Chemoprevention of colorectal cancer : experimental and clinical aspects

Colorectal cancer is a leading cause of cancer-related mortality worldwide. Therefore, an appropriate prevention strategy should be urgently established. Chemoprevention involves the use of oral agents to suppress the development of cancer. Recent progress in the molecular analysis of colorectal cancer has revealed many candidate molecules for chemoprevention. Many new agents targeting these molecules have also been developed. These agents are largely classified into three categories : 1) Signal transduction modulators including epidermal growth factor (EGF) receptor inhibitors, anti-vascular endothelial growth factor (VEGF) antibodies, and inhibitors of oncogene products. 2) Epigenetic modulators including peroxisome proliferative activated receptor (PPAR)-γ agonists, estrogen receptor (ER)-β , and histone deacetylase inhibitors. 3) Anti-inflammatory modulators including cyclooxygenase (COX)-2, EP 1-4, and NF-kB. Of these agents, some actually proceeded to human clinical trials, and have been shown to be active chemopreventive agents

EGFR Down-regulation Predicts anti-EGFR Response

ABC, antibody-binding capacity; ADCC, antibody-dependent cellular cytotoxicity; ATCC, American Type Culture Collection; BSA, bovine serum albumin; CR, complete response; CRC, colorectal cancer; CT, computed tomography; ECACC, European Collection of Authenticated Cell Cultures; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ETS, early tumor shrinkage; FBS, fetal bovine serum; FISH, fluorescent in situ hybridization; HRP, horseradish peroxidase; HSRRB, Health Science Research Resources Bank; IHC, immunohistochemistry; MesNa, Mercaptoethanesulfonic acid sodium; mCRC, metastatic colorectal cancer; mAb, monoclonal antibody; mAbs, monoclonal antibodies; PARP, poly (ADP-ribose) polymerase; PBS, phosphate buffered saline; PD, progressive disease; p-ERK, phosphorylated ERK; PNA-LNA, peptide nucleic acid-locked nucleic acid; PR, partial response; PVDF, polyvinylidene difluoride; RECIST, Response Evaluation Criteria in Solid Tumors; RIKEN BRC, RIKEN BioResource Center; SD, stable disease; SDS, sodium dodecyl sulfate; SDS-PAGE, SDS-polyamide gel electrophoresis; TBS-T, Tris-buffered saline with 0.1% Tween; TGF-α, transforming growth factor-α

Difference between genders with metabolic syndrome

Background Nonalcoholic fatty liver disease (NAFLD) is known to be strongly associated with obesity, visceral fat, metabolic syndrome (MS), lifestyle, and lifestyle-related diseases in both males and females. However, the prevalence of NAFLD, MS, and clinical backgrounds is different between males and females. Objective We conducted a cross-sectional study to examine the differing influence of lifestyle-related factors and visceral fat on fatty liver (FL) with elevation of liver enzymes between males and females with MS. Methods We enrolled 42,134 persons who underwent a regular health check-up, and after excluding subjects who fulfilled excluding criteria, the remaining subjects were 2,110 persons with MS. We examined the differing influence of lifestyle-related factors and visceral fat on FL with elevation of alanine aminotransferase (ALT) (ALT elevation was defined as ALT level of ≥31 IU/l in the present study). Results The odds rations for FL with ALT elevation were as follows: WC, 1.83 (95% confidence interval (CI) 1.36-2.46); dyslipidemia, 1.89 (95% CI 1.34-2.68); hemoglobin A1c, 1.36 (95% CI 1.00-1.85); visceral fat type MS (V-type MS), 5.78 (95% CI 4.29-7.80); and light drinker, 0.56 (95% CI 0.41±0.78) in males with MS and BMI, 2.18 (95% CI 1.43－3.33); WC, 1.85 (95% CI 1.27-2.70); diastolic blood pressure, 1.69 (95% CI 1.16-2.45); triglyceride, 2.22 (95% CI 1.56-3.17); impaired glucose tolerance, 1.66 (95% CI 1.11-2.47); and V-type MS, 3.83 (95% CI 2.57-5.70) in females with MS. The prevalence of FL with ALT elevation and ALT was significantly higher in V-type MS than in the subcutaneous fat type MS in both males and females with MS (P < 0.001). Conclusion Although V-type MS and WC is a common significant predictor of an increased prevalence of FL with ALT elevation in both males and females with MS, gender, lifestyle-related factors, and MS type in individuals with MS should be considered for the development of FL with ALT elevation

Pladienolide is active on gastric cancer

The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction

Trastuzumab タンザイ リョウホウ ガ チョコウ シタ セツジョ フノウ シンコウ イガン ノ 1レイ

Trastuzumab, a humanized monoclonal antibody directed against human epidermal growth factor receptor２ （HER２）, has been shown to be active against metastatic gastric cancer that overexpress HER２. A ７８-year-old man presented with an edema in the lower legs. He was diagnosed as having advanced gastric cancers with multiple liver metastases in our hospital. Immunohistochemistry of the tumor cells revealed HER２ overexpression with an intensity of ３＋. The patient was treated with DS-T chemotherapy （Docetaxel＋S‐１＋Trastuzumab） because of the presence of renal dysfunction. Due to the adverse effect appeared with his skin, DS-T chemotherapy has been canceled and trastuzumab chemotherapy was continued. After １１ months of trastuzumab monotherapy, metastatic liver tumors were diminished. There is very few report of a positive response to trastuzumab in a patient with HER２‐overexpressing metastatic gastric cancer

IRIS plus panitumumab for metastatic CRC

Background Irinotecan plus S-1 (IRIS) is the only oral fluoropyrimidine-based regimen reported to be non-inferior to FOLFIRI and widely used in clinical practice for metastatic colorectal cancer (mCRC) patients. However, the combination of IRIS plus an anti-EGFR agent has not been evaluated previously. This study aimed to investigate the feasibility and efficacy of IRIS with panitumumab as second-line therapy for wild-type KRAS mCRC. Methods Main inclusion criteria were patients with wild-type KRAS mCRC refractory to one prior chemotherapy regimen for mCRC, ECOG PS 0-2, and age ≥ 20 years. Patients received panitumumab (6mg/kg) and irinotecan (100mg/m2) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was the feasibility of the therapy. The secondary endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results A total of 36 patients received protocol treatment in eight centers. Of these, 23 patients (63.9%) completed protocol treatment, demonstrating achievement of the primary endpoint. The most frequent grade 3/4 toxicities were diarrhea (16.7%), acne-like rash (13.9%), and neutropenia (11.1%). The overall RR was 33.3% (12/36). Of these 4 five underwent conversion surgery. Median PFS and OS were 9.5 months (95% CI 3.5-15.4 months) and 20.1 months (95% CI 16.7-23.2 months), respectively. Conclusion IRIS plus panitumumab has an acceptable toxicity profile and a promising efficacy in patients with previously treated wild-type KRAS mCRC. Accordingly, this regimen can be an additional treatment option for second-line chemotherapy in wild-type KRAS mCRC

FDR-gem plus S-1 with RT for pancreatic cancer

Purpose: This study was conducted to identify the maximum-tolerated dose (MTD) of fixed-dose-rate gemcitabine (FDR-gem) administered concurrently with S-1 and radical radiation for locally advanced pancreatic cancer (LAPC) and to provide efficacy and safety data. Methods: Patients with unresectable pancreatic cancer confined to the pancreatic region were treated with FDR-gem (300-400mg/m2, 5mg/m2/min) on days 1, 8, 22, 29 and 60mg/m2 of S-1 orally on days 1-14, 22-35. A total radiation dose of 50.4 Gy (1.8 Gy/day, 28fractions) was delivered concurrently. Results: Twenty-five patients were enrolled; all were evaluable for toxicity assessment. In phase I, eight patients were treated in sequential cohorts of three to five patients per dose level. The MTD was reached at level 2, and dose-limiting toxicities were neutropenia and thrombocytopenia. The recommended doses were 300mg/m2 of gemcitabine and 60mg/m2 of S-1 daily. The overall response rate was 25% and disease control rate (partial response plus stable disease) was 92%. The progression-free survival was 11.0 months. The median overall survival and 1-year survival rate were 16.0 months and 73%, respectively. Conclusion: The combination of FDR-gem and S-1 with radiation is a feasible regimen that shows favorable antitumor activity with an acceptable safety profile in patients with LAPC

A case of epilepsy with myoclonic atonic seizures caused by SLC6A1 gene mutation due to balanced chromosomal translocation

Introduction Epilepsy with myoclonic atonic seizures (EMAtS) was previously thought to occur in normally developing children. We report a female case of EMAtS and mild developmental delay before onset. Importantly, a de novo balanced chromosomal translocation was recognized in the patient. Case presentation The patient was a 4-year-old girl. Mild developmental delay was observed during infancy. At the age of one and a half years, she developed atonic seizures once a month. At 4 years of age, her seizures increased to more than 10 times per hour. An ictal electroencephalogram (EEG) showed a 3–4-Hz spike-and-wave complex, which was consistent with atonic and myoclonic seizures of the trunk, eyelids, and lips. Therefore, EMAtS was diagnosed based on the symptoms and EEG findings. After administration of valproic acid (VPA), the epileptic seizures disappeared immediately. At the age of 5 years and 2 months, the seizures recurred but disappeared again when the dose of VPA was increased. Subsequently, no recurrence was observed until 6 years and 3 months of age on VPA and lamotrigine. Chromosome analysis of the patient disclosed 46,XX,t(3;11)(p25;q13.1)dn. Long-read sequencing of the the patient’s genomic DNA revealed that the 3p25.3 translocation breakpoint disrupted the intron 7 of the SLC6A1 gene. Conclusion The SLC6A1 disruption by chromosome translocation well explains the clinical features of this patient. Long-read sequencing is a powerful technique to determine genomic abnormality at the nucleotide level for disease-associated chromosomal abnormality