Masato Ozaka

Efficacy of a glycyrrhizin suppository for the treatment of chronic hepatitis C: a pilot study

Intravenous administration of glycyrrhizin has potential efficacy on decreasing serum aminotransferase levels in patients with chronic hepatitis. However, patients receiving this treatment are recommended to attend hospital regularly for several years. To improve the quality of life for these patients, we developed a glycyrrhizin suppository. In this pilot study, we examined the most effective and safe material contents of the suppository and revealed clinical efficacy for patients with biopsy-proven chronic hepatitis C comparing intravenous administration of glycyrrhizin. As content combinations of the suppository, a mixture of 300 mg of glycyrrhizinic ammonium salt and 60 &mgr;g of sodium capric acid, with pH neutralization, was confirmed to be most effective and safe condition, based on analysis of serum glycyrrhizin levels and the grade of rectal irritations in tested patients. The efficacy on decreasing serum alanine aminotransferase levels for 12-week administration of the suppository in 13 patients with chronic hepatitis C was similar to that in another 13 patients intravenously administered glycyrrhizin. Moreover, no serious side effects were observed. In conclusion, the usage of the newly developed suppository of glycyrrhizin can improve the quality of life for chronic hepatitis C patients, especially those who do not respond with viral clearance to interferon therapy. Using this suppository, larger and longer-term studies are needed.

Prognostic value of neutrophil-lymphocyte ratio and level of C-reactive protein in a large cohort of pancreatic cancer patients: a retrospective study in a single institute in Japan.

OBJECTIVE Recent studies suggest that systemic inflammatory response is closely associated with cancer patient prognosis. Although several inflammatory prognostic markers have been proposed, the data to support their validity are lacking in large Japanese cohorts. METHODS This is a retrospective study to examine the prognostic value of inflammatory markers, such as C-reactive protein, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and modified Glasgow prognostic scale, in pancreatic cancer. Selection criteria were admittance to hospital between January 2008 and December 2012, histologically confirmed adenocarcinoma, diagnosis of invasive ductal pancreatic cancer compatible by computed tomography imaging, and followed-up until death or for 180 days or longer. The primary end point was overall survival, which was measured from the day of histological diagnosis. RESULTS There were 440 patients who met the selection criteria. Of the 440 cases, 200 (45.5%) received curative resection (166 Stage I/II and 34 Stage III patients), 237 (53.9%) received chemotherapy (4 Stage I/II, 92 Stage III and 141 Stage IV patients), and the remaining 3 received palliative care. Univariate and multivariate regression analyses revealed that advanced computed tomography stage, high level of C-reactive protein (0.45 mg/dl or greater), neutrophil-lymphocyte ratio (2.0 or greater) and CA19-9 level (1000 U/ml or greater) were significantly associated with worse prognosis. CONCLUSIONS We verified the results of previous studies, and showed that neutrophil-lymphocyte ratio and C-reactive protein also had prognostic value in a large Japanese PC cohort.

Phase 1 and pharmacological trial of OPB‐31121, a signal transducer and activator of transcription‐3 inhibitor, in patients with advanced hepatocellular carcinoma

To evaluate the safety, pharmacokinetics and antitumor activity of OPB‐31121, a signal transducer and activator of transcription‐3 inhibitor, in patients with advanced hepatocellular carcinoma (HCC).

Improved survival with combined gemcitabine and S‐1 for locally advanced pancreatic cancer: pooled analysis of three randomized studies

The long‐term prognosis for localized pancreatic cancer (PC) remains poor. Three randomized trials (GEST phase III, JACCRO PC‐01 phase II and GEMSAP phase II) evaluated gemcitabine (Gem) with or without S‐1 for patients with metastatic and locally advanced PC. A pooled analysis based on published data examined whether Gem with S‐1 (GS) is superior to Gem alone in overall survival (OS) in patients with locally advanced PC.

Phase II clinical trial using novel peptide cocktail vaccine as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients

We investigated peptide cocktail vaccine OCV‐C01 containing epitope peptides derived from KIF20A, vascular endothelial growth factor receptor (VEGFR)1 and VEGFR2 combined with gemcitabine in the adjuvant treatment for resected pancreatic cancer patients. A single‐arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28‐day treatment cycle, patients received weekly subcutaneous injection of OCV‐C01 for 48 weeks and gemcitabine was administered intravenously at 1,000 mg/m2 on days 1, 8 and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease‐free survival (DFS) and secondary endpoints included safety, overall survival (OS) and immunological assays on peptide‐specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. The median DFS was 15.8 months [95% confidence interval (CI), 11.1–20.6] and the DFS rate at 18 months was 34.6% (95% CI, 18.3–51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8–82.5). The administration of OCV‐C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with KIF20A‐specific CTL responses and without (p = 0.027), and between patients with KIF20A expression and without (p = 0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A‐specific CTL responses. OCV‐C01 combined with gemcitabine was tolerable with a median DFS of 15.8 months, which was favorable compared with previous data for resected pancreatic cancer.

Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study

Background The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin. Methods Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression ≥6 months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12 weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. Results Thirty-three patients were enrolled. The median age was 62 (range: 35–77) years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12 weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8–57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m2. Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade ≥1 and grade ≥3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade ≥1 and grade ≥3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment-related deaths. Conclusion Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression ≥6 months previously during prior oxaliplatin-based therapy.

Ultrasound-guided vs endoscopic ultrasound-guided fine-needle aspiration for pancreatic cancer diagnosis

AIM To clarify the effectiveness and safety of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of pancreatic cancer (PC). METHODS Patients who were diagnosed with unresectable, locally advanced or metastatic PC between February 2006 and September 2011 were selected for this retrospective study. FNA biopsy for pancreatic tumors had been performed percutaneously under extracorporeal ultrasound guidance until October 2009; then, beginning in November 2009, EUS-FNA has been performed. We reviewed the complete medical records of all patients who met the selection criteria for the following data: sex, age, location and size of the targeted tumor, histological and/or cytological findings, details of puncture procedures, time from day of puncture until day of definitive diagnosis, and details of severe adverse events. RESULTS Of the 121 patients who met the selection criteria, 46 had a percutaneous biopsy (Group A) and 75 had an EUS-FNA biopsy (Group B). Adequate cytological specimens were obtained in 42 Group A patients (91.3%) and all 75 Group B patients (P = 0.0192), and histological specimens were obtained in 41 Group A patients (89.1%) and 65 Group B patients (86.7%). Diagnosis of malignancy by cytology was positive in 33 Group A patients (78.6%) and 72 Group B patients (94.6%) (P = 0.0079). Malignancy by both cytology and pathology was found in 43 Group A (93.5%) and 73 Group B (97.3%) patients. The mean period from the puncture until the cytological diagnosis in Group B was 1.7 d, which was significantly shorter than that in Group A (4.1 d) (P < 0.0001). Severe adverse events were experienced in two Group A patients (4.3%) and in one Group B patient (1.3%). CONCLUSION EUS-FNA, as well as percutaneous needle aspiration, is an effective modality to obtain cytopathological confirmation in patients with advanced PC.

Outcomes and Tolerability of Systemic Chemotherapy for Pancreatic or Biliary Cancer Patients Aged 75 Years or Older

BACKGROUND The incidence of pancreatic or biliary tract cancer is increasing in our aging population, but little is known of treatment outcomes in elderly patients with pancreatic or biliary tract cancer. PATIENTS AND METHODS Patients with pancreatic or biliary tract cancer who received chemotherapy in our institute between September 2007 and August 2009 were retrospectively reviewed to compare treatment outcomes between the elderly (aged 75 years or older) and the younger patients. Data were collected of patient backgrounds, adverse events and dose intensity within the first two cycles and overall survival time. RESULTS Of the 102 who met the inclusion criteria, 19 were elderly who were introduced to full dose chemotherapy. Medication for their comorbidities was required in 15 (79%) of the 19 elderly patients and in 27 (33%) of 83 younger patients. The frequencies of haematological adverse events of grades 3 or 4 were 42% and 39%, and those of non-haematological adverse events were 21% and 16%, for the elderly and younger, respectively. Similar dose intensities were delivered to the elderly and younger. Also, similar proportions of elderly and younger received dose reductions. There was no difference in overall survival between the elderly and the younger. CONCLUSION No clear difference in treatment outcomes was seen between the elderly and the younger patients who received gemcitabine alone. Gemcitabine chemotherapy appears to be safe and the same treatment effect was seen even in older patients with pancreatic or biliary tract cancer.

Complete response of a pancreatic adenosquamous carcinoma to chemoradiotherapy

A 51-year-old woman with an unresectable pancreatic tumor that was histologically diagnosed as an adenosquamous carcinoma underwent chemoradiotherapy with 5-fluourouracil (FU) and low-dose cisplatin (low-dose FP). Because we recognized a partial response to the chemoradiotherapy, we subsequently administered combined chemotherapy with S-1 and cisplatin. After one course of this combined chemotherapy, the tumor was further reduced in size and became difficult to discern on abdominal computed tomography (CT). We have continued to administer the S-1 and cisplatin combined chemotherapy, and the patient is still alive. After 20 months of treatment, the tumor has not recurred (as assessed by abdominal CT). Additionally, we have not seen elevation of tumor markers. This report presents the successful use of chemoradiotherapy with low-dose FP and additional combined chemotherapy with S-1 and cisplatin for unresectable pancreatic adenosquamous carcinoma.

Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients

BackgroundAfter analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer.MethodsOf the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status.ResultsThe ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab.ConclusionsPatient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors.