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).

Public health nurses leaving remote islands: An investigation into the turnover rate of remote island PHNs in Japan.

INTRODUCTION: This study investigated the number of public health nurses (PHNs) and the turnover rates of PHNs working in small municipal administrations on remote islands throughout Japan. METHODS: A questionnaire survey was administered on 359 remote islands, each with a population of less than 5000, including islands connected to the Japanese mainland by a bridge or road. The survey questionnaire asked about the number of PHNs stationed on the remote islands, their length of service, the number of retirees, and the ages of those who had retired. RESULTS: Of the 353 islands which responded, 30 islands had a total of 77 PHNs. Of those 30 islands, 29 were isolated islands that were not connected to the mainland by a bridge or road. The turnover rate of PHNs on the 29 islands was 13.3%. CONCLUSION: The turnover rate of 13.3% for PHNs on remote islands (with no bridge or road) with a population of less than 5000 was higher than the 7.9% turnover rate for PHNs in municipalities of equal size. To maintain the quality of life of island residents, preventing PHNs from leaving their jobs is an important challenge.

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.

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.

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.

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.

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).

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.

Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s.

Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive functions in human tumorigenesis. However, whether the major mechanism underlying the p53-dependent apoptosis is transactivation dependent or independent remains unclear. Using 179 mutant p53s with diverse transcriptional activities for distinct p53-binding sequences in yeast, we evaluated both their sequence-specific transcriptional activities on six p53 target genes and their ability to induce apoptosis in Saos-2 cells. These mutant p53s also represented diversity in their ability to both transactivate target genes and induce apoptosis. We identified 17 mutant p53s with superior ability to induce apoptosis than wild-type p53 that tend to cluster at residues 121 or 290 to 292. There was no significant correlation between the two functional properties on any single target gene examined. Furthermore, the 17 mutant p53s were not classified in a specific cluster by hierarchical cluster analysis on their diverse transcriptional activities, indicating that these mutant p53s were not similar in the transcriptional activity of downstream genes. These results suggested that transactivation-dependent apoptosis does not always play a major role in p53-dependent apoptosis, indirectly supporting the importance role of the transactivation-independent mechanism.

[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 relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.

Tumor suppressor p53 forms a homo-tetramer through its COOH-terminal oligomerization domain and acts as a sequence-specific transcription factor. We have analysed the interrelation among the transcriptional activities, the structure and the cancer-related mutations in the oligomerization domain by using a comprehensive missense mutation library. Here, we examined the ability of 184 mutant p53s in the domain to form an oligomer by expressing these mutant p53s in yeast, and compared the data with the previous information. We showed that specific residues in the alpha-helix and the beta-strand of the oligomerization domain were critical for both oligomer formation and sequence-specific transactivation, and the activities were closely related. In particular, the alpha-helix was more sensitive to amino-acid substitutions than the beta-strand. We found identity in the interrelation between the two activities, that is, monomer mutants were transcriptionally inactive whereas dimer and tetramer mutants retained their transcriptional activities. In TP53 mutation databases, a small number of mutations have been reported in this domain. Surprisingly, most do not encode p53s defective in functional properties. These results indicate that, although oligomer formation is essential for p53 transactivation function, the inactivation of oligomer formation and therefore the inactivation of transactivation may not be essential for tumor suppression by p53 because they do not lead to oncogenic proteins.

[A case of malignant melanoma from the esophagus responding to weekly paclitaxel therapy].

A 44-year-old man had a tumor in the lower thoracic esophagus at a health check, and was initially diagnosed as an undifferentiated carcinoma of the esophagus by the esophago-gastric endoscope. Although curative chemoradiotherapy was scheduled after the diagnosis, the interim evaluation revealed that the tumor was malignant melanoma of the esophagus with right renal metastasis. Since then, CVD (cisplatin, vindesine and dacarbazine) therapy, palliative radiotherapy and DAC-Tam (dacarbazine, nimustine, cisplatin and tamoxifen) therapy were carried out, but all of them proved ineffective, and multiple newly metastatic lesions appeared in liver and lymph nodes. Oral intake was impossible because of progressing stricture of the esophagus. As a fourth-line therapy, weekly paclitaxel therapy was started, and his oral intake was improved after the second course. He received the therapy as an outpatient for four months. After the third course, tumor lesions were evaluated as a partial response by CT. Consequently, five courses of the therapy were performed with modest adverse effects. Weekly paclitaxel therapy was reasonably safe as reported in other reports and considered to be a promising regimen for malignant melanoma of the esophagus.

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.

AFP-producing hepatoid adenocarcinoma in association with Barrett's esophagus with multiple liver metastasis responding to paclitaxel/CDDP: a case report.

A case of alpha-fetoprotein (AFP)-producing hepatoid adenocarcinoma in association with Barrett's esophagus with multiple liver metastases, responding to chemotherapy, is reported. A 47-year-old man was admitted to our hospital with abdominal pain after subtotal esophagectomy for an esophageal adenocarcinoma in association with Barrett's esophagus, and was diagnosed as having multiple liver tumors. Most tumor markers were normal, but the serum AFP level was markedly elevated. Dynamic computed tomography and ferumoxide enhanced magnetic resonance imaging did not provide evidence of any primary hepatocellular carcinoma. Since microscopic examination of the resected tumor showed a poorly-differentiated adenocarcinoma with hepatoid features displaying AFP-immunoreactivity, the liver tumors were thus considered to be metastatic deposits. Surgery was not feasible so chemotherapeutic agents were tried, and the combination of paclitaxel (TXL) and cisplatin (CDDP) gave a partial response and good control for a period. This is the first report, to our knowledge, of effective chemotherapy for liver metastases from an AFP-producing hepatoid adenocarcinoma of the esophagus.

[Retrospective analysis on efficacy and toxicity of 5-fluorouracil (5-FU) and l-leucovorin (l-LV) in advanced or recurrent colorectal cancer].

The aim of this study was to evaluate the efficacy and toxicity of 5-fluorouracil (5-FU) and l-leucovorin (I-LV) in 50 patients with advanced or recurrent colorectal cancer in our institute. The dose of 5-FU was 600 mg/m2 and the dose of l-LV was 250 mg/m2. Objective response were 36.8% of patients who had administration of full-dose and 14.8% of patients who had the administration of reduced dose or prolonged interval. No significant difference was observed in clinical benefit rates between patients administrated in full-dose and patients in reduced dose or prolonged interval. Median survival time (MST) of patients in reduced dose or prolonged interval is longer than patients in full-dose. These data suggest that 5-FU/l-LV can be given in the outpatient and yields improved prognosis and minimal adverse reactions even in patients in reduced dose or prolonged interval.

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.

[Reading span as an individual difference and cognitive problem solving performance].

This study investigated the performance on a computer game called Mastermind, playing of which consumes a large amount of working memory resource. First, 143 college students took a Japanese version of reading span test (RST). They then played Mastermine under two conditions: with or without display of past game records. There were 105 participants who relied under both conditions on a tactical strategy that caused high memory load, and their performance data were analyzed. Results indicated that low-span readers (87 students) were more constrained than high- and medium-span readers (18 students) under the condition without display, and performance of the low was affected by the content of display. It was argued that working memory resource that RST measured was involved in the process of cognitive problem solving.

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.