Yukiko Mori

Safety and Antitumor Activity of Anti–PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer

PURPOSE Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer. PATIENTS AND METHODS Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014. RESULTS Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination. CONCLUSION This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).

Gli-1 Expression Is Associated with Lymph Node Metastasis and Tumor Progression in Esophageal Squamous Cell Carcinoma

Objective: We investigated the expression and function of the hedgehog (Hh) pathway in human esophageal squamous cell carcinoma (ESCC). Methods: The expression of Hh pathway molecules were detected in 34 human ESCC cell lines by RT-PCR. Subsequently, we investigated the effects of cyclopamine, a specific inhibitor of the Hh pathway, on cell proliferation, migration and invasion. Next, the effects of siRNA targeting Gli-1 were examined. Immunohistochemically, the expression of Gli-1 was studied in 104 ESCC specimens and compared with the clinicopathological characteristics of the patients. Results: Gli-1 were expressed in 31 of 34 cell lines (91%), while Sonic hedgehog (SHh), Patched (Ptch), and Smoothened (Smo) expression was noted in all 34 cell lines. Cyclopamine significantly inhibited cell proliferation and migration in ESCC cells that expressed Gli-1. siRNA targeting Gli-1 inhibited cell growth in ESCC cells. Gli-1 was expressed in 52 of 104 cancer specimens (50%). Gli-1 expression was associated with tumor depth (p < 0.001), positive lymph node metastasis (p = 0.004) and a poor prognosis (p = 0.0047). Conclusion: Our results raise the possibility that the inhibition of the Hh pathway could be a novel target for esophageal cancer therapy.

Clinical Significance of Osteopontin in Esophageal Squamous Cell Carcinoma: Comparison with Common Tumor Markers

Objective: Osteopontin (OPN) is a secreted integrin-binding glycophosphoprotein that may have a role in head and neck squamous cell carcinoma (SCC). To evaluate the clinical significance of OPN in esophageal squamous cell carcinoma (ESCC), we compared plasma OPN levels with those of common tumor markers. Methods: Preoperative plasma OPN levels were measured by enzyme immunoassay in 103 ESCC patients. Serum SCC antigen, Cyfra 21-1, and carcinoembryonic antigen (CEA) levels were also measured routinely at admission by radioimmunoassay. Results: Plasma OPN levels ranged from 82.8 to 1,980 ng/ml. High OPN level was associated with lymph node metastasis (p = 0.05), but not with tumor histology or depth of invasion. The overall survival of the patients with high OPN levels was worse than that of those with low OPN levels (p = 0.02). SCC antigen and Cyfra 21-1 levels were associated with the depth of tumor invasion, the tumor diameter, lymph node metastasis, and the overall survival, but CEA was not associated with these clinicopathological factors. Combined evaluation of OPN plus Cyfra 21-1 or OPN plus SCC antigen was useful as an independent prognostic indicator. Conclusion: Measurement of the plasma OPN level, as well as serum SCC antigen and Cyfra 21-1, may help to predict the progression of ESCC.

Neutrophil-to-lymphocyte ratio for predicting palliative chemotherapy outcomes in advanced pancreatic cancer patients

Several previous studies reported that the neutrophil‐to‐lymphocyte ratio (NLR) could be a promising prognostic factor for patients with cancer. We aimed to determine the prognostic value of NLR in patients with advanced pancreatic cancer (APC) following palliative chemotherapy. We retrospectively reviewed 252 consecutive APC patients receiving palliative chemotherapy between January 2006 and December 2012. We classified the patients according to the pretreatment NLR values (≤5 or >5) into two groups and investigated the difference in treatment outcomes, including time to treatment failure (TTF) and overall survival (OS). A total of 212 patients had pretreatment NLR values of ≤5 (group A), while 40 patients had an NLR of >5 (group B). TTF and OS were significantly shorter in group B than in group A (3.1 vs. 8.7 months and 6.0 vs. 12.8 months, respectively; both P < 0.01). After adjustment for putative prognostic factors, including distant metastasis, status of recurrent/unresectable disease, pretreatment carbohydrate antigen 19‐9 levels, and carcinoembryonic antigen levels using the Cox regression model, elevated pretreatment NLR remained an independent poor prognostic factor for OS (hazard ratio, 1.92; 95% confidence interval, 1.27–2.90; P < 0.01). In addition, patients in group B whose NLR dropped to ≤5 before the second cycle of chemotherapy showed longer TTF and OS compared with those whose NLR remained at >5. Our results support the idea that NLR can be a promising prognostic and predictive marker for APC patients receiving palliative chemotherapy.

The Biological Role of the Low-Affinity p75 Neurotrophin Receptor in Esophageal Squamous Cell Carcinoma

In this study, we investigated the clinicopathologic significance of the low-affinity p75 neurotrophin receptor (p75NTR; which is expressed in the stem/progenitor cell fraction of normal esophageal epithelial cells) in 187 resected esophageal squamous cell carcinoma (ESCC) specimens and found that ∼50% of ESCC expressed p75NTR. Our investigation using ESCC cell lines showed that p75NTR was intensely expressed in the cells with high colony-forming capacity but they were sensitive to cell death on inhibition of p75NTR expression with transient transfection of small interfering RNA (siRNA). These findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies. Purpose: p75NTR is expressed in a stem/progenitor cell fraction of human normal esophageal epithelial cells. In this study, we investigated the expression and biological role of p75NTR in ESCC. Experimental Design: The expression of p75NTR in 187 resected ESCC specimens was immunohistochemically investigated. The expression of p75NTR in 30 ESCC cell lines (KYSEs) was assessed by reverse transcription-PCR, immunocytochemistry, and flow cytometry. The p75NTR-bright and p75NTR-dim/negative cells were isolated from KYSE150 by magnetic beads and colony formation was investigated. The role of p75NTR in KYSEs was assessed by transient transfection of siRNA. Results: p75NTR was expressed in 92 of 187 (49.2%) tumors. In well-differentiated tumors, positive staining was apparent in the first one to two layers from infiltrative margin of the tumors where most of the cells were actively proliferating. In moderately differentiated tumors, p75NTR was expressed in wider range from the margin of the tumors whereas p75NTR was diffusely distributed in poorly differentiated tumors. p75NTR was expressed in all examined KYSEs and the mean proportion of the p75NTR-bright fraction was 30.1%. The size of p75NTR-positive colonies was larger than that of p75NTR-negative colonies derived from KYSE150 (P < 0.0001). The purified p75NTR-bright cells formed p75NTR-positive large colonies more frequently than the p75NTR-dim/negative cells (P < 0.0001). Down-regulation of p75NTR expression by siRNA resulted in marked growth inhibition with induction of apoptosis. Conclusions: Our findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies.

Associations between glutathione S-transferase π Ile105Val and glyoxylate aminotransferase Pro11Leu and Ile340Met polymorphisms and early-onset oxaliplatin-induced neuropathy

PURPOSE Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase pi (GSTP1) Ile(105)Val, and glyoxylate aminotransferase (AGXT) Pro(11)Leu and AGXT Ile(340)Met. EXPERIMENTAL DESIGN Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment. RESULTS Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1(105)Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant (P=0.098). There were similar numbers of patients carrying at least one AGXT(105)Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P=0.725). The AGXT(11)Leu allele was not found in any of our patients or controls. CONCLUSIONS We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile(105)Val and AGXT Ile(340)Met polymorphisms. Given that no AGXT(11)Leu allele was found among our study population (n=177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.

Oxaliplatin-Free Interval as a Risk Factor for Hypersensitivity Reaction among Colorectal Cancer Patients Treated with FOLFOX

Background: Hypersensitivity reaction (HSR) and sensory neuropathy are major complications of oxaliplatin-based chemotherapy. Preplanned withdrawal of oxaliplatin after the first six cycles and reintroduction at the time of disease progression (stop-and-go strategy) may reduce neurotoxicity. However, the effect of an oxaliplatin-free interval on HSR occurrence remains poorly understood. Patients and Methods: Data on patients with colorectal cancer who received FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) treatment between June 2005 and June 2009 were retrieved from the prospective cohort database of the Outpatient Oncology Unit of the Kyoto University Hospital. Factor analysis was performed. Results: Among patients who received six or fewer cycles of FOLFOX, the incidence of HSR was low (7/99, 7.1%). For patients who received more than six cycles, the incidence of HSR was higher among patients treated with stop-and-go FOLFOX than among patients treated with continuous FOLFOX (25/61, 41.0% vs. 13/63, 20.6%; p = 0.019). Interestingly, most cases of HSR during stop-and-go FOLFOX occurred during the second or third cycle of the reintroduction phase (21/25, 84%). Multivariate analysis identified undergoing an oxaliplatin-free interval as an independent risk factor (p = 0.016). Conclusions: An oxaliplatin-free interval may increase the risk of HSR. Special vigilance is needed during the second and third cycles after reintroduction of oxaliplatin.

A case of progressive digital ischemia after early withdrawal of gemcitabine and S-1 in a patient with systemic sclerosis.

The safety of chemotherapy for patients with systemic sclerosis is unclear, and there are few published reports documenting the side effects of chemotherapy in patients with this condition. Here, we report the case of a patient with systemic sclerosis who developed severe digital ischemia during combination gemcitabine/S-1 chemotherapy for pancreatic cancer. In spite of aggressive treatment, the digital ischemia progressively worsened and gangrenous changes developed in multiple fingers and toes. In this patient, the systemic sclerosis had been well controlled, with no digital ischemic symptoms for the previous 6 years, so this progressive clinical course in spite of aggressive treatment strongly suggests that the chemotherapy triggered or aggravated the digital necrosis. To the best of our knowledge, this is only the third reported case of a patient with systemic sclerosis developing digital necrosis after gemcitabine-based chemotherapy. The incidence of digital necrosis during chemotherapy in patients with systemic sclerosis is unknown, and the mechanism by which it occurs is unclear, but the three reports published to date, including the present case, suggest that physicians should be very cautious about administering gemcitabine-based chemotherapy to patients with systemic sclerosis. Any resulting digital ischemia might be refractory to treatment and worsen progressively, even if chemotherapy is withdrawn in the early stages of digital ischemia.

Safety and efficacy of modified FOLFOX6 for treatment of metastatic or locally advanced colorectal cancer. A single-institution outcome study.

Background: Although a variety of FOLFOX regimens (5-fluorouracil and L-leucovorin combined with oxaliplatin) are widely used for the treatment of advanced colorectal cancer, the neurotoxicity caused by oxaliplatin is often problematic. The aim of this observational study was to assess the safety and efficacy of a modified version of the FOLFOX6 regimen (mFOLFOX6) when administered using the ‘stop-and-go’ strategy. Patients and Methods: A total of 112 eligible patients treated between June 2005 and July 2007 were identified using the prospective cohort database system of Kyoto University Hospital. Results: The median follow-up was 16.3 months (range 1.6–33.9), and the response rate was 33.3% (95% CI 14.5–52.2), 40.0% (95% CI 22.5–57.5) and 14.0% (95% CI 3.6–24.3) for patients who received mFOLFOX6 as first-line therapy, second-line therapy and third- or later-line therapy, respectively. The estimated median progression-free survival was 8.7 months (95% CI 2.3–15.1) and 8.2 months (95% CI 7.3–9.1) for patients on first-line and second-line therapy, respectively. The median overall survival was not reached as of April 2008 for the patients on first-line therapy, while it was 27.1 months (95% CI 22.0–32.2) for those on second-line therapy. Severe neurotoxicity occurred in only 4 patients (3.6%). Conclusion: mFOLFOX6 administered using the stop-and-go strategy significantly reduced oxaliplatin-induced neurotoxicity relative to conventional FOLFOX treatment, without compromising efficacy.

Comparative outcomes between initially unresectable and recurrent cases of advanced pancreatic cancer following palliative chemotherapy.

Objectives The objective of this study was to compare the clinical outcomes between initially unresectable and recurrent advanced pancreatic cancer (APC) patients after palliative chemotherapy. Methods Data of a total of consecutive 269 patients with pathologically confirmed APC patients who received palliative chemotherapy between January 2006 and April 2012 were reviewed. Patients were classified into initially unresectable and recurrent group, and overall survival (OS) was compared between the 2 groups. Results The median OS was significantly longer in the recurrent group compared with the initially unresectable group (383 vs 308 days; hazard ratio [HR], 0.59; 95% confidence interval, 0.44–0.80; P < 0.01). After adjustment for distant metastasis, performance status, and levels of carbohydrate antigen 19-9, carcinoembryonic antigen, C-reactive protein, and lactate dehydrogenase, the status of recurrent or unresectable disease remained as an independent prognostic factor with a clinically relevant HR value (HR, 0.66; 95% confidence interval, 0.48–0.90; P = 0.01). In addition, the 2-year OS rate of the recurrent group was significantly higher than that of the unresectable group (24.2% vs 9.6%, P = 0.01). Conclusions Our results suggested that the status of recurrent or initially unresectable disease was an independent prognostic factor in APC patients receiving palliative chemotherapy.