer Ther; 11(1); 204–13. ©2011 AACR.

Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G1 arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G1 arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188–97. ©2010 AACR.

Supplementary Data from Identification of c-Src as a Potential Therapeutic Target for Gastric Cancer and of MET Activation as a Cause of Resistance to c-Src Inhibition

Supplementary Figure 1 from Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations

Supplementary Figure 2 from Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations

Supplementary Figure Legends 1-3 from Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations

Supplementary Figure 3 from Role of Survivin in EGFR Inhibitor–Induced Apoptosis in Non–Small Cell Lung Cancers Positive for EGFR Mutations

A 69-year-old man was clinically diagnosed as stage IV gastric cancer with peritoneal dissemination. We performed systemic chemotherapy consisting of S-1 plus oxaliplatin as a first line, and ramucirumab plus nab-paclitaxel as a second line. However, CT and EGD revealed growth of the primary tumor and the lymph nodes along the lesser curvature and adjacent to the cardia. In addition, CT revealed ascites in the rectovesical pouch. Therefore, treatment was switched to nivolumab. After 3 treatment courses, CT revealed shrinkage of lymph nodes and disappearance of ascites. After 12 courses of nivolumab, however, EGD revealed growth of the tumors in the stomach with minor hemorrhage, prompting the consideration of gastrectomy. At the time of laparotomy, the peritoneal dissemination had completely disappeared, and peritoneal cytology was negative. Therefore, total gastrectomy with D2 and paraaortic lymphadenectomy was performed, after 21 months following the initial diagnosis. To our knowledge, there are no previous reports that have demonstrated the disappearance of peritoneal dissemination and ascites in response to nivolumab, resulting in curative gastrectomy.

As the nanoparticle albumin-bound paclitaxel (nab-PTX) is free of ethanol and premedication, the duration of administration is shorter and patients can drive themselves to and from the hospital. In the 2018 Japanese gastric cancer treatment guidelines, ramucirumab (RAM) plus weekly nab-PTX is conditionally recommended for previously treated patients with advanced gastric cancer. Here, we retrospectively analysed the efficacy and safety of RAM+nab-PTX for such patients in community hospitals. From January 2018 to December 2019, 43 patients with metastatic and recurrent gastric cancer received RAM+nab-PTX treatment. Six patients (13.9%) were older than 80 years and 9 patients (20.9%) showed ECOG-PS 2. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AEs) were reviewed retrospectively. Median PFS was 114 days (95% confidence interval [CI]: 84-190) and median OS was 297 days (95% CI: 180-398). ORR and DCR were 32.4% and 72.2%, respectively. The incidence rates of ≥grade 3 neutropenia and febrile neutropenia were 53.5% and 2.3%, respectively. No treatment-related deaths occurred. RAM plus nab-PTX combination therapy demonstrated manageable toxicity even patients who were elderly or had an ECOG-PS 2. This treatment is useful in community hospital settings.

This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC). The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed. Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8 mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients. Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC. UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR).

Background and study aims Salvage therapy for esophageal cancer following chemo-radiation therapy (CRT) has not been established. We aimed to evaluate endoscopic submucosal dissection (ESD) as a salvage therapy based on histopathological features of lesions. Patients and methods We compared 10 lesions in eight patients with local residual, recurrent, or metachronous esophageal squamous cell carcinoma treated by ESD after CRT (CRT group) and 59 lesions treated by ESD without CRT (non-CRT group) during the same period. Results The en bloc resection rate was 100 % while the complete resection rate was 80.0 % in the lesions after CRT, indicating no difference between the CRT and non-CRT groups. Pathological examination showed that fibrosis was more intense in the lamina propria mucosa, muscularis mucosa, and submucosa. The muscularis mucosa was thicker in both non-tumor and tumor sites in the CRT group compared to the non-CRT group. However, severe submucosal fibrosis was observed only in one lesion in the CRT group. The maximum diameter of the submucosal artery was significantly larger in the CRT group (P Conclusions Compared to the non-CRT group, the lesions in the CRT group were accompanied by fibrosis while the muscularis mucosa were thicker; however, severe fibrosis of the submucosa was rare. It is important to dissect the muscularis mucosa appropriately during ESD, which makes successful dissection of the submucosa possible. Attention should be paid to bleeding from large arteries.

Lenvatinib, a novel potent multikinase inhibitor, was approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on results from phase III trial (SELECT study). Thyroid cancer is a diverse disease that includes anaplastic thyroid cancer (ATC), which the most aggressive form of the disease, although it accounts for

Introduction Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non–small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4– ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK -rearranged NSCLC. Materials and Methods Eleven patients with ALK -rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. Results The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 0-20.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Conclusion Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK -rearranged NSCLC.

We propose a new method for fitting a high-quality planar curve to styling design data by using a curvature continuous ( G 2 ) quadratic B-spline curve. In order to attain G 2 continuity of the B-spline curve, we use a non-uniform knot vector, which also enables the curve to be composed of fewer segments as compared to a uniform curve. In our method, control points and the knot vector of the B-spline curve are calculated separately; therefore, we can avoid solving a complicated nonlinear optimization problem. By conducting experiments, we demonstrate that high-quality curves can be generated from both artificial noisy data and real-world scanned data. We propose a method for fitting a G 2 quadratic B-spline curve to planar styling design data. G 2 continuity is attained by using a non-uniform knot vector of the B-spline curve.High-quality curves have been obtained from noisy styling design data.

Background The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer. Patients and methods We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS). Results Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027). Conclusions Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of ≥95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments. Clinical trial registration The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.

SummaryAmatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m2. Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m2 and one at 200 mg/m2; the maximum tolerated dose of this study was determined to be 200 mg/m2. Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m2. The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).

// Hisato Kawakami 1 , Isamu Okamoto 1, 2 , Kimio Yonesaka 1 , Kunio Okamoto 1 , Kiyoko Shibata 1 , Yume Shinkai 1 , Haruka Sakamoto 1 , Michiko Kitano 1 , Takao Tamura 1 , Kazuto Nishio 3 , Kazuhiko Nakagawa 1 1 Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan 2 Center for Clinical and Translational Research, Kyushu University Hospital, Higashiku, Fukuoka 812–8582, Japan 3 Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589–8511, Japan Correspondence to: Isamu Okamoto, e-mail: okamotoi@kokyu.med.kyushu-u.ac.jp Keywords: colorectal cancer, heregulin, resistance, cetuximab, patritumab Received: September 21, 2014 Accepted: October 26, 2014 Published: December 19, 2014 ABSTRACT We previously showed that tumor-derived heregulin, a ligand for HER3, is associated with both de novo and acquired resistance to cetuximab. We have now examined whether patritumab, a novel neutralizing monoclonal antibody to HER3, is able to overcome such resistance. Human colorectal cancer (DiFi) cells that are highly sensitive to cetuximab were engineered to stably express heregulin by retroviral infection, and the effects of cetuximab and patritumab on the resulting DiFi-HRG cells were examined. DiFi-HRG cells released substantial amounts of heregulin and showed resistance to cetuximab. Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies cetuximab resistance in these cells. In contrast, patritumab in combination with cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination therapy also inhibited the growth of DiFi-HRG tumor xenografts in nude mice to a greater extent than did treatment with either drug alone. Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin-induced HER3 activation.

Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.

The purpose of the study was to identify factors that predict unplanned admission for metastatic cancer patients visiting the emergency department (ED). Patients visiting the ED of a general hospital from April 2012 to March 2013 were investigated retrospectively. Data including demographics, vital signs, and laboratory measurements were collected from a chart review for each patient. Factors related to emergency admission were identified by univariate and multivariate analyses. A total of 15,716 individuals visiting the ED during the study period included 1244 (7.9%) patients with cancer. Among the 491 cancer patients with metastasis, univariate analysis revealed that emergency admission was significantly associated with an age of ≥76 years; an altered mental status; fever (≥38 °C); a blood oxygen saturation of

Targeting of tumor angiogenesis with vaccines is a potentially valuable approach to cancer treatment. Elpamotide is an immunogenic peptide derived from vascular endothelial growth factor receptor 2, which is expressed at a high level in vascular endothelial cells. We have now carried out a phase I study to evaluate safety, the maximum tolerated dose, and potential pharmacodynamic biomarkers for this vaccine. Ten HLA-A*24:02-positive patients with advanced refractory solid tumors received elpamotide s.c. at dose levels of 0.5, 1.0, or 2.0 mg once a week on a 28-day cycle. Five patients experienced an injection site reaction of grade 1 and 2, which was the most frequent adverse event. In the 1.0 mg cohort, one patient experienced proteinuria of grade 1 and another patient developed both hypertension and proteinuria of grade 1. No adverse events of grade 3 or higher were observed, and the maximum tolerated dose was therefore not achieved. The serum concentration of soluble vascular endothelial growth factor receptor 2 decreased significantly after elpamotide vaccination. Microarray analysis of gene expression in PBMCs indicated that several pathways related to T cell function and angiogenesis were affected by elpamotide vaccination, supporting the notion that this peptide induces an immune response that targets angiogenesis in the clinical setting. In conclusion, elpamotide is well tolerated and our biomarker analysis indicates that this anti-angiogenic vaccine is biologically active. Clinical trial registration no. UMIN000008336.

Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G1 arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G1 arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188–97. ©2010 AACR.

Objective: The optimal management of elderly patients with limited-disease small cell lung cancer (LD-SCLC) has not been established. Methods: The records of elderly (� 70 years of age) patients with LD-SCLC who had been treated with etoposide and cisplatin chemotherapy with early concurrent twice-daily thoracic radiotherapy (TRT) were reviewed retrospectively. Results: Of the 25 elderly patients with LD-SCLC identified, 12 (48%) individuals received etoposide‐cisplatin chemotherapy with early concurrent twice-daily TRT. The main toxicities of this treatment regimen were hematologic, with neutropenia of Grade 4 being observed in all patients and febrile neutropenia of Grade 3 in eight patients during the first cycle of chemoradiotherapy. The toxicity of TRT was acceptable, with all patients completing the planned radiotherapy within a median of 29 days (range, 19‐33). No treatment-related deaths were observed. The median progression-free survival and overall survival times were 14.2 months (95% confidence interval, 4.3‐18.2) and 24.1 months (95% confidence interval, 11.3‐27.2), respectively. Conclusions: Etoposide‐cisplatin chemotherapy with early concurrent twice-daily TRT was highly myelotoxic in elderly patients with LD-SCLC, although no treatment-related deaths were observed in our cohort. Prospective studies are required to establish the optimal schedule and dose of chemotherapy and TRT in such patients.

PURPOSE: N-isopropyl-p[I-123]iodoamphetamin (IMP) is transiently taken up by the lungs after intravenous injection and its concentration in arterial blood varies depending on the degree of I-123 IMP uptake and subsequent washout. A method that does not require arterial blood sampling would be valuable to measure cerebral blood flow (CBF) using I-123 IMP. METHODS: The authors developed a new theory and a convenient new method of CBF determination using I-123 IMP that does not require blood sampling. Dynamic images of the head and chest were acquired immediately after intravenous injection of I-123 IMP in a series of 42 consecutive patients with cerebrovascular disorders or other brain diseases (31 men, 11 women; mean age, 58 +/- 11 years). Changes in the I-123 IMP counts of the regions of interest set in the head and pulmonary trunk were analyzed by the graph plot method, and the F values (CBF index slope) determined were compared with the mean CBF levels obtained by simultaneous autoradiography. RESULT: The F values correlated well with the mean CBF obtained by autoradiography (r = 0.818, P < 0.001). CONCLUSIONS: This innovative I-123 IMP graph plot analysis method using the time-activity curve of the head and pulmonary trunk alone is a noninvasive, convenient way to measure CBF. It is expected to become the most useful clinical technique for measuring CBF with I-123 IMP. This method can be used for patient follow-up and for comparing different patient groups evaluated in regional CBF studies.

Background Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene ( EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance. Materials and methods PC-9 and 11_18 cell lines ( EGFR -mutated NSCLC cell lines) were cultured with 1μM nicotine for 3 months and were designated as PC-9/N and 11_18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro . Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR -mutated NSCLC who were treated with gefitinib. Results The PC-9/N and 11_18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment. Conclusions Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI.

Background Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity. Patients and Methods We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (≥60 mg/m2) of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%). Results Cisplatin-induced nephrotoxicity was observed in 127 patients (32%). Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004) and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio, 1.357; P = 0.047) were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004). The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025). Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012). Conclusions A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further investigation in a prospective trial.

We performed a pharmacokinetic phase I trial of the combination of S-1 granules and nedaplatin for head and neck squamous cell carcinoma (HNSCC).Patients were treated with both nedaplatin on day 1 at a dose starting at 80 mg/m(2) (level 1) escalating up to 90 mg/m(2) (level 2), and S-1 granules at a daily dose of 80 mg/m(2) on days 1 to 14 every three weeks. The primary end-point was determination of the recommended dose.Twenty patients were enrolled. Dose-limiting toxicities occurred in one out of six patients at dose level 1 (neutropenia) and in all three patients at level 2 (neutropenia and thrombocytopenia). The recommended dose was determined as level 1. Pharmacokinetic parameters of S-1 granule did not differ from the capsula formulation. The response rate was 42.1%.This combination was well-tolerated and manifested a promising activity against HNSCC.

We report contemporaneous bronchoscopic findings for a case of bevacizumab-related pulmonary hemorrhage in a patient with advanced non-small cell lung cancer (NSCLC). Flexible bronchoscopy at diagnosis revealed abnormal capillary dilation that was suggestive of endobronchial involvement at the primary tumor location. The patient developed massive hemoptysis despite of marked tumor shrinkage achieved by bevacizumab-containing chemotherapy. Emergency flexible bronchoscopy for hemoptysis suggested that the location of the primary tumor was the source of bleeding. Subsequent follow-up flexible bronchoscopy revealed an ulcerative mucosal-like lesion associated with a white necrotic substance as well as attenuation of the dilation of submucosal vessels compared with that apparent at diagnosis. Our case report highlights the potential mechanistic insights into bevacizumab-related bleeding and importance of performing bronchoscopy at diagnosis in NSCLC patients, given that abnormal bronchoscopic findings may be a risk factor for bleeding.

e20585Background: Based on the mechanism of action and preclinical evidence of overcoming EGFR-TKI resistance in EGFR mutant non-small cell lung cancer (NSCLC) cells by targeting survivin, a member...

e20042Background: Concurrent platinum-based chemotherapy with thoracic radiation therapy (TRT) is well established with standard therapy in locally advanced NSCLC pts. Nanoparticle albumin-bound pa...

Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation–positive non–small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR–TKIs contributes to EGFR–TKI-induced apoptosis in EGFR mutation–positive NSCLC cells. We have now investigated the role of survivin expression in EGFR–TKI resistance induced by PTEN loss. The EGFR–TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation–positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation–positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT–survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation–positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR–TKI resistance in EGFR mutation–positive NSCLC. Mol Cancer Ther; 11(1); 204–13. ©2011 AACR.

The molecular mechanism by which epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non–small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation–positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation–positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI–induced apoptotic death in these cells. Cancer Res; 70(24); 10402–10. ©2010 AACR.

The title carbenium ion 1 was observed by low temperature NMR in solution. Its strong oxidizing power was demonstrated by the reduction potential and the effective oxidation of methoxy-substituted benzopinacolone 3 .

Publisher Summary This chapter deals with the ionic dissociation of carbon–carbon σ bonds in hydrocarbons and the formation of authentic hydrocarbon salts. Carbon compounds are most commonly constructed using covalent bonds, and the nature of the bond is of prime importance in all organic compounds. Among the compounds of carbon, hydrocarbons, which are made up of only hydrogen and carbon, are the simplest known group of organic compounds having exclusively covalent bonds. The search for such novel hydrocarbons depends primarily on the synthesis and examination of highly stabilized hydrocarbon cations and anions. The details of structural features such as the length of the carbon–carbon bond σ that easily undergoes heterolysis and the spatial arrangement of ions in hydrocarbon salts are intriguing subjects. Electrical characterization of the hydrocarbon salts, though they are not stable enough to air and light, might be useful as new functional materials.

The title carbenium ion 1 was observed by low temperature NMR in solution. Its strong oxidizing power was demonstrated by the reduction potential and the effective oxidation of methoxy-substituted benzopinacolone 3 .

The perchlorates of 7-tropylionorbornane, 2-tropyliobicyclo[2.2.2]octan be, and 2-tropylioadamantane were found to undergo stereomutation in acetonitrile at 25-85°C, as evidenced by following the change in the 13 C NMR spectra of their deuterium-labeled compounds is acetonitrile-d 3 . Addition of tetracyanoethylene to their solutions in acetonitrile gave the [8+2] cycloaddition products of the corresponding heptafulvenes, indicating the intermediacy of the heptafulvenes. This stereomutation was too slow to detect in dichloromethane at the same temperature. Therefore, it is concluded that the stereomutation proceeds through the abstraction of the α-hydrogen by acetonitrile as a base followed by the protonation of the heptafulvene intermediate from the rear side

Four solid hydrocarbon salts 2.1, 3.1, 4.1 and 5.1 consisting of Kuhn's anion, tris(7H-dibenzo[c,g]-fluorenylidenemethyl)methide ion (C 67 H 39 − , 1) as a carbanion moiety, and tris[1-(5-isopropyl-3,8-dimethyl-azulenyl)]cyclopropenylium (C 48 H 51 + , 2), tricyclopropylcyclopropenylium (C 12 H 15 + , 3), 1-[(2,3-diphenylcycloprop-2-enylidene)methyl]-2,3-diphenylcyclopropenylium (C 31 H 21 + , 4), or 1,3,5-tricyclopropyltropylium (C 16 H 19 + , 5) as a carbocation moiety were prepared and their properties investigated. The salt formation was proved by satisfactory elemental analyses, IR spectra (KBr disk), and UV-vis (DMSO) spectra, the spectra consisting of those of the respective cations and Kuhn's anion superimposed. Essentially complete ionization of the hydrocarbon salts 2.1 and 3.1 in DMSO was also evidenced by electric conductivity measurements

Tris(cyclopentadienyl)methane trianion has been synthesized via triferrocenylmethyl derivatives. The dynamic 1H NMR spectroscopy indicates the barrier to internal rotation of cyclopentadienido rings.

Optically active (1-methylpropyl)tropylium ion ( 1 ) and (2-bicyclo[2.2.2]octyl)tropylium ion ( 2 ) have been synthesized. The first-order rate constants of racemization via intermolecular prototropy of 1 provide a novel scale for the kinetic Bronsted basicity of organic solvents.

For patients with advanced or metastatic breast cancer (MBC) who have been heavily pretreated with conventional chemotherapy, there continues to be a significant unmet need for additional treatment options that are effective, well-tolerated and easily administered. Eribulin is a water-soluble, non-taxane microtubule dynamics inhibitor. With a mechanism of action distinct from currently available tubulin-targeting compounds, eribulin inhibits microtubule polymerisation but not depolymerisation and induces tumor cell apoptosis. In the single-arm, multicenter phase II trial in Japan, 80 patients pretreated with an anthracycline and a taxane were enrolled. Patients had received one to five prior chemotherapy regimens (median of 3) including 0 to 3 regimens (median of 2) in the metastatic setting. Eribulin 1.4 mg/m2 was iv. administered over 2–5 min on days 1 and 8 of each 21-day cycle. The independent review indicated the overall response rate (ORR) of 21.3% for the primary efficacy end point. Stable disease (SD) occurred in 30 patients (37.5%) and the clinical benefit rate (CR + PR + SD for 6 months or longer) was 27.5%. The median duration of response was 3.9 months, progression-free survival was 3.7 months and overall survival was 11.1 months. The most frequent treatment-related grade 3/4 adverse events were neutropenia (95.1%), leukopenia (74.1%) and febrile neutropenia (FN) (13.6%). Grade 3 peripheral neuropathy occurred in 3.7% of patients (no grade 4). The study suggested that eribulin exhibited efficacy and tolerability in patients with heavily pretreated MBC. Recently, eribulin gained the approval for MBC in Japan, as in other countries. Since then, a number of patients with MBC were treated with eribulin in our hospital. The patients included who belonged to aged population, who received several regimens of prior chemotherapy and/or who showed worsened performance status. For eribulin treatment, we managed the hematological and non-hematological toxic effects by the appropriate modification of starting dose, dosing schedule or dose reduction dependent upon the patient conditions. Our clinical observations suggest that eribulin can be the potential drug to contribute to the long-term disease control in pretreated MBC patients. The considerable event and management will be reviewed and discussed in this session.

Purpose Acquired resistance to cetuximab is a major problem in the treatment of colorectal cancers. We previously showed that the HER3/HER4 ligand heregulin induced resistance to cetuximab by increasing the association between HER2 and HER3, and subsequent activation of downstream targets. We have now investigated strategies to overcome such resistance, using patritumab, a novel neutralizing HER3 antibody. Experimental design We established DiFi cells that stably express heregulin (DiFi-HRG cells) as a result of retroviral infection, and examined the antitumor effect of cetuximab, patritumab, and the combination of both in these cells in vitro and vivo. Results DiFi-HRG cells secreted large amount of heregulin and exhibited resistance to cetuximab. Cetuximab alone down-regulated ERK phosphorylation, whereas it had no effect on AKT phosphorylation, suggesting that continuous AKT activation underlain underlies resistance to cetuximab in these cells. In contrast, Patritumab in combination with cetuximab markedly reduced the level of phosphorylation of HER2 HER3 and AKT, as well as ERK, and induced apoptosis that was accompanied by upregulation of BIM and by downregulation of survivin in vitro. Furthermore, the combination therapy also markedly inhibited the growth of DiFi-HRG tumors in nude mice to a greater extent than did treatment with either drug alone. Conclusion Our data indicate that HER2/HER3 signaling activated by a heregulin-autocrine loop confers resistance to cetuximab, and that patritumab restored sensitivity to cetuximab by inhibition of HER3 phosphorylation that is stimulated by heregulin. Citation Format: Hisato Kawakami, Isamu Okamoto, Kimio Yonesaka, Kunio Okamoto, Kiyoko Kuwata, Yume Morita, Haruka Yamaguchi, Kazuto Nishio, Kazuhiko Nakagawa. Novel HER3 neutralizing antibody, patritumab abrogates cetuximab resistance mediated by a heregulin-autocrine loop in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1844. doi:10.1158/1538-7445.AM2014-1844