Expression of Vincristin-induced Peripheral Neuropathy Related to Different Administration Methods.

Vincristine (VCR) is an important drug used in R-CHOP regimens for the treatment of non-Hodgkin's lymphoma. The purpose of this study was to examine whether the administration method affects the incidence of VCR-induced peripheral neuropathy. We investigated the ratio of VCR-induced peripheral neuropathy during rapid intravenous infusion and intravenous drip infusion. A total of 71 patients who had received six or more courses of R-CHOP from January, 2015 to December, 2016 at Komaki City Hospital and Ogaki Municipal Hospital were retrospectively investigated. Peripheral neuropathy was observed in 27/39 patients (69 %) and 24/32 (75 %) in rapid intravenous infusion and intravenous drip infusion of VCR, respectively (P = 0.79). Peripheral neuropathy was observed at a high frequency in this study. Additionally, there was no difference in frequency of peripheral neuropathy due to the difference in administration method. In both groups, the degree of peripheral neuropathy was grade 1 and grade 2 in most patients. However, in rapid intravenous infusion, grade 3 peripheral neuropathy was observed. Some cases required dose reduction and discontinuation in rapid intravenous infusion. In contrast, there were no discontinuing patients in the intravenous drip infusion. Therefore, it was suggested that intravenous drip infusion of VCR reduced serious peripheral neuropathy because the ratio requiring dose reduction and discontinuation was less than that in the rapid group. In conclusion, this study is informative as there are few reports focusing on the administration method of vincristine.

Association between immune-related dermatologic adverse events and efficacy of pembrolizumab in non-small cell lung cancer patients.

We retrospectively evaluated the incidence of skin immune-related adverse effects (irAEs) in patients treated with pembrolizumab (PMB) and explored and the relationship between skin irAEs and PMB efficacy. Thirty-two patients with non-small cell lung cancer treated with PMB between April 2017 and May 2018 were enrolled. The patients were separated into two groups, namely, skin irAEs and no-skin irAEs group. We investigated the ratio and degree of express skin irAEs, period of skin irAEs and treatment, and the PFS between the two groups. Additionally, we evaluated the PFS between the irAE and no-irAEs groups. The median patient age was 76.5 (range 56-92) years. The European Cooperative Oncology Group Performance Status (ECOG PS) score of 26, 5, and 1 was 0-1, 2, and 3, respectively. The male/female ratio was 23/9. In terms of clinical stages, 6, 21, and 5 patients were in stages III and IV, and postoperative relapse, respectively. Skin irAEs were observed in 10 patients (31%). The progression-free survival of patients with skin irAEs (median, 390 days) was longer than that of patients without skin irAEs (median, 128.5 days). Overall, we suggested a significant association between skin irAEs and the efficacy of PMB in treating non-small cell lung cancer. As skin irAEs can be an indicator of treatment efficacy, it is important for medical staff, including pharmacists, to closely observe these adverse events.

Somatic mutations of LKB1 and beta-catenin genes in gastrointestinal polyps from patients with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer, mainly in the gastrointestinal tract. We examined mutations of the LKB1, beta-catenin, APC, K-ras, and p53 genes in 27 gastrointestinal hamartomatous polyps from 10 patients in nine PJS families. Of these hamartomatous polyps, one intestinal polyp had an adenomatous lesion, and one gastric polyp contained adenomatous and carcinomatous lesions. Germ-line mutations of the LKB1 gene were detected in six PJS families. Somatic mutations of the LKB1 gene were found in 5 polyps, whereas loss of heterozygosity (LOH) at the LKB1 locus at 19p was seen in 14 other polyps. In adenomatous lesions microdissected from hamartomatous polyps, both beta-catenin mutation and 19p LOH were detected. Furthermore, a carcinomatous lesion in a gastric hamartomatous polyp was found to contain a mutation of the p53 gene and LOH at the p53 locus in addition to LOH at the LKB1 locus and a beta-catenin mutation. K-ras mutations were detected in a few polyps, whereas no APC mutation or 5q LOH was detected in hamartomatous polyps. These results suggest that gastrointestinal hamartomatous polyps in PJS patients develop through inactivation of the LKB1 gene by germ-line mutation plus somatic mutation or LOH of the unaffected LKB1 allele, and that additional mutations of the beta-catenin gene and p53 gene convert hamartomatous polyps into adenomatous and carcinomatous lesions.

The relationship between frequencies of extracolonic manifestations and the position of APC germline mutation in patients with familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) patients develop various extracolonic lesions; however, the relationship between germline mutation of the APC gene and extracolonic manifestations is mostly unknown. To examine the genotype-phenotype relationship, we compared the APC mutation and clinical data. METHODS: Germline mutations from codon 157 to 1465 of the APC gene were identified in 39 families of FAP and clinical data were collected from 80 patients of these families. Germline mutations were classified into two groups: mutations from exon 4 to 9 (codon 157 to 416, Group 1) and those from exon 10 to 15H (codon 564 to 1465, Group 2). The complication rates of extracolonic manifestations were compared between these two groups. RESULTS: Frequencies of duodenal polyps and gastric adenomas in Group 2 were higher than those in Group 1 (p < 0.0001 and p < 0.0004, respectively) and development of osteoma was more frequent in Group 2 (p = 0.01). The number of colorectal polyps and retinal pigments also correlated with the germline mutation, which was consistent with previous reports. However, such correlations were less obvious with regard to gastric fundic polyps, desmoid tumors, soft tissue tumors and colorectal cancer. CONCLUSION: There are two types with regard to extracolonic manifestations of FAP: one is more severely affected according to the position of germline mutation of the APC gene and the other is not affected.

Massive pleural effusion and ascites resulting from esophagectomy with extensive lymphadenectomy for cancer of the abdominal esophagus.

Chylothorax is an uncommon but well recognized complication of esophagectomy. We present the case of a 57 year-old man with squamous cell carcinoma of the abdominal esophagus who underwent subtotal esophagectomy by right thoracotomy. Post-operatively, the volume of pleural effusion from the right chest was increased (1600-2000 ml/day). The effusion was straw colored, not changing to milky after meals. The characteristics and composition of the pleural fluid were similar to those of chyle. We therefore treated this patient using methods for treatment of chylothorax, conservatively, by administration of OK-432 and minocycline/hydrochloride into the pleural cavity from the chest tube with success. We discuss the pathophysiology of this unusual condition and its treatment.

Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.

We have previously detected an increased frequency of loss of heterozygosity (LOH) on chromosome 18q during progression of colorectal carcinomas. To clarify the target of 18qLOH, mutation of Smad4 and Smad2 genes was analysed in 176 colorectal tumors with different stages, including liver metastasis, from 111 sporadic, 52 familial adenomatous polyposis (FAP) and nine hereditary nonpolyposis colorectal cancer (HNPCC) patients. Mutation of other Smad gene families in the TGF-beta signaling pathway was also examined. Twenty-one Smad4 mutations and one Smad2 mutation were detected, whereas mutation of Smad3, 6 and 7 genes was not detected. Smad4 mutations included seven frameshift, one inframe deletion, four nonsense and nine missense mutations, 95% of which resulted in alteration of Smad4 protein regions included in homo-oligomer and hetero-oligomer formation. Frequencies of tumors with Smad4 mutation were 0/40 (0%) in adenoma, 4/39 (10%) in intramucosal carcinoma, 3/44 (7%) in primary invasive carcinoma without distant metastasis, 6/17 (35%) in primary invasive carcinoma with distant metastasis, and 11/36 (31%) in distant metastasis (metastatic/non-metastatic: P=0.006 approximately 0.01). Loss of the other allele was observed in 19 of 20 (95%) invasive and metastasized carcinomas with Smad4 mutations. In four cases both primary and metastasized carcinomas in the same patients showed the same mutations. The present results suggest that Smad4 gene is one of true targets of 18qLOH, and that its inactivation is involved in advanced stages, such as distant metastasis, in human colorectal carcinogenesis.

Posttraumatic intra-gallbladder hemorrhage in a patient with liver cirrhosis.

We report a case of intra-gallbladder hemorrhage secondary to blunt abdominal trauma in a patient with liver cirrhosis. A 58-year-old man was admitted to a local hospital with persistent right upper quadrant abdominal pain. Anemia was detected, and computed tomography (CT) revealed a high-density mass in the gallbladder lumen. He was transferred to our hospital because a gallbladder tumor was suspected. He had a history of habitual alcohol abuse and had sustained blunt abdominal trauma in the right upper quadrant 29 days before admission to our hospital (4 days before to the admission local hospital). The intra-gallbladder high-density mass depicted on the CT scan, observed as non-shadowing low-level echoes, was deemed to represent a blood clot on ultrasonography (US) performed 31 days after the trauma. US-guided percutaneous transhepatic gallbladder aspiration and cholecystography confirmed the presence of an old blood clot in the lumen. Because of the patient's persistent pain, a cholecystectomy was performed. The distended gallbladder was filled with old clotted blood.

Molecular and clinical study of familial adenomatous polyposis for genetic testing and management.

Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenomatous polyps, predominantly in the colorectal region. Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis. We examined germline mutations of the APC gene and clinical features among eighty-seven individuals who consisted of thirty-nine FAP-patients, thirty-seven of their family members with a 1 in 2 risk of predisposition to this disease, and eleven normal persons. We accurately identified nine heterozygotes, among individuals with a 1 in 2 risk by genetic testing, without the uncertainty of the recurrence risk calculated by Bayes' theorem. Six of the nine heterozygotes were confirmed to have colorectal polyps by colonoscopic examination. Since they were diagnosed at 12.7 years-of-age on average, and were no more than 20 years old, they could be treated to prevent colorectal cancer. Based on the genotype-phenotype correlation, we concluded that the germline mutations responsible for the sparse polyps phenotype of FAP-patients tend to locate from codon 1055 in the proximal region of the APC gene, while those for the profuse type locate from codon 1102 in the distal region. Among the thirty-nine FAP-patients, we found that those with the germline mutations within codon 1055 and codon 1262 had colorectal carcinomas of an advanced stage, at a high rate (71.4%). Special attention and aggressive intervention is needed in these patients and relatives at risk. With reasonable and appropriate management, it should be possible to prolong and improve the quality of life of those family members both affected and at risk.

Accessory breast cancer: a case report and review of the Japanese literature.

The case of a 31-year-old woman with accessory breast cancer in the left axilla is described. She had noticed a swelling in the left axilla during her three pregnancies. The preoperative diagnosis of accessory breast cancer was made on the basis of ultrasound-guided fine-needle aspiration biopsy (US-FNAB) and clinical history. She was treated by wide local resection and regional lymph node dissection. Although cancer originating from accessory breast tissue has been reported very rarely, knowledge of this disorder may facilitate the correct diagnosis of axillary tumors. US-FNAB is a useful and simple technique for the tissue diagnosis of axillary tumors.

Scintigraphic assessment of double tract reconstruction after total gastrectomy.

BACKGROUND/AIMS: This study was carried out to evaluate the clinical significance of double tract reconstruction after total gastrectomy. METHODS: 25 patients, 14 with jejunal pouch double tract reconstructions and 11 with rho-double tract reconstructions, were studied. Scintigraphy was used to evaluate duodenal and jejunal passage, and the jejunal/duodenal ratio was calculated. The patients were classified into 3 groups based on this ratio: group A (n = 14) ratio <1; group B (n = 6) ratio 1-2, and group C (n = 5) ratio >2. The reflux score, scintigraphic reflux index, emptying time of the jejunal pouch or rho-limb, and various nutritional parameters were compared between the 3 groups. RESULTS: The emptying time was shortest in group B, but there was no significant difference among the 3 groups in the Sigstad dumping scores. The reflux score, scintigraphic reflux index, and most nutritional parameters also showed no significant differences between the 3 groups. Leakage at the duodenojejunostomy did not occur in any patient. CONCLUSION: Our findings suggest that there was no preferential passage via the duodenum or jejunum after double tract reconstruction. This method is also useful for decompression of the duodenal stump and group B seemed to have the ideal reconstruction on the basis of emptying time.

Thyroid cancer in uremic patients.

BACKGROUND: The combination of thyroid cancer and secondary uremic hyperparathyroidism has thus far been reported in only 25 cases. METHODS: Here we report our experience of 19 patients with secondary hyperparathyroidism who underwent parathyroidectomy. RESULTS: Thyroid nodules were present in five patients (26.3%), including one with a benign nodule and four with papillary thyroid cancer (21.1%). CONCLUSION: Our experience suggests that, in order to make a correct diagnosis, clinicians should consider the possibility of thyroid cancer in uremic patients with secondary hyperparathyroidism.

Usefulness of K-ras gene mutation at codon 12 in bile for diagnosing biliary strictures.

Point mutations of the K-ras gene at codon 12 are often detected in the pancreatic juice of patients with pancreatic cancer. Detection of these mutations may, thus, have diagnostic implications. K-ras mutations may also have diagnostic potential for other biliary tumors. We sought to detect K-ras mutations in DNA obtained from bile in patients with biliary tract cancers, pancreatic cancer and benign biliary disease but who had obstructive jaundice. In 35 patients, bile was collected during percutaneous transhepatic choledocal drainage (PTCD) catheters. K-ras gene mutations at codon 12 in the samples were examined using mutant-allele-specific-amplification (MASA). We compared these results with cytological analyses of bile. K-ras mutations at codon 12 in bile were detected in 11 of 14 (79%) of the patients with biliary duct cancer, 3 of 9 (33%) with pancreatic cancer but not in patients with gallbladder cancer (n=3), papilla of Vater's cancer (n=3) or benign biliary diseases (n=6). In the patients, where cytological evaluation did not reveal malignant cells, K-ras mutations in bile were detected in 5 of 7 (71%) patients with biliary duct cancer and 2 of 5 (40%) with pancreatic cancer. This approach, when used in conjunction with bile cytology, may improve the yield in diagnosing suspected malignant tumors of the pancreatic-biliary system.

Comparison of variant expression of estrogen receptor mRNA in normal breast tissue and breast cancer.

To investigate whether estrogen receptor abnormalities are associated with resistance of breast cancer to endocrine therapy, we compared estrogen receptor mRNA between normal breast tissue and carcinoma. Using the RT-PCR, paired cancer and normal breast tissue specimens from 15 patients were analyzed. Exon-deleted variants were found in both tumor and normal tissue, with differences of variant expression between normal and tumor tissue being observed. One patient showed multiple deletions in the hormone-binding domain. Alterations in the amount and/or kind of variant ER expression may be important in determining the response of breast cancer to endocrine therapy.

Extrinsic neural control of nitric oxide synthase expression in the myenteric plexus of rat jejunum.

1. The role of extrinsic innervation in the expression of nitric oxide synthase (NOS) in the myenteric plexus remains unknown. In this study, we investigated the effect of extrinsic denervation on NOS expression in rat jejunum. 2. NG-nitro-L-arginine methyl ester (L-NAME)-sensitive non-adrenergic, non-cholinergic (NANC) relaxations induced by transmural nerve stimulation were significantly increased in muscle strips obtained from rats treated with splanchnic ganglionectomy or 6-hydroxydopamine (6-OH-dopamine). Truncal vagotomy or treatment of the coeliac ganglia with capsaicin did not significantly affect NANC relaxations. 3. The number of NOS-immunopositive cells in the myenteric plexus was significantly increased in tissues obtained from rats treated with splanchnic ganglionectomy or 6-OH-dopamine. 4. Western blot analysis and Northern blot analysis showed a significant increase in the density of the immunoreactive NOS band and the NOS mRNA band, respectively, of the tissues obtained from rats treated with splanchnic ganglionectomy or 6-OH-dopamine. 5. Truncal vagotomy or treatment of the coeliac ganglia with capsaicin did not significantly affect the density of NOS band or NOS mRNA band. 6. It is concluded that neuronal NOS expression in the myenteric plexus is independent of vagus nerve and is negatively regulated by the splanchnic nerves in the rat small intestine.

Evaluation of ultrasound-guided fine-needle aspiration biopsy for thyroid nodules.

BACKGROUND: We retrospectively studied whether ultrasound-guided fine-needle aspiration biopsy (US-FNAB) showed improved sensitivity in patients with palpable thyroid nodules. METHODS: A total of 70 patients (72 lesions) with thyroid nodules underwent US-FNAB and 94 patients (94 lesions) underwent FNAB guided by manual palpation (standard FNAB). The diagnoses obtained by US-FNAB were compared with the surgical findings. RESULTS: The sensitivity of US-FNAB for palpable thyroid nodules was 62% the specificity was 74% the accuracy was 68% the positive predictive value was 100%, the negative predictive value was 70% and the inadequate biopsy rate was 17%. In contrast, the sensitivity of standard FNAB was 45%, the specificity was 51%, the accuracy was 48% the positive predictive value was 96, the negative predictive value was 55, and the inadequate biopsy rate was 30%. The accuracy of US-FNAB was significantly higher than that of standard FNAB. For tumors < or = 2 cm in diameter, the sensitivity and accuracy of US-FNAB were both significantly higher than those of standard FNAB. CONCLUSION: These findings suggest that US-FNAB can improve the preoperative diagnosis of thyroid cancer, especially in patients with tumors < or = 2 cm in diameter.

Gastroesophageal reflux after distal gastrectomy: possible significance of the angle of His.

OBJECTIVE: We investigated whether the angle of His influences gastroesophageal reflux after distal gastrectomy. METHODS: Thirty-eight patients having distal gastrectomy and 10 controls underwent upper gastroesophageal fluoroscopy to measure the angle of His, and gastroesophageal reflux was assessed by scintigraphy. The association between scintigraphic reflux and the angle of His was then evaluated. RESULTS: In distal gastrectomy patients with and without reflux symptoms, the angle was 108.82 +/- 21.88 degrees and 96.07 +/- 13.25 degrees, respectively; it was 74.14 +/- 10.85 degrees in the controls. The angle was significantly larger in the patients than in the controls (p < 0.01). In addition, the angle in the symptomatic gastrectomy group tended to be larger than in the asymptomatic group. The angle was also significantly larger in patients with a scintigraphic reflux index > or =6% than in those with an index <6% (p < 0.05). CONCLUSIONS: These findings suggest that the angle of His plays a role in reflux after distal gastrectomy and that the severity of reflux may be estimated by measuring this angle.

Anoabdominal rectal resection and colonic J pouch-anal anastomosis: 10 years' experience.

BACKGROUND: Coloanal anastomosis and radiotherapy for the treatment of lower rectal carcinoma have been receiving increasing attention. METHODS: Patients with rectal cancer were divided into two groups: anoabdominal rectal resection and colonic J pouch-anal anastomosis (CAA) plus preoperative intraluminal brachytherapy (IBT) (group 1; 68 patients) and CAA without IBT (group 2; 23 patients). Group 3, comprising 59 patients who underwent abdominoperineal excision (APE), was examined as a control group. Comparative results were reviewed. RESULTS: Postoperative complications occurred more frequently in group 1 than in group 2. Actuarial 5-year survival rates were 73 per cent in group 1, 64 per cent in group 2 and 63 per cent in group 3. Cumulative local recurrence rates at 5 years were 11 per cent in group 1, 38 per cent in group 2 and 21 per cent in group 3. Intestinal continuity breakdown was seen in 14 per cent of all patients at 5 years after initial operation. CONCLUSION: The combination of CAA and preoperative IBT resulted in decreased local recurrence. IBT followed by CAA can be a good restorative option for combating lower rectal cancer.

Red cell survival in patients with nonalcoholic liver cirrhosis before and after distal splenorenal shunt.

We previously reported severe hemolysis in one patient immediately after distal splenorenal shunt (DSRS). The purpose of the present study was to evaluate changes in red cell survival after DSRS. In ten patients with nonalcoholic cirrhosis in whom DSRS was performed for esophageal varices, red cell survival and splenic quantitative hemodynamic studies were performed before and after DSRS. The splenic venous blood flow per unit volume (flow/volume ratio) was calculated. The red cell survival was significantly (P < 0.05) shortened after DSRS; the apparent half-life survival time (T 1/2) before and after DSRS was 24.6 +/- 5.9 (mean +/- SD) and 16.3 +/- 8.5 days, respectively. After DSRS, the spleen volume was significantly (P < 0.05) decreased, whereas the splenic venous blood flow was slightly increased. The spleen flow/volume ratio was significantly (P < 0.05) increased after DSRS. There was a significant and negative correlation (r = -0.684, P < 0.05) between the postoperative percentage change in T 1/2 and the spleen flow/volume ratio. These findings suggest that the red cell survival period is significantly decreased, after DSRS in patients with nonalcoholic cirrhosis, and that the increased splenic blood flow per unit spleen volume after DSRS may play an important role in the hemolytic reaction in the spleen after this procedure.

Results of preoperative intraluminal brachytherapy combined with radical surgery for middle and lower rectal carcinomas.

BACKGROUND: Radiation therapy in the treatment of rectal carcinoma has received attention. We attempted to learn whether preoperative intraluminal brachytherapy (IBT) gives an advantage in local control and/or prolongation of survival. METHODS: One hundred and fifteen patients with middle and lower rectal carcinoma with penetration into or through the rectal wall were consecutively treated with preoperative IBT and radical operation. Patients were divided into the moderate-dose group (group A: 16-40 Gy; n = 96) and the high-dose group (group B: 40-80 Gy; n = 19). A control group of 115 rectal carcinoma patients who received no radiation prior to radical surgery was compared (group C). RESULTS: The rate of sphincter-saving resection was 72% in group A, 63% in group B, and 42% in group C (group A vs. group C; P < 0.0001). The local recurrence rate at 5 years was 11% in group A, 6% in group B, and 26% in group C (group A vs. group C; P = 0.005). The 5-year survival rate was similar among the three groups. CONCLUSIONS: These results suggested that IBT contributed to the improvement of local control but not survival after radical resection of rectal carcinomas. The application of IBT might be useful in preserving the intestinal continuity for rectal carcinomas.

DNA damage-associated dysregulation of the cell cycle and apoptosis control in cells with germ-line p53 mutation.

Lymphoblastoid cell lines (LCLs) with heterozygous p53 mutations at residues 286A, 133R, 282W, 132E, and 213ter were established from five independent Li-Fraumeni syndrome families. When cell cycle regulation in response to gamma-irradiation was studied, these LCLs showed an abnormal G1 checkpoint associated with defective inhibition of cyclin E/cyclin-dependent kinase 2 activity in all cases except for 282W LCL, which showed a normal G1 checkpoint. On the other hand, the control of S-phase-G2 as determined by cyclin A/cyclin-dependent kinase 2 activity was defective in all these LCLs. The mitotic checkpoint was also defective in the two LCLs analyzed as either competent or incompetent for G1 arrest. When radiation-induced apoptosis, which requires wild-type p53 function under optimal conditions, was studied, all of these LCLs showed significant failure compared to normal LCLs. These findings indicate that although p53-dependent transactivation and G1-S-phase cell cycle control are variably dysregulated, the induction of apoptosis and control of the cell cycle at S-phase-G2 and the mitotic checkpoint in response to DNA-damaging agents are consistently dysregulated in heterozygous mutant LCLs. This suggests that these dysfunctions underlie, at least in part, the susceptibility of Li-Fraumeni syndrome families to cancer. Furthermore, the approach presented is a potentially useful method for studying individual carriers of different germ-line p53 mutations and different biological features.