A double-blind, randomized, multicenter phase 3 study of palonosetron vs granisetron combined with dexamethasone and fosaprepitant to prevent chemotherapy-induced nausea and vomiting in patients with breast cancer receiving anthracycline and cyclophosphamide.

PURPOSE: To investigate whether palonosetron is better than granisetron in preventing chemotherapy-induced nausea and vomiting (CINV) in a three-drug combination with dexamethasone and fosaprepitant (Fos) in patients with breast cancer who are placed on anthracycline and cyclophosphamide (AC-based regimen). PATIENTS AND METHODS: Chemo-naive women with primary breast cancer were randomly administered either palonosetron 0.75 mg (day 1) or granisetron 1 mg (day 1) combined with dexamethasone (12 mg at day 1, 8 mg at day 2 and day 3) and Fos 150 mg (day 1) before receiving AC-based regimen in a double-blind study. The primary endpoint was the complete response (CR) rate of emesis in cycle 1 in the delayed phase. This was defined as neither vomiting nor rescue drug usage for emesis at >24-120 hours after chemotherapy. Secondary endpoints were the CR in the acute/overall phase (0-24/0-120 hours, respectively, after chemotherapy), no nausea and vomiting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and safety. RESULTS: From December 2012 to October 2014, 326 patients were treated and evaluated (164/162 evaluable patients in granisetron/palonosetron arm, respectively). The CR during the delayed phase was 60.4% in the granisetron regimen and 62.3% in the palonosetron regimen. The CR during acute phase (73.2% vs 75.9%, respectively) and the CR during overall phase (54.9% in both regimens) were very identical. A significantly higher number of patients in the palonosetron arm were free from nausea during the delayed phase (28% vs 40.1%; P = .029). Adverse events were also identical, although infusion site reactions (ISR) were higher (20.3%-23.3%) than preceding studies in both regimens. CONCLUSION: In combination with dexamethasone and Fos, this study suggests that palonosetron is not better than granisetron in chemo-naive patients with primary breast cancer receiving AC-based regimen. Administration of Fos in peripheral veins after AC-based regimen increased ISR.

NUT carcinoma of the nasal cavity that responded to a chemotherapy regimen for Ewing's sarcoma family of tumors: a case report.

BACKGROUND: Nuclear protein in testis (NUT) carcinoma (NC) is a rare epithelial malignancy characterized by rearrangement of the NUT gene on chromosome 15. If NC is not suspected, it is often diagnosed as other malignancies. We present the case of NC of the nasal cavity that responded to a chemotherapy regimen for Ewing's sarcoma family of tumors (ESFT). CASE PRESENTATION: A 49-year-old male presented with epistaxis and pain in the left eye. The patient had a tumor in the left nasal cavity at initial visit and it was biopsied. Firstly, the man was diagnosed with ESFT based on a histopathological examination. The tumor markedly responded to standard cytotoxic chemotherapy for ESFT with distant metastasis. After the start of therapy, a chromosomal analysis revealed an atypical translocation in ESFT and additional immunostaining was positive for anti-NUT antibody. Ultimately, the patient was definitively diagnosed with NC. He received multidisciplinary therapy and symptoms were temporarily relieved. However, he died 9 months after the diagnosis of NC. CONCLUSIONS: When a pathologically undifferentiated tumor is evident along the midline of the body, NC must be included in the differential diagnosis, and immunohistochemical staining or genetic testing/chromosomal analysis needs to be performed.

A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy.

PURPOSE: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. METHODS: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. RESULTS: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%-83%) in the overall phase and 91% (95% CI: 78%-97%) in the acute phase and 70% (95% CI: 55%-83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. CONCLUSIONS: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Irinotecan monotherapy as third-line or later treatment in advanced gastric cancer.

BACKGROUND: Patients with advanced gastric cancer (AGC) are often treated with irinotecan monotherapy as salvage-line therapy. However, the survival benefit of this therapy remains to be elucidated. METHODS: Medical records of AGC patients who were treated with irinotecan monotherapy as salvage-line treatment in six institutions from 2007 to 2014 were reviewed. RESULTS: A total of 146 patients had prior fluoropyrimidine and taxane therapies, and 75.3% had prior platinum therapy. The median age was 66 (range 27-81) years, and 102 males (69.9%) were included. Performance status (PS) was 0/1/2/3 in 53/70/19/4 patients. Eighty-nine patients (61.0%) had two or more metastatic sites. Irinotecan monotherapy as 3rd-/4th-line therapy was performed in 135/11 (92.5%/7.5%). The median number of administrations was 4 (range 1-62). Forty-six patients (31.5%) required initial dose reduction at the physician's discretion. The overall response rate was 6.8%, and the disease control rate was 43.1%. The median PFS was 3.19 months [95% confidence interval (CI) 2.30-4.08 months], and the median OS was 6.61 months (95% CI 5.94-7.28 months). Grade 3/4 adverse events were hematological toxicity (46 patients, 31.5%) and non-hematological toxicity (50 patients, 34.2%). Hospitalization due to adverse events was required in 31 patients (21.2%). Patients with relative dose intensity (RDI) less than 80% showed similar survival to those with RDI 80% or higher. CONCLUSIONS: Irinotecan monotherapy was relatively safely performed as salvage-line treatment for AGC in Japanese clinical practice. Careful patient selection and intensive modification of the dose of irinotecan might possibly be associated with favorable survival.

Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer.

A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R=0.429), whereas EETS and DPR were less correlated with OS (R=0.0682, 0.186). EETS was well correlated with DPR (R=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy.

Efficacy and Safety Analysis of Oxaliplatin-based Chemotherapy for Advanced Gastric Cancer.

BACKGROUND: Significant efficacy of oxaliplatin-based chemotherapy has been demonstrated for advanced gastric cancer (AGC). However, the appropriate dose of oxaliplatin, and the efficacy and toxicity of administration of oxaliplatin subsequent to cisplatin therapy still remain unclear. PATIENTS AND METHODS: In total, 55 patients with AGC that were scheduled to receive oxaliplatin-based chemotherapy were prospectively examined. RESULTS: The median age was 67 years and oxaliplatin was administered to 39 (71%) patients as first-line and in 16 (29%) patients as second-line therapy. An initial dose of 130 or 100 mg/m2 of oxaliplatin was administered to 11 and 36 patients, respectively. The overall response rates (ORR) and median progression free survival (mPFS) were 86 and 33%, and 7.2 and 7.8 months, respectively. Compared to 100 mg/m2, the relative dose intensity was significantly lower and severe toxicity tended to increase with oxaliplatin at 130 mg/m2 A total of 10 patients (18%) had a prior cisplatin-based therapy. The ORR of the patients pretreated with cisplatin was 14% and the mPFS was 6.1 months. CONCLUSION: An initial oxaliplatin dose of 130 mg/m2 resulted in a good response, but tended to increase the risk of toxicity. Subsequent oxaliplatin-based therapy after cisplatin exhibited modest efficacy, especially in cases with cisplatin intolerance.

Efficacy and Safety of TAS-102 in Clinical Practice of Salvage Chemotherapy for Metastatic Colorectal Cancer.

BACKGROUND: TAS-102 is an anti-metabolite which demonstrated activity against multidrug-resistant advanced colorectal cancer. Its major toxicities are hematological disorders. PATIENTS AND METHODS: Background, TAS-102 efficacy, toxicities and outcomes for patients with multidrug-resistant advanced colorectal cancer from six Institutions of the Kyushu Medical Oncology Group were retrospectively surveyed. RESULTS: Forty-three patients, including fragile patients due to declining performance status and other comorbidities (37%) were analyzed. Efficacy was reflected in an objective overall response of 3%, median progression-free survival of 74 days (2.5 months) and median overall survival of 229 days (7.6 months). The most frequent Common Terminology Criteria for Adverse Events grade 3/4 adverse events were neutropenia (44%), leukopenia (26%) and anemia (23%). Febrile neutropenia was found in 7%. Sub-group analysis demonstrated an improved outcome on treatment with the sequence regorafenib-TAS-102. CONCLUSION: TAS-102 was safely administered to modestly fragile patients with equivalent efficacy to that for the non-fragile population. Further investigation of sequential treatment using regorafenib and TAS-102 is needed.

Amrubicin monotherapy for patients with extrapulmonary neuroendocrine carcinoma after platinum-based chemotherapy.

PURPOSE: Extrapulmonary neuroendocrine carcinomas (EPNEC) are rarely observed and are associated with poor outcomes. Based on the clinicopathological similarity, treatment used for small cell lung carcinoma has also been employed for EPNEC, but the response to such therapy has not been well examined. The goal of this study was to investigate amrubicin (AMR) monotherapy as a salvage therapy for EPNEC arising from digestive organs. METHODS: Patients with EPNEC of the digestive organs who had prior platinum-based chemotherapy and were subsequently treated with AMR between July 2005 and December 2013 at any one of four institutions were retrospectively examined to characterize the safety and efficacy of AMR. RESULTS: Thirteen patients (ten males, three females; median age 64 years) were examined. Primary cancer sites included stomach (n = 6), rectum (n = 3), esophagus (n = 2), liver (n = 1) and pancreas (n = 1). Prior irinotecan- and etoposide-containing chemotherapies were used in ten and six patients, respectively. Median initial dose of AMR was 40 mg/m(2)/day for three consecutive days, and median of treatment cycles was 4 (range 1-9). The objective response rate (ORR) was 38.5%. Median progression-free survival (PFS) and overall survival (OS) were 107 (range 22-275) and 215 days (range 71-535), respectively. Common severe adverse events (grade 3/4) were neutropenia (84.6%) and febrile neutropenia (30.8%). Patient with longer platinum-free interval (>90 days) exhibited longer PFS and OS than those with shorter platinum-free interval (190 vs. 63 days and 348 vs. 145 days, respectively). CONCLUSIONS: AMR showed evidence of clinical activity and safety when used for the treatment of EPNEC. It might be especially useful for populations with sensitive relapse.

Reduced dose of salvage-line regorafenib monotherapy for metastatic colorectal cancer in Japan.

BACKGROUND: Salvage-line regorafenib monotherapy exhibited a marked survival benefit for metastatic colorectal cancer (mCRC). However, the toxicity of this regimen has resulted in the clinical use of a reduced dose of regorafenib. PATIENTS AND METHODS: Thirty-two Japanese mCRC patients (median age=61 years) who had been treated with regorafenib were retrospectively examined. RESULTS: Best objective response rate was 0% and stable disease (SD) was 31%. Median progression-free survival was 81 days and median overall survival was 233 days. Adverse events of any grade were observed in all patients: 17 (53%) patients suffered grade 3 or 4 adverse events including fatigue (13%), anorexia (13%), hand-foot skin reaction (22%) and elevations of alanine aminotransferase/aspartate aminotransferase (19%/16%). One patient with grade 5 liver dysfunction was identified (3%). Twenty-nine (91%) patients required treatment dose reduction or a delay in treatment. The relative dose intensity was 59%. Regorafenib treatments were terminated because of disease progression (59%) or adverse events (34%). CONCLUSION: Despite a decrease in the intensity of regorafenib treatment, because of severe adverse events, a fairly favorable efficacy was achieved in Japanese patients.

Human Nanog pseudogene8 promotes the proliferation of gastrointestinal cancer cells.

There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. Immunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in GI cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation.

Involvement of riboflavin kinase expression in cellular sensitivity against cisplatin.

Flavin adenine dinucleotide (FAD) is an essential coenzyme for glutathione reductase (GR) which catalyzes the reduction of oxidized glutathione to regenerate the reduced form involved in protection against oxidative stress. Riboflavin kinase (RFK) also known as flavokinase is involved in the first step of bioactivation of riboflavin (RF) to form flavin mononucleotide (FMN) which can be subsequently converted to FAD in an ATP-dependent reaction catalyzed by FAD synthetase (FADS). We investigated the involvement of RFK in cisplatin resistance using human prostate cancer PC3 cells. RFK overexpression renders cells resistant not only to cisplatin but also to hydrogen peroxide (H2O2) and diamide. Furthermore, knockdown of RFK expression induced apoptosis. We demonstrated that overexpression of RFK increased the levels of FAD, FMN and total glutathione and the expression of GR and glutathione S-transferase-π (GSTπ). RFK expression is up-regulated in cisplatin-resistant P/CDP6 cells in addition to FAD, total glutathione level, GR and GSTπ. Knockdown of RFK expression also sensitized both PC3 and P/CDP6 cells to cisplatin. Moreover, cellular levels of RFK expression correlate well with Gleason score, known as a good indicator of patient prognosis. The present study suggests that RFK expression is involved not only in cellular protection from oxidative stress but also in malignant progression of prostate cancer.

Enhanced expression of PCAF endows apoptosis resistance in cisplatin-resistant cells.

Histone acetyltransferase (HAT) regulates transcription. We have previously shown that two HAT genes, Clock and Tip60, are overexpressed, and upregulate glutathione biosynthesis and the expression of DNA repair genes in cisplatin-resistant cells. To better understand the mechanism of HAT-related drug resistance, we investigated the role of another HAT gene, p300/CBP-associated factor (PCAF), and found that PCAF was also overexpressed in cisplatin-resistant cells and endowed an antiapoptotic phenotype through enhanced E2F1 expression. PCAF-overexpressing cells showed enhanced expression of E2F1 and conferred cell resistance to chemotherapeutic agents. Downregulation of PCAF decreased E2F1 expression and sensitized cells to chemotherapeutic agents. Moreover, knockdown of PCAF induced G(1) arrest and apoptosis. These results suggest that PCAF is one of pleiotropic factors for drug resistance and seems to be critical for cancer cell growth.

Y-box binding protein-1 is a novel molecular target for tumor vessels.

Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many reports indicate that YB-1 is highly expressed in tumor cells and is a marker for tumor aggressiveness and clinical prognosis. Here, we show clear evidence that YB-1 is expressed in the angiogenic endothelial cells of various tumors, such as glioblastoma, esophageal cancer, gastric cancer, colon cancer, and lung cancer, as well as in tumor cells. YB-1 was highly expressed in glomeruloid microvascular endothelial cells of brain tumors and microvessels in the desmoplastic region around multiple solid tumors. On the other hand, no or low YB-1 expression was observed in normal angiogenic endothelial cells from fetal kidney, newborn lung, and placenta. The endothelial cells in inflammatory regions of granulomas were also weakly labeled. Knockdown of YB-1 expression by small-interfering RNA induced G1 cell cycle arrest and inhibited the growth of human umbilical vein endothelial cells stimulated by growth factors. Taken together, YB-1 plays an important role in the growth of not only tumor cells but also tumor-associated endothelial cells, suggesting that YB-1 is a promising target for cancer therapy.

Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway.

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more "normal" 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.

Programmed cell death protein 4 down-regulates Y-box binding protein-1 expression via a direct interaction with Twist1 to suppress cancer cell growth.

Programmed cell death protein 4 (PDCD4) has recently been shown to be involved in both transcription and translation, and to regulate cell growth. However, the mechanisms underlying PDCD4 function are not well understood. In this study, we show that PDCD4 interacts directly with the transcription factor Twist1 and leads to reduced cell growth through the down-regulation of the Twist1 target gene Y-box binding protein-1 (YB-1). PDCD4 interacts with the DNA binding domain of Twist1, inhibiting its DNA binding ability and YB-1 expression. Immunohistochemical analysis showed that an inverse correlation between nuclear PDCD4 and YB-1 expression levels was observed in 37 clinical prostate cancer specimens. Growth suppression by PDCD4 expression was completely recovered by either Twist1 or YB-1 expression. Moreover, PDCD4-overexpressing cells are sensitive to cisplatin and paclitaxel but not to etoposide or 5-fluorouracil. In summary, PDCD4 negatively regulates YB-1 expression via its interaction with Twist1 and is involved in cancer cell growth and chemoresistance.

Schedule-dependent synergistic interaction between gemcitabine and oxaliplatin in human gallbladder adenocarcinoma cell lines.

To define the most effective combination schedule of gemcitabine and oxaliplatin (L-OHP), we investigated the in-vitro interaction between these drugs in a panel of four human gallbladder adenocarcinoma cell lines (HAG-1, GB-d1, NOZ, and G-415). Cytotoxic activity was determined by the WST-1 assay. Different schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. Simultaneous and sequential treatments of gemcitabine followed by L-OHP exhibited synergistic effects in all four cell lines, whereas the reverse sequence largely showed an antagonism. Gemcitabine exclusively arrested cells at the G0/G1 phase, and L-OHP at the G2/M phase, as measured by flow cytometric analyses. Apoptosis was most prominent when cells were treated simultaneously or in a sequence gemcitabine followed by L-OHP, producing apoptosis in treated cells (27-30%). In contrast, the reverse sequence yielded only 6-7% induction of apoptosis, the rate being not significantly different from those induced by each drug singly. Moreover, this sequence dependence was further confirmed by the experiment, which compared the number of HAG-1 cells 7 days after these combination schedules. These findings suggest that the interaction of gemcitabine and L-OHP is highly schedule dependent, with the most efficacious interaction observed in either simultaneous combination or in a sequence combination of gemcitabine followed by L-OHP.

Myeloid/natural killer cell blast crisis representing an additional translocation, t(3;7)(q26;q21) in Philadelphia-positive chronic myelogenous leukemia.

We encountered a patient in blast crisis (BC) with chronic myelogenous leukemia (CML) who showed immunophenotypic features similar to those previously described in acute myeloid/natural killer (NK) cell precursor leukemia. The blasts were positive for CD7, CD33, CD34, and CD56. Cytogenetic analysis disclosed a Philadelphia chromosome (Ph) and t(3;7)(q26;q21). Molecular analysis did not detect any EVI1/CDK6 chimeric transcript generated by t(3;7)(q26;q21), but did indicate overexpression of EVI1, which occurs frequently in progression to myeloid BC in CML. Three cases of myeloid/NK cell precursor BC in CML have been reported, but this case is the first to present with Ph and EVI1 abnormality. These observations suggested that a myeloid/NK cell precursor might have been involved in the Ph-positive clone and have been a target for blastic transformation of CML, although EVI1 expression is not specific for transformation to BC from myeloid/NK lineage.