Extensive bowel necrosis related to bevacizumab in metastatic rectal cancer patient: a case report and review of literature.

Recently, bevacizumab has become a key drug for treatment of metastatic colorectal cancer. Molecularly targeted agents such as bevacizumab can cause life-threatening adverse effects, though they are generally considered less toxic than cytotoxic drugs. Here, we review the case of a 76-year-old male rectal cancer patient with liver metastasis who suffered extensive bowel necrosis after administration of 5-fluorouracil-based chemotherapy with bevacizumab, and required a subtotal colectomy and end-ileostomy. Microscopic findings revealed extensive mucosal necrosis in the resected colon specimen and necrosis at the muscularis propria of the descending colon. Pathological findings suggested that the mucosal damage induced by chemotherapy may be exacerbated by treatment with bevacizumab, resulting in extensive necrosis.

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication.

BACKGROUND: Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis. METHODS: We examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens. RESULTS: HOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system. CONCLUSIONS: HOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment.

Pancreatic metastases from renal cell carcinoma: a case report and literature review of the clinical and radiological characteristics.

Metastatic pancreatic cancer is rare, accounting for approximately 2% of all pancreatic malignancies, and most cases arise from renal cell carcinoma. We report the case of a 63-year-old woman, who presented with a pancreatic tumor detected during her annual health examination. She had undergone left nephrectomy 13 years previously for renal cell carcinoma. Computed tomography (CT) revealed two tumors in the head and body of the pancreas, a hypervascular tumor and a hypovascular tumor with an enhanced rim, respectively. She underwent pylorus-preserving pancreaticoduodenectomy, and metastatic pancreatic tumors arising from the kidney with clustered clear cell carcinoma immunohistochemically positive for CD10 were diagnosed. This report presents the different enhancement features of different lesions on CT scans. Because the enhancement features of lesions have been reported to vary according to the size of the metastatic tumor, a knowledge of the history of renal cell carcinoma is crucial for diagnosis.

Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models.

Radiotherapy (RT) is a standard treatment for patients with advanced prostate cancer (PCa). Previous preclinical studies showed that SDF1α/CXCR4 axis could mediate PCa metastasis (most often to the bones) and cancer resistance to RT. We found high levels of expression for both SDF1α and its receptor CXCR4 in primary and metastatic PCa tissue samples. In vitro analyses using PCa cells revealed an important role of CXCR4 in cell invasion but not radiotolerance. Pharmacologic inhibition of CXCR4 using AMD3100 showed no efficacy in orthotopic primary and bone metastatic PCa models. However, when combined with RT, AMD3100 potentiated the effect of local single-dose RT (12 Gy) in both models. Moreover, CXCR4 inhibition also reduced lymph node metastasis from primary PCa. Notably, CXCR4 inhibition promoted the normalization of bone metastatic PCa vasculature and reduced tissue hypoxia. In conclusion, the SDF1α/CXCR4 axis is a potential therapeutic target in metastatic PCa patients treated with RT.

Two cases of bowel perforation associated with sunitinib treatment for renal cell carcinoma.

Sunitinib, a multitargeted tyrosine kinase inhibitor, is widely used in the treatment of carcinoma. Adverse events associated with this treatment, including fatigue, diarrhea, and hematotoxicity, have been reported in clinical trials. Bowel perforation is a surgical emergency that requires immediate treatment depending on the location and progression of the tumor. We report 2 cases of bowel perforation during sunitinib treatment. The patients presented with diffuse peritonitis, and emergency exploratory laparotomy was performed. We speculate that the underlying mechanisms were decrease in capillary density of the normal mucosa in case 1 and tumor shrinkage because of sunitinib treatment in case 2. To the best of our knowledge, this is the first study to report the pathological findings implicating bowel perforation due to sunitinib treatment. Further investigations are needed to clarify the risk factors for intestinal perforations associated with sunitinib treatment.

[FOLFIRI with bevacizumab chemotherapy for a patient with recurrence of rectal cancer under haemodialysis for chronic renal failure].

As pharmacokinetics in patients undergoing haemodialysis is different from patients with normal renal function, it remains unclear whether chemotherapy can be performed safely for patients with haemodialysis as well as those who have normal renal function. Here, we report a case with recurrence of rectal cancer who received FOLFIRI with bevacizumab chemotherapy under haemodialysis, and obtained good tumor control. A 47-year-old woman had undergone haemodialysis for 10 years due to chronic renal failure. At 45 years of age, she received abdominoperineal resection due to rectal cancer (pStage II). Four months after the surgery, liver metastasis was found, for which partial resection of the liver and adjuvant chemotherapy [UFT (400 mg/body)/UZEL (75 mg/body)] were performed. Eighteen months after the liver resection, multiple lung metastases were found. Therefore, intensive chemotherapy using FOLFIRI (CPT-11: 90 mg/m2) with bevacizumab (2.5 mg/m2) was performed. Severe neutropenia (grade 3, 4), but not non-hematologic adverse events such as diarrhea and bevacizumab-specific adverse events, was observed. As she did not recover easily from neutropenia in spite of treatment with G-CSF, a dose reduction of the FOLFIRI regimen was gradually performed. Although chemotherapy was conducted approximately monthly, the tumor response reflected a stable disease 8 months after 8 courses of chemotherapy. We suggest that it is important to investigate the pharmacokinetics of toxic agents such as CPT-11, (SN38) for dose modification, and for the safe and continuous chemotherapy of patients receiving haemodialysis.

Functional outcome, quality of life, and efficacy of probiotics in postoperative patients with colorectal cancer.

PURPOSE: We investigated the functional outcome and health-related quality of life (QOL) of patients who underwent a surgical resection of colorectal cancer, and reviewed the efficacy of probiotics for improving bowel function. METHODS: A questionnaire was mailed to 193 patients. Questionnaires contained the Medical Outcomes Study Short-Form 36-Item Health Survey and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 as QOL scores, the Wexner incontinence score, and original questionnaire items about bowel functions. Probiotics, containing Bacillus natto and Lactobacillus acidophilus, were given to 77 patients for 3 months; after 3 months of treatment, the same questionnaire was administered. The results were analyzed by location of the resected cancer: rectal, colonic, right, and left. RESULTS: In the rectal group, defecation frequency, anal pain, and the Wexner score were significantly worse than in the colonic group. In the right group, the fecal form was looser and nighttime defecation frequency was higher than those of the left group. Three items in the QOL score of the right group were significantly worse compared with the left group. Functional outcome including defecation frequency, feeling of incomplete defecation, and five items in the QOL score were significantly improved after taking probiotics. Improvement in functional outcome and/or QOL was observed in all groups. CONCLUSIONS: Not only rectal resection but also rightside colectomy affected bowel dysfunction. Probiotics could be an effective treatment for improvement in functional outcome and QOL after colorectal resection.

[Catamenial pneumothorax; report of a case].

A 40-year-old female had right-sided pneumothorax. She was treated with a chest tube. On the 2nd day, her menstruation started. Because of a persistent air leak, she underwent a thoracoscopic operation on the 15th day. During the operation, we noted a pulmonary bulla at the apex and multiple blue berry spots both on the visceral pleura and the tendinous part of the diaphragm. We performed a resection of the pulmonary bulla, partial diaphragmatic excision plus suture. Section of visceral pleura and diaphragm shows ductal structures, which is insistent with endometriosis. The serum CA125 level decreased to 39 U/ml. Following surgery, oral contraceptives was started and no recurrence was encountered thereafter.

Pharmacist's Intervention Considering the Prognosis for a Terminal Cancer Patient: A Case Report.

Prognostic prediction has been reported to affect the decision of doctors and non-physician health care providers such as nurses, social workers, pastors, and hospice volunteers on the selection of appropriate medical interventions. This was a case of a 65-year-old woman who presented with a poor oral intake. The patient had a history of sigmoid colon cancer with abdominal wall metastasis and peritoneal dissemination. On the day of admission, nausea, anorexia, and malaise were noted, requiring immediate intervention. The patient's prognosis was predicted using the Palliative Prognostic Index. The pharmacist suggested the use of dexamethasone tablets in order to alleviate the patient's symptoms. Indeed, the administration of dexamethasone alleviated the symptoms of nausea, loss of appetite, and malaise. To the best of our knowledge, this is the first case report to demonstrate that prognosis prediction is important not only for other medical staff but also for pharmacists when deciding the need to initiate a treatment and continue such treatment, and when providing pharmacist interventions.

Current consensus on the diagnosis and treatment of H. pylori-associated gastroduodenal disease.

Helicobacter pylori (H. pylori) is a spiral shaped bacterium that resides in the stomach mucosa. Isolation of H. pylori from the stomach mucosa changed the erstwhile widely held belief that the stomach contains no bacteria and is actually sterile. Once H. pylori is safely ensconced in the mucus, it is able to neutralize the acid in the stomach by elaborating an enzyme called urease. Urease converts urea, of which there is an abundant supply in the stomach (derived from saliva and the gastric juice), into bicarbonate and ammonia, which are strong bases. These bases form a cloud of acid-neutralizing chemicals in the vicinity of the organisms, protecting them from the acid in the stomach. This urea hydrolysis reaction is utilized for the diagnosis of H. pylori infection in the urea breath test (UBT) and the rapid urease test (RUT). In Japan, both invasive tests, such as bacterial culture, histopathology and RUT, and non-invasive tests such as UBT and serology are conducted for the diagnosis of H. pylori infection. For confirming the results of eradication therapy, UBT is considered to be the most sensitive and specific. In order to treat H. pylori infection, a new one-week triple therapy regimen (lansoprazole or omeprazole + amoxicillin + clarithromycin) has been approved for use in patients with peptic ulcer disease in Japan. As for H. pylori eradication in the case of other diseases in which the bacterium has been implicated (e.g., chronic atrophic gastritis, gastric MALT lymphoma, gastric cancer, non-ulcer dyspepsia, chronic urticaria, idiopathic thrombocytopenic purpura (ITP)), further basic and clinical investigation is required.

Ileosigmoid knot at week 13 of pregnancy: report of a case.

The ileosigmoid knot (ISK) is a rare cause of intestinal obstruction. ISK is a condition in which the ileum wraps around the base of the sigmoid colon and forms a knot, leading to high mortality with rapid progression to bowel gangrene. We herein report a rare case of ISK at week 13 of pregnancy. The ISK was diagnosed by computed tomography, and the patient underwent emergency surgery for acute abdomen. Laparotomy showed segmental gangrenous change in the sigmoid colon, which was twisted around the distal ileal loop. The gangrenous bowel was resected, and primary anastomosis was performed. To our knowledge, the present case involves the first and earliest pregnancy in which a preoperative diagnosis of ISK was made and successful treatment was performed with surgery. A radiologic approach should be undertaken for prompt diagnosis and optimal management, even in early pregnancy.

Expression of Epidermal Growth Factor Receptor Detected by Cetuximab Indicates Its Efficacy to Inhibit In Vitro and In Vivo Proliferation of Colorectal Cancer Cells.

Cetuximab is a chimeric mouse-human monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). However, EGFR expression determined by immunohistochemistry does not predict clinical outcomes of colorectal cancer (CRC) patients treated with cetuximab. Therefore, we evaluated the correlation between EGFR levels detected by cetuximab and drug sensitivities of CRC cell lines (Caco-2, WiDR, SW480, and HCT116) and the A431 epidermoid carcinoma cell line. We used flow cytometry (FCM) to detect EGFR-binding of biotinylated cetuximab on the cell surface. Subcloned cell lines showing the highest and lowest EGFR expression levels were chosen for further study. Cytotoxic assays were used to determine differential responses to cetuximab. Xenograft models treated with cetuximab intraperitoneally to assess sensitivity to cetuximab. Strong responses to cetuximab were specifically exhibited by subcloned cells with high EGFR expression levels. Furthermore, cetuximab inhibited the growth of tumors in xenograft models with high or low EGFR expression levels by 35% and 10%-20%, respectively. We conclude that detection of EGFR expression by cetuximab promises to provide a novel, sensitive, and specific method for predicting the sensitivity of CRC to cetuximab.

Bouveret's syndrome with a concomitant incidental T1 gallbladder cancer.

Bouveret's syndrome, which is a gastric outlet obstruction caused by a gallstone in the duodenum, is a rare complication of gallstone disease. We report a case of Bouveret's syndrome in an 81-year-old woman who also exhibited incidental gallbladder cancer. She was admitted to our hospital complaining of upper abdominal pain and vomiting. A computed tomography examination showed a cholecystoduodenal fistula, a large impacted stone at the gastric outlet, and a dilated stomach. She was diagnosed as having Bouveret's syndrome. The patient underwent an upper gastrointestinal endoscopy and a mechanical lithotripsy was successfully performed for the stone. She then underwent a cholecystectomy with primary closure of the duodenal fistula. An intra-operative histopathology examination revealed severe cholecystitis with an adenocarcinoma in part of the gallbladder. Gallbladder bed resection and regional lymph node dissection were also performed. To the best of our knowledge, this is the first published report of a case in which Bouveret's syndrome and gallbladder cancer co-existed.

Change in the actin cytoskeleton during seismonastic movement of Mimosa pudica.

The seismonastic movement of Mimosa pudica is triggered by a sudden loss of turgor pressure. In the present study, we compared the cell cytoskeleton by immunofluorescence analysis before and after movement, and the effects of actin- and microtubule-targeted drugs were examined by injecting them into the cut pulvinus. We found that fragmentation of actin filaments and microtubules occurs during bending, although the actin cytoskeleton, but not the microtubules, was involved in regulation of the movement. Transmission electron microscopy revealed that actin cables became loose after the bending. We injected phosphatase inhibitors into the severed pulvinus to examine the effects of such inhibitors on the actin cytoskeleton. We found that changes in actin isoforms, fragmentation of actin filaments and the bending movement were all inhibited after injection of a tyrosine phosphatase inhibitor. We thus propose that the phosphorylation status of actin at tyrosine residues affects the dynamic reorganization of actin filaments and causes seismonastic movement.