Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201).

BACKGROUND: Advanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer. METHODS: This multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma. DISCUSSION: GEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

Phase II Study of the Reuse of Trastuzumab with Docetaxel beyond Progression after First-Line Treatment in Second-Line Treatment for Unresectable, Metastatic Gastric Cancer (T-CORE1203).

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.

Phase II study of trifluridine/tipiracil (TAS-102) therapy in elderly patients with colorectal cancer (T-CORE1401): geriatric assessment tools and plasma drug concentrations as possible predictive biomarkers.

PURPOSE: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. METHODS: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. RESULTS: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). DISCUSSION: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. TRIAL REGISTRATION NUMBER: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network).

Patients' understanding of communication about palliative care and health condition in Japanese patients with unresectable or recurrent cancer: a cross-sectional survey.

BACKGROUND: Understanding treatment goal is essential for decision-making among patients with unresectable/recurrent solid cancers. However, no previous studies in Japan have examined the association between patients' understanding and physicians' explanations. We aimed to examine agreement between patients' and physicians' reports of communication about palliative care and current health condition among patients with unresectable/recurrent cancer and explore factors associated with optimistic understanding in Japan. METHODS: In this cross-sectional, multicenter, observational survey in Japan, 178 patients with unresectable/ recurrent solid cancers and 16 physicians responded to questionnaires. The primary outcome was agreement between patients' and physicians' reports of communication about palliative care and current health condition. RESULTS: Of 56 patients who reported their communication about palliative care, 25/56 (44.6%) agreed with physician reports, and 31/56 (55.4%) were more optimistic than their physicians. Regarding current overall health condition, 45/122 (36.9%) patients gave reports that agreed with physicians' reports, and 77/122 (63.1%) were optimistic relative to physicians. Physicians' general approach about disclosure were not associated with patients' understanding. CONCLUSIONS: Fewer than 50% of Japanese patients with unresectable/recurrent cancer agreed with their physicians, whereas most others were more optimistic about palliative care communication and their health condition as compared to physicians. Effective communication is essential to ensure informed decisionmaking.

Impact of palliative chemotherapy and best supportive care on overall survival and length of hospitalization in patients with incurable Cancer: a 4-year single institution experience in Japan.

BACKGROUND: This study aimed to analyze the determinants of patients' choice between palliative chemotherapy and best supportive care (BSC) and to investigate how this choice affects overall survival (OS) and length of hospitalization according to Eastern Cooperative Oncology Group (ECOG) performance status (PS). METHODS: An oncologist explained the palliative chemotherapy and BSC options to 129 patients with incurable cancer during their first consultation. Data on the ECOG PS, treatment decision, OS, and the length of hospitalization were retrospectively collected over 4 years. RESULTS: Patients with an ECOG PS of 0-2 chose palliative chemotherapy more often than those with an ECOG PS of 3-4 (P < 0.01). Patients with ≤70 years chose palliative chemotherapy more often than those with > 70 (P < 0.05). And patients with gastric cancer and colon cancer chose palliative chemotherapy more often than those with CUP (carcinoma of unknown primary) (P < 0.05, P < 0.05 respectively). Factors associated with a significantly poorer OS in an adjusted analysis included the ECOG PS and treatment decision (hazard ratios: 0.18 and 0.43; P < 0.001, P < 0.01 respectively). In patients with an ECOG PS of 0-2, palliative chemotherapy was not associated with a longer OS compared with BSC (median OS: 14.5 vs. 6.8 months, respectively; P = 0.144). In patients with an ECOG PS of 3-4, palliative chemotherapy resulted in a significant survival gain compared to with BSC (median OS: 3.8 vs. 1.4 months, respectively; P < 0.05). Strong positive correlations between OS and the length of hospitalization were observed in patients with an ECOG PS of 3-4 who underwent palliative chemotherapy (r2 = 0.683) and the length of hospitalization was approximately one-third of their OS. CONCLUSIONS: The determinants for treatment choice were age, ECOG PS and type of cancer, not sex difference. Oncologists should explain to patients that OS and the length of hospitalization vary according to the ECOG PS when selecting between palliative chemotherapy and BSC.

Studies on Aculeines: Synthetic Strategy to the Fully Protected Protoaculeine B, the N-Terminal Amino Acid of Aculeine B.

A synthetic strategy for accessing protoaculeine B (1), the N-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of 1 with a 12-mer poly(propanediamine). The synthesis of mono(propanediamine) analog 2, as well as core amino acid 3, was demonstrated by this strategy. New amino acid 3 induced convulsions in mice; however, compound 2 showed no such activity.

Circulating tumor cell count as a biomarker of a specific gastric cancer subgroup characterized by bone metastasis and/or disseminated intravascular coagulation - an early indicator of chemotherapeutic response.

The incidence of gastric cancer coupled with multiple bone metastases, and/or disseminated intravascular coagulation (DIC), is characterized by the clinical presentation of rapid progression and a poor prognosis, and differs from typical gastric cancers. Circulating tumor cells (CTCs) are negligible in typical advanced gastric cancers, however, a considerable number of CTCs in the bloodstream may be detected in the subgroup demonstrating multiple bone metastases and/or DIC. The present study analyzed two cases, with the first case regarding a 51-year-old male who exhibited a CTC count of 275 cells/7.5 ml following an initial, ineffective, chemotherapy cycle. The patient underwent a second chemotherapy course that was effective, and the cell count was observed to reduced to 2 cells/7.5 ml. A decreased CTC count was first confirmed on day 16 following treatment. During the chemoresistant phase, the CTC count was observed to increase again. The second case presented by the current study describes a 59-year-old female who exhibited a CTC count of 235 cells/7.5 ml prior to chemotherapy. This subsequently decreased to 7 cells/7.5 ml following an effective course of chemotherapy. Notably, the CTC count increased alongside disease progression in this case. Within the rare subgroup of gastric cancer patients with multiple bone metastases and/or DIC, CTC count may serve as an early biomarker allowing the evaluation of therapeutic efficacy. However, due to the aggressive nature of this type of cancer, imaging analysis is not recommended as it may typically take several months to complete.

A Curcumin Analog, GO-Y078, Effectively Inhibits Angiogenesis through Actin Disorganization.

BACKGROUND: The inhibition of angiogenesis is a theoretically ideal chemotherapy for cancer, but there remains room for improvement. Most inhibitors of angiogenesis approved to date target vascular endothelial growth factors (VEGFs); however, VEGFs are only one of the many classes of participant in tumor angiogenesis. Because tumor angiogenesis is orchestrated by many components, including growth factors, signal transducers, and effectors, its regulation exhibits redundancy. Curcumin can associate with many proteins, and it reportedly inhibits tumor angiogenesis. OBJECTIVE: We investigated the ability of a new curcumin analog, GO-Y078, to inhibit tumor angiogenesis. RESULTS: GO-Y078 inhibited human umbilical vascular endothelial cell sprouting. GO-Y078 also induced complete anoikis in vascular endothelial cells. Moreover, GO-Y078 suppressed the migration and invasion of vascular endothelial cells into extracellular matrix proteins. However, expression analysis revealed that GO-Y078 did not suppress molecules involved in VEGF signaling. Rather, GOY078 induced actin disorganization, dissociation of vinculin from actin, and destruction of focal adhesion, resulting in the inhibition of vascular endothelial cell mobility. GO-Y078 also suppressed in-vivo vasculogenesis in Xenopus laevis tadpoles. CONCLUSION: Actin organization is a common effecter related to vascular endothelial cell mobility in angiogenesis. We demonstrated that GO-Y078 inhibits angiogenesis through actin disorganization.

Cohort study of consistency between the compliance with guidelines for chemotherapy-induced nausea and vomiting and patient outcome.

BACKGROUND: Chemotherapy-induced nausea and vomiting is one of the most influential factors that affect patient quality of life; thus, preventing this adverse event could lead to better patient outcome. Standard preventive guidelines for antiemetic treatment have already been established based on the emetogenicity of chemotherapeutic agents. It is important that compliance with in-house guidelines and their effect on patient outcome is monitored. METHODS: In 3 years since the Akita university hospital antiemetic guidelines were outlined, we assessed the incidence of chemotherapy-induced nausea and vomiting using the antiemesis tool of the Multinational Association of Supportive Care in Cancer. Compliance of the guidelines was extracted from the hospital clinical record, and the chemotherapy-induced nausea and vomiting was examined by the patient reported outcome. RESULTS: Seventy-three patients answered the questionnaire. The overall compliance rate with the guidelines for early nausea and vomiting was 98.6% and with the delayed nausea and vomiting was 87.7%. The complete response rate for the early and delayed chemotherapy-induced nausea and vomiting was 77.8% and 73.8%, respectively. The overall relative risk of early nausea and vomiting was 0.22 (P < 0.05), whereas the relative risk for delayed nausea and vomiting was 2.09 (P < 0.05). Breakthrough vomiting was observed in 3 cases in the low-risk group only. These data suggest that delayed nausea and vomiting is difficult to prevent, particularly in the low-risk group. Further, it seems that the individual sensitivity for emetogenicity might differ among patients. CONCLUSIONS: In addition to standard prevention guidelines based on emetogenicity, individual care based on patient reports should be considered for the complete prevention of chemotherapy-induced nausea and vomiting.

Utility of measuring circulating tumor cell counts to assess the efficacy of treatment for carcinomas of unknown primary origin.

BACKGROUND/AIM: Carcinomas of unknown primary origin (CUPs) account for 3%-5% of all malignancies. The majority of CUPs have unfavorable prognosis and are chemoresistant. Predictive biomarkers should be established to improve therapeutic outcomes. Metastatic ability of CUPs may be related to the existence of circulating tumor cells (CTCs). PATIENTS AND METHODS: Ten patients diagnosed with CUP visiting the Akita University Hospital participated in this study. CTCs were calculated by the CellSearch system. RESULTS: The present observational study indicates that CTCs were detected in 50% of CUPs, and in 80% chemotherapeutically-naïve cases. Furthermore, decrease in CTC count between the pre-treatment and post-treatment phases were observed in chemosensitive cases. CONCLUSION: Rapid assessment of the efficacy of chemotherapy by CTC count may become a useful predictive biomarker of CUPs.

Protoaculeine B, a putative N-terminal residue for the novel peptide toxin aculeines.

A new polyamine-modified indole derivative protoaculeine B (1) was isolated from Okinawan marine sponge Axinyssa aculeata. The structure of 1 was assigned on the basis of spectral data along with chemical transformations. Because the structure of 1 greatly inferred the N-terminal amino acid for highly modified peptide toxin aculeines, the probable structure for aculeine B was proposed on the basis of high-resolution mass spectral analysis.

Preliminary estimation of the prevalence of chemotherapy-induced dysgeusia in Japanese patients with cancer.

BACKGROUND: Although dysgeusia is a common adverse event in chemotherapy patients; it has not been evaluated using objective methods, and its prevalence and frequency have not been quantified. METHODS: Salt-impregnated taste strips were used to objectively assess dysgeusia in patients receiving chemotherapy at Akita University (n = 38) and those off chemotherapy (n = 9). Participant characteristics, and ongoing and previous chemotherapies were evaluated, and their associations with dysgeusia analyzed. RESULTS: Dysgeusia developed in 38.8% (14/38) of chemotherapy patients, and was most prevalent in patients receiving 5-fluorouracil (5-FU) or its oral analogs (48.1%, 13/27). Particularly, dysgeusia developed in 55.6% (10/18) of patients receiving oral 5-FU analogs; however, prevalence in patients receiving and off chemotherapy was not significantly different. Patients aged ≥70 years also tended to experience dysgeusia (75.0%, 6/8). CONCLUSIONS: Association with dysgeusia may be higher for some chemotherapeutic drugs. Dysgeusia should be routinely assessed in chemotherapy patients with objective methods such as paper strips; interventions for its prevention may be required.

A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients.

BACKGROUND: A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients. METHODS: Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated. RESULTS: Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range, 47-1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179-1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin administration for >9 months. CONCLUSIONS: Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.

Practical utility of circulating tumour cells as biomarkers in cancer chemotherapy for advanced colorectal cancer.

Molecular-targeted therapies require the assessment of targets and their related molecules. Circulating tumour cells (CTCs) are considered a very good source of samples for these purposes. In this study, we applied a practical method for examining CTCs to evaluate the effects of chemotherapy on advanced colorectal cancer (CRC). Even in stage IV CRC, CTCs were detected in only 38.5% (n=5/13) of the cases. However, in cases where CTCs were detected, the change in the number of CTCs compared before and after chemotherapy appeared to be associated with the therapeutic outcome. Changes in the number of CTCs may be a good predictive biomarker. Problems with this method are yet to be resolved, including the detection rate and the stability of the sample source for subsequent molecular analysis.

Acquired/intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesis.

Mutations at codons 12 and 13 of the KRAS gene have been identified as level I predictive biomarkers against the treatment of advanced colorectal cancer with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. It is thought that the genetic analysis of KRAS mutations associated with metastatic colorectal cancer can be routinely conducted using DNA obtained on one occasion from one organ, from the primary or a metastatic site, whichever is preferentially available. However, the issue of tumor heterogeneity resulting from acquired/intratumoral mutations remains. Recently, the possibility of acquired/intratumoral mutations in the KRAS gene has been reported by two research groups and has ranged from 7.4 to 15.4%. Specimens were collected from advanced colorectal cancer patients with resected primary, and at least one metastatic, site. Direct sequence analysis was performed for KRAS, BRAF and PIK3CA, and immunohistochemistry for glutathione S-transferase II (GSTP) and EGFR. In the current study, we identified an acquired mutation rate of approximately 11.1% in the KRAS gene (1/9). This figure is not negligible. Our observation indicates, particularly in the case of metastatic recurrence after a long interval, that there may be considerable tumor heterogeneity resulting from acquired or intratumoral mutations of the KRAS gene.

(18)FDG-PET at 1-Month Intervals Is a Better Predictive Marker for GISTs That Are Difficult to Be Diagnosed Histopathologically: A Case Report.

Imatinib mesylate is a tyrosine kinase inhibitor of c-KIT and PDGFRA. Imatinib mesylate is an effective drug that can be used as a first-choice agent for treatment of GISTs. Prior to treatment, molecular diagnosis of c-KIT or PDGFRA is necessary; however, in some types of GISTs, it is impossible to obtain a sufficient amount of specimen for diagnosis. An inoperable or marginally resectable GIST in a 79-year-old female was difficult to be diagnosed at a molecular pathological level, and hence, exploratory treatment was initiated using imatinib combined with (18)FDG-PET evaluation at 1-month intervals. PET imaging indicated a positive response, and so we continued imatinib treatment in an NAC setting for 4 months. As a result, curative resection of the entire tumor was successfully performed with organ preservation and minimally invasive surgery. (18)FDG-PET evaluation at 1-month intervals is beneficial for GISTs that are difficult to be diagnosed histopathologically.

[TP53 mutations and molecular epidemiology].

Tumor suppressor p53 protein is activated by a variety of cellular stresses through several pathways and transactivates its downstream genes, including regulators of cell cycle, apoptosis and DNA repair. The loss of p53 function by TP53 gene mutations therefore fails to activate these genes and is thought to be a critical cause of carcinogenesis and/or tumor progression. TP53 is one of the most frequently mutated genes in human cancer. TP53 mutations are found in about 50% of human cancers, although the frequency of TP53 mutations differs among tumor types. However, the degree of functional disorder of mutant p53 varies according to the type of TP53 mutation. And the effects of p53 on cancer formation and/or progression are influenced by the degree of p53 dysfunction. So it is important to analyze the effects of TP53 mutations carefully according to the oncogenicity of each mutation from the molecular epidemiological point of view. Here, together with some cautions needed for analyzing and interpreting the significance of TP53 gene mutations, we present some examples of the identified specific mutation spectrum and the correlation between the prognosis and TP53 mutation in some cancers.

The screening of the second-site suppressor mutations of the common p53 mutants.

Second-site suppressor (SSS) mutations in p53 found by random mutagenesis have shown to restore the inactivated function of some tumor-derived p53. To screen novel SSS mutations against common mutant p53s, intragenic second-site (SS) mutations were introduced into mutant p53 cDNA in a comprehensive manner by using a p53 missense mutation library. The resulting mutant p53s with background and SS mutations were assayed for their ability to restore the p53 transactivation function in both yeast and human cell systems. We identified 12 novel SSS mutations including H178Y against a common mutation G245S. Surprisingly, the G245S phenotype is rescued when coexpressed with p53 bearing the H178Y mutation. This result indicated that there is a possibility that intragenic suppressor mutations might restore the protein function in an intermolecular manner. The intermolecular mechanism may lead to novel strategies for restoring inactivated p53 function and tumor suppression in cancer treatment.

Experimental demonstration of the induction synchrotron.

We report an experimental demonstration of the induction synchrotron, the concept of which has been proposed as a future accelerator for the second generation of neutrino factory or hadron collider. The induction synchrotron supports a superbunch and a superbunch permits more charge to be accelerated while observing the constraints of the transverse space-charge limit. By using a newly developed induction acceleration system instead of radio-wave acceleration devices, a single proton bunch injected from the 500 MeV booster ring and captured by the barrier bucket created by the induction step voltages was accelerated to 6 GeV in the KEK proton synchrotron.