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Among Asian countries, laparotomic and laparoscopic bariatric surgeries were introduced in Japan after its establishment in Taiwan. However, despite high prevalence of potential patients with obesity and diabetes, the wider incorporation of surgery into treatment regimen has been stalling for decades in Japan. While the unique Japanese national health insurance system has guaranteed fair healthcare delivery, it might have worked as a barrier to the development of bariatric and metabolic surgeries (BMS). The present article reviews the status of BMS in Japan and discusses recent issues related to its use. To focus on and identify the major obstacles inhibiting the widespread use of BMS, we have comprehensively covered some major areas including the insurance system, surgical indication, accreditation and training system, original research, and national registry.

Background Cytokeratin-positive interstitial reticulum cells (CIRCs), which are a subgroup of fibroblastic reticular cells (FRCs), are known to be present in the lymph nodes. There have been only a few cases of tumors derived from CIRCs. Case presentation We have reported a new case involving a CIRC tumor in a 75-year-old man and reviewed the literature. The resected mediastinal lymph nodes showed epithelial-like proliferation of large atypical round and polygonal epithelioid cells. The tumor cells expressed CK8, CK18, CAM5.2, AE1/AE3, epithelial membrane antigen, vimentin, fascin, and some FRC markers, which is consistent with the diagnosis of a CIRC tumor. Following chemotherapy, the CIRC tumor was observed to have responded very well and became difficult to confirm on imaging, but a small cell lung carcinoma developed 12 months later. Chemoradiotherapy was performed, but the patient passed away 29 months after the initial diagnosis. The autopsy revealed the recurrence of the CIRC tumor, residual small cell lung carcinoma, and a very small latent carcinoma of the prostate. The relapsed CIRC tumor cells had a spindle shape; they were highly pleomorphic and had invaded the superior vena cava. Conclusion We first reported autopsy findings of CIRC tumors and demonstrated the transformation of the tumor from the epithelioid cell type to the spindle cell type.

Characteristics of Staphylococcus aureus infections include biofilm formation, leading to the spread of bacteria to the bloodstream causing sepsis and metastatic infections. In particular, in methicillin-resistant S. aureus (MRSA) infections, biofilm formation critically hampers treatment and causes poor prognosis. We explored the biofilm formation of MRSA in the presence or absence of plasma and compared morphological characteristics, accumulation of antibiotics, and resistance to bactericidal activity, using continuous optimizing confocal reflection microscopy. Addition of plasma significantly increased biofilm formation, which is characterized by an uneven surface and aggregation of bacteria (hereafter plasma biofilm). The flow-cell system, which enabled a continuous supply of plasma, accelerated biofilm formation in both the tested strains of MRSA (BAA1556 and N315). Accumulation of green fluorescence-labeled vancomycin was observed within 5 minutes in the plasma-free biofilm, but not in the plasma biofilm. Delay of accumulation was also observed for daptomycin in plasma biofilm. Plasma biofilm bacteria were more resistant to anti-MRSA antibiotics than plasma-free biofilm bacteria. These data demonstrate that the plasma biofilm of S. aureus is substantially different from the plasma-free biofilm. Plasma biofilm, especially in the flow-cell system, could be a clinically relevant model to analyze MRSA infections and treatment.

Background Although preoperative detection of pleural adhesions is important in thoracic surgery, it is not widely performed. We report the availability of a pocket-sized ultrasound device for the preoperative detection of pleural adhesions. Methods Between September 2019 and September 2020, pleural adhesions were assessed preoperatively using a pocket-sized ultrasound device in 62 patients who underwent thoracic surgery. Evaluations were performed using the Vscan Dual Probe on the wards or just before surgery in the operating theater. We used a linear probe to scan the chest wall where the incision was scheduled, and evaluated the sliding sign. We compared ultrasound results with intraoperative findings. Results Of the 62 patients, the sliding sign was observed in 58 patients, 56 of whom demonstrated no pleural adhesions intraoperatively. The sensitivity was 96.6%. Four patients were negative for the sliding sign; of these, three had pleural adhesions and one did not. The specificity was 75.0%. Among all 62 patients, the diagnostic accuracy of ultrasound for pleural adhesions was 95.2%. False negatives were caused by loose adhesions. False positives were caused by the absence of vertical lines on ultrasound. Accuracy was not influenced by the timing of the test. Conclusions A pocket-sized ultrasound device was useful for the preoperative detection of pleural adhesions in thoracic surgery.

Background Current medical treatments can achieve remission of ulcerative colitis (UC). Surgery is required when potent drug treatment is ineffective or when colon cancer or high-grade dysplasia develops. The standard procedure is restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis, commonly performed as two- or three-stage RPC with diverting ileostomy. Postoperative stoma outlet obstruction (SOO) is frequent, but the causes are not well known. Aim To identify the risk factors for SOO after stoma surgery in patients with UC. Methods We retrospectively reviewed the files of 148 consecutive UC patients who underwent surgery with stoma construction. SOO was defined as small bowel obstruction symptoms and intestinal dilatation just below the penetrating part of the stoma on computed tomography. Patients were divided into two groups: Those who developed SOO within 30 d after surgery and those who did not. Patient characteristics, intraoperative parameters, the stoma site, and rectus abdominis muscle thickness were collected. Moreover, we identified the patients who repeatedly developed SOO. Univariate and multivariate analyses were performed to identify risk factors for SOO and recurring SOO. Results Eighty-nine patients who underwent two-stage RPC were included between January 2008 and March 2020. Postoperatively, SOO occurred in 25 (16.9%) patients after a median time of 9 d (range 2-26). Compared to patients without SOO, patients with SOO had a significantly higher rate of malignant tumors or dysplasia (36.0% vs 17.1%, P = 0.032), lower total glucocorticoid dose one month before surgery (0 mg vs 0 mg, P = 0.026), higher preoperative total protein level (6.8 g/dL vs 6.3 g/dL, P = 0.048), higher rate of loop ileostomy (88.0% vs 55.3%, P = 0.002), and higher maximum stoma drainage volume (2300 mL vs 1690 mL, P = 0.004). Loop ileostomy (OR = 6.361; 95%CI 1.322-30.611; P = 0.021) and maximum stoma drainage volume (OR = 1.000; 95%CI 1.000-1.001; P = 0.015) were confirmed as independent risk factors for SOO. Eighteen patients with SOO were treated conservatively without recurrence (sSOO group). Seven (28.0%) patients repeatedly developed SOO (rSOO group) during the observation period. A significant difference was observed in the rectus abdominis muscle thickness between the two groups (sSOO 9.3 mm, rSOO 12.7 mm, P = 0.006). Muscle thickness was confirmed as an independent risk factor for recurring SOO (OR = 2.676; 95%CI 1.176-4.300; P = 0.008). Conclusion In this study, high maximum stoma drainage volume and loop ileostomy are independent risk factors for SOO. Additionally, among patients with a thick rectus abdominis muscle, the risk of SOO recurrence is high.

Introduction. Empirical vancomycin (VAN) treatment failure for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia, with significantly higher mortality, has been reported for MRSA strains with reduced VAN susceptibility. Aim. Our goal was to study the effect of sub-culture on VAN minimum inhibitory concentration (MIC) values compared to direct susceptibility of MRSA-positive blood cultures. Methodology. Using 19 MRSA-positive blood cultures and 19 seeded MRSA-positive blood cultures, we compared the VAN MICs from direct susceptibility testing of MRSA-positive blood cultures and MRSA sub-cultured from positive blood cultures. Results. In comparing direct VAN MICs from MRSA-positive blood cultures and standard agar dilution, nearly half of the MICs from agar dilution were lower, with one sample decreasing from 1.5 to 0.75 µg ml−1. Furthermore, in seeded blood cultures, 80 % or more showed lower values from standard agar dilution compared to direct VAN MICs. Conclusion. Our results reveal a trend towards lower MICs after positive blood culture isolates are sub-cultured. Some clinical failures among MRSA infections treated with VAN may result from this phenomenon.

Aim Cancer pain impairs not only physical functions but also social functions and roles. Consequently, the overall health‐related quality of life of patients with cancer pain deteriorates. Opioid analgesics are recommended for treating moderate to strong cancer pain. Advances in human genome research have fueled a growing interest to understand individual differences in responsiveness to opioid analgesics. This study aimed to explore and identify novel loci for genes predisposing an individual to opioid analgesic responsiveness. Methods A total of 71 cancer patients rated their pain on an 11‐point numerical rating scale twice before and after increasing opioid analgesics. A genomewide association study focusing on single nucleotide polymorphisms (SNPs) was conducted to associate pain decrease with increased dosage of opioid analgesics based on weight (ie, responsiveness to opioid analgesics). A genomewide significance (P < 5E‐8) was set for multiplicity of analyses to control for false positives. Results Two SNPs passed the genomewide threshold for significance. One exonic SNP (rs1641025) was located in the ABAT [4‐aminobutyrate aminotransaminase (GABA transaminase)] gene on chromosome 16. The other SNP (rs12494691) was located on chromosome 3, which was not associated with any known genes. These SNPs were not associated with opioid‐related adverse effects. Conclusions Our results preliminarily suggest that both SNPs might be potential candidate loci for responsiveness to opioid analgesics, and GABA transaminase might be a possible target for developing adjuvant pharmacotherapy with opioid analgesics in adjuvant pharmacotherapy. Our results should be validated in a large‐scale study with a larger sample size., A genome‐wide association study revealed two candidate single nucleotide polymorphisms for responsiveness to opioid analgesics in patients with cancer pain, one of which locates on the GABA transaminase gene.

Gastric leakage and stricture are challenging complications of sleeve gastrectomy (SG). Failure of endoscopic intervention necessitates revision surgery. We describe two cases in which proximal gastrectomy with double tract reconstruction (PG with DTR) was performed in patients with chronic gastric fistula and twisted gastric tube after SG. Following resection of the affected part of the proximal stomach, reconstruction was achieved with three anastomoses [esophagojejunostomy (EJ), gastrojejunostomy (GJ), and jejunojejunostomy]. DTR provides two exit routes, the remnant stomach and the distal jejunum. The GJ was created 15 cm below the EJ with a stoma 10 mm in diameter, which can pass a standard endoscope. Both cases were a success without any short-term complications. PG with DTR could be an alternative option for refractory complications of SG.

Transverse sinus-sigmoid sinus (TS-SS) dural arteriovenous fistula (dAVF) is common type of dAVF, on the other hand, anterior condylar confluence (ACC) dAVF is relatively rare. There has been no report presenting patients with TS-SS dAVF and ACC dAVF identified simultaneously yet. We present a case of TS-SS dAVF and ACC dAVF that developed subcortical hemorrhage of left temporal lobe. A 66-year-old woman with no past history was transferred to our hospital for sudden-onset consciousness disturbance, and was urgently admitted after the detection of a subcortical hemorrhage in the left temporal lobe. We suspected a dAVF based on magnetic resonance angiography and performed digital subtraction angiography (DSA). DSA revealed that the left occipital artery, left ascending pharyngeal artery, left middle meningeal artery, left tentorial artery, and posterior meningeal artery flowed into the TS-SS and ACC. DSA also showed outflow from the TS-SS to the brain surface through the vein of Labbe and the vein of Trolard. We performed transvenous embolization to prevent re-bleeding, she was then discharged from our hospital and her remaining sensory aphasia gradually improved. In the present study, the active investigation to determine the cause of subcortical hemorrhage led to a definitive diagnosis. The combination of ACC dAVF and TS-SS dAVF has not been reported thus far and this is considered a valuable case.

Methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to daptomycin (DAP) were isolated from 4 patients receiving DAP from November 2013 to May 2014. These patients were treated with DAP for more than 7 days in all the cases. The pulsed-field gel electrophoresis (PFGE) patterns for MRSA isolates recovered from each patient pre- and post-DAP therapy were identical. Sequencing of mprF detected 2 amino acid substitutions (T345I or L826F) in 2 of the isolates. These results suggest that in vivo MRSA was resistant to DAP during DAP therapy. Furthermore, the MICs for DAP can vary by±1 dilution depending on the susceptibility test. When testing DAP susceptibility, there is a need to monitor reproducibility using different susceptibility tests, including the CLSI method.

Pro- and anti-inflammatory cytokines (adipokines) associated with adipose tissue can modulate inflammatory processes and lead to systemic inflammatory conditions such as metabolic syndrome. In the present pilot study, we investigated 3 major adipokines (leptin, adiponectin, and resistin) and 2 nonspecific proinflammatory cytokines (tumor necrosis factor α and interleukin-6) with regard to their association with postoperative pain intensity.We analyzed a total of 45 single-nucleotide polymorphisms of the adipokines in 57 patients with postlaparotomy pain. We adjusted for multiple testing to reduce the chance of false-positive results by controlling the false discovery rate. Serum levels of the adipokines and proinflammatory cytokines were measured in another 36 patients undergoing laparotomy. A stepwise multiple linear regression analysis using these measurements and opioid dosages as independent variables was performed to explore the factors associated with postoperative pain.Only 1 variant of the resistin gene (rs3745367) demonstrated a significant association with postoperative pain (P.002). Patients exhibiting homozygosity for the minor alleles (n = 7; numerical rating scale [NRS], 2.3 ± 1.3) demonstrated lower pain intensity compared with those exhibiting homozygosity for the major alleles (n = 29; NRS, 3.8 ± 1.0; P = .004) and heterozygosity for the minor alleles (n = 21; NRS, 4.2 ± 0.8; P.001). Only serum resistin levels showed a positive association with postoperative pain.A genetic variant of resistin and serum resistin levels were associated with postoperative pain intensity, while other adipokines and cytokines exhibit no such association. Resistin can alter the inflammatory responses in postoperative wounds, although it could be a determinant factor that is independent of inflammatory processes. Resistin may be a novel marker for postoperative pain intensity.

Background We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA non-small cell lung cancer patients. Methods Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary endpoints were relative total administration dose, toxicity, and 3-year disease-free survival. Results From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients (73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). Grade 1–3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94). Conclusions The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1–3 elevation of bilirubin. Trial registration This randomized multicenter study was retrospectively registered with the UMIN-CTR (UMIN000016086, registration date December 30, 2014).

Background Despite the widespread use of opioids for the treatment of cancer pain, results from several surveys consistently show that pain is still prevalent in some patients with malignant diseases. The purinergic P2Y12 receptor is a primary site leading to microglial activation and hyperalgesic pain behaviors and is considered a key regulator in the prevention of the aggravation of clinical pain conditions. Genetic variability in the P2RY12 gene may contribute to individual differences in pain and opioid sensitivity. Methods We genotyped 31 single nucleotide polymorphisms (SNPs) throughout the P2RY12 gene and compared genotypes against pain measurements and opioid requirements in Japanese cancer pain patients (N = 90). The most promising SNP association with pain severity was validated by genotyping an additional postoperative pain patient cohort (N = 355). Results Five SNPs (rs3732765, rs9859538, rs17283010, rs11713504, and rs10935840) of the P2RY12 gene were significantly associated with cancer pain severity, although opioid requirements were comparable in each genotype of the five SNPs. The alleles of these SNPs represented one absolute linkage disequilibrium block of the P2RY12 gene. In the second association study of postoperative pain, subjects carrying the minor T allele of the rs3732765 SNP demonstrated more intense 24-hour postoperative pain compared with subjects not carrying this allele although total 24-hour postoperative opioid consumptions based on weight were comparable. Conclusions Polymorphisms of the P2RY12 gene may predict individual differences in both cancer and postoperative pain severity; this might be caused by functional alteration of nociceptive neurons through neuron-glia interaction.

An association between postoperative analgesic requirements in subjects who underwent orthognathic surgery and the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene was suggested by our previous genome-wide association study. To verify this association, we analyzed the association between the rs1465040 SNP and analgesic requirements, including opioid requirements, after open abdominal surgery. The association between the rs1465040 SNP and postoperative analgesic requirements was confirmed in the open abdominal surgery group (P = 0.036), suggesting that the TRPC3 SNP may contribute to predicting postoperative analgesic requirements.

Background The oxaliplatin-based regimen FOLFOX is widely used to treat patients with advanced colorectal cancer (CRC). However, dose-limiting toxicity after continuous oxaliplatin administration can lead to peripheral neuropathy. Several agents, including opioids, that have been employed to treat oxaliplatin-induced peripheral neuropathy (OIPN) have been examined in clinical settings regarding their protective and therapeutic effects. However, the pharmacotherapy of these agents has not yet been established. Therefore, we investigated the efficacy and tolerability of oxycodone for OIPN and subsequently with FOLFOX therapy in CRC patients. Methods This was a single-center retrospective study of 64 CRC patients who underwent FOLFOX therapy at the Toho University Sakura Medical Center (Sakura, Japan). Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group), whereas the additional 35 patients (non-OXY group) were not given oxycodone during the FOLFOX treatment course. The incidence and severity of OIPN and the number of FOLFOX cycles were measured and compared between the two groups. Neurological toxicities were assessed according to the Common Terminology Criteria for Advanced Events, version 3.0. Results All study patients had OIPN. Most patients experienced grade 1 or 2 sensory neuropathy. Grade 3 sensory neuropathy was observed in two patients in the non-OXY group. All patients in the OXY group completed the scheduled FOLFOX therapy, whereas FOLFOX therapy was discontinued in ten patients in the non-OXY group due to severe peripheral neuropathy. The median numbers of FOLFOX cycles in the OXY and non-OXY groups were 13 (range, 6–46) and 7 (range, 2–18), respectively (P

We report a unique case of giant obstructing inflammatory polyposis associated with ulcerative colitis (UC). A 25-year-old Japanese man with an UC history of 2 years and 6 months was referred to our institution because of diarrhea and melena. His computed tomography scan showed marked dilation of the transverse and descending colon; therefore, we performed total colectomy. Macroscopic evaluation of the excised specimen indicated constricting lesions with giant polyposis in the transverse and descending colon. The polyposis consisted of narrow worm- or noodle-like polyps that bridged over the irregular ulcers. Histologic evaluation of the excised specimen indicated transmural inflammation with a thickened proper muscular layer overlaid with inflammatory polyposis. Based on these data, a diagnosis of giant inflammatory polyposis should be considered in patients who have had UC. Although giant inflammatory polyposis is considered benign, surgical treatment may be indicated to avoid serious complications.

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. The adrenergic system is reportedly involved in the mechanisms of pain and analgesia. Here, we focused on one of the adrenergic receptor genes, ADRB1, and analyzed the influence of single-nucleotide polymorphisms (SNPs) in the ADRB1 gene on individual differences in pain and analgesic sensitivity. We examined associations between pain and fentanyl sensitivity and the two SNPs, A145G and G1165C, in the human ADRB1 gene in 216 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. The patients who carried the A-allele of the A145G SNP were more sensitive to cold pressor–induced pain than those who did not carry this allele, especially in male patients. The analgesic effect was significantly less in females who carried the G-allele of the G1165C SNP than the females who did not carry the G-allele. The haplotype analysis revealed a significant decrease in 24-h postoperative fentanyl use in female 145A/1165C haplotype carriers. These results suggest that SNPs in the ADRB1 gene are associated with individual differences in pain and analgesic sensitivity, and analyzing these SNPs may promote personalized pain treatment in the future. Keywords:: β1-adrenergic receptor, gene polymorphism, opioid, pain, individual difference

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3–2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower ‘Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.

治癒切除不能な進行・再発結腸および直腸癌に対してOxaliplatin（l-OHP）の適応が承認され，多くの施設で投与されている．末梢神経障害による神経因性疼痛はl-OHPの用量制限毒性の1つである．原因として神経線維細胞のNaチャンネルの異常が注目されたが，その機序は解明されていない．カルシウム・マグネシウム製剤をl-OHP投与の前後に施行するなどの対応策が講じられているが，我が国では未だ有効な予防法はない．当科でOxycodone投与によって，l-OHPによる神経因性疼痛が著明に軽減しl-OHPの継続投与が可能であった3例を経験した．これらの症例ではOxycodoneの低用量，短期間投与でl-OHPによる神経因性疼痛を軽減できたことから，Oxycodone併用投与はl-OHPの継続投与を可能とする一助となり得ると考える．

Individual differences in sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. Still controversial is whether the single nucleotide polymorphisms (SNPs) of the human OPRM1 gene encoding the mu-opioid receptor influence the analgesic effects of opioids. We examined associations between fentanyl sensitivity and the two SNPs, A118G and IVS3+A8449G, in the human OPRM1 gene in 280 Japanese patients undergoing painful orofacial cosmetic surgery, including bone dissection. Regarding the A118G SNP in exon 1, in a cold pressor-induced pain test before surgery, less analgesic effects of fentanyl were shown in subjects carrying the minor G allele of the A118G SNP (median of difference between pain perception latencies before and after fentanyl injection [PPLpost-PPLpre]: 12s) compared with subjects not carrying this allele (PPLpost-PPLpre: 15s, p=0.046). Furthermore, the IVS3+A8449G SNP in intron 3, which represents a complete linkage disequilibrium block with more than 30 SNPs from intron 3 to the 3' untranslated region, was associated with 24-h postoperative fentanyl requirements. Subjects carrying the minor G allele of the IVS3+A8449G SNP required significantly less fentanyl for 24-h postoperative pain control (median: 1.5microg/kg) compared with subjects not carrying this allele (median: 2.5microg/kg, p=0.010). Although further validation is needed, the present findings shed light on the involvement of OPRM1 3' untranslated region polymorphisms in fentanyl sensitivity in addition to the A118G SNP and open new avenues for personalized pain treatment with fentanyl.

Opiate analgesics have been widely used for severe acute pain and chronic cancer-related pain. Individual differences in the effectiveness of opiates and their side effects limit the clinical benefits and increase risks of drug abuse. Genetic factors might affect variations of opiate sensitivity. The mu opioid peptide receptor (MOP) is the principal site of pharmacologic actions for most clinically important opiate drugs. Recent studies using various knockout mice and recombinant-inbred strain CXBK mice have indicated that the analgesic effect of morphine is dependent on the amount of the MOP. There are more than 100 polymorphisms identified in the human MOP (OPRM1) gene. These polymorphisms might be correlated with OPRM1 mRNA stability and opiate sensitivity, including opiate analgesia, tolerance, and dependence. More precise studies on the relationship between gene polymorphisms and opiate sensitivity will enable realization of personalized pain treatment by predicting opiate sensitivity and requirement for each patient.

Background Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although several candidate gene variations have been reported by candidate gene studies or genome-wide association studies (GWASs) to be associated with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese subjects. Results The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and CPD, the nonsynonymous rs2653349 SNP (located on the gene that encodes orexin [hypocretin] receptor 2) was selected as the most notable SNP associated with FTND, with a p value of 0.0005921 in the two-stage GWAS. This possible association was replicated for the remaining 374 samples. This SNP was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and susceptibility to goiter. Conclusions Although the p value did not reach a conventional genome-wide level of significance in our two-stage GWAS, we obtained significant results in the subsequent analyses that suggest that the rs2653349 SNP (Val308Ile) could be a genetic factor that is related to nicotine dependence and possibly pain, schizotypal personality traits, and goiter in the Japanese population. Electronic supplementary material The online version of this article (doi:10.1186/s13041-015-0142-x) contains supplementary material, which is available to authorized users.

Primary signet ring adenocarcinoma (SRA) of the lung is a rare condition. An 81-year-old man was referred to our hospital because of bloody sputum. Chest radiography showed a tumor in the right lung and biopsies revealed typical SRA. No tumors except for the one in the right lung were found. Therefore, diagnosis of primary lung SRA was made. The SRA cells showed intracytoplasmic mucin that were characterized by crescentic nuclei displaced toward one end of the cell. The tumor cells showed negative immunostaining for thyroid transcription factor 1 (TTF-1), but positive immunostaining for CDX2, cytokeratin-20 (CK20), Ki-67 (labeling = 50%), p53, and focally CK7. A right lower lobectomy and lymph node dissection were performed via video-assisted thoracic surgery. After surgery, uracil-tegafur (184 mg/m 2 /day) was administered for five days, followed by a 2-day rest period for a duration of two years in total. No recurrence was observed during the monthly-follow ups, and the patient did not experience any complications. In conclusion, we describe an extremely rare case of primary enteric adenocarcinoma with predominantly signet ring features of the lung. Our case report includes in-depth immunohistochemical and molecular data.

症例は33歳の女性で, 腹部違和感を主訴に2003年6月当院を受診した. 既往で1歳9か月時に大網嚢胞腫摘出術を受けていた. 理学的所見では右上腹部に境界不明瞭で軟らかい腫瘤が3～4横指大に触知され, 腹部超音波検査, 腹部CTで右上腹部に嚢胞性腫瘍が認められた. 原発不明の嚢胞性腫瘍の診断にて手術を施行, 腫瘍は胃結腸間膜内に手拳大に透見され多房性を呈し, 内容は漿液性の液体であった. 隣接する他臓器との連続性はなく, 嚢腫を摘出した. 病理組織学的にリンパ管腫と診断された. 成人の大網リンパ管腫の発生はまれである. 本例では小児期に大網嚢腫の手術歴があり, 再発かまたは初発時と同様の機序で新たに発生した可能性が推察された. 30年以上経過後の再発は検索した範囲では報告がない. 再発防止を念頭においた処置が重要であると考えられた.

p53-mediated apoptosis may involve the induction of redox-controlling genes, resulting in the production of reactive oxygen species. Microarray expression analysis of doxorubicin exposed, related human lymphoblasts, p53 wild-type (WT) Tk6, and p53 mutant WTK1 identified the p53-dependent up-regulation of manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx). Consensus p53 binding sequences were identified in human MnSOD and GPx promoter regions. A 3-fold increase in the MnSOD promoter activity was observed after the induction of p53 in Li-Fraumeni syndrome (LFS) fibroblast, TR9-7, expressing p53 under the control of a tetracycline-regulated promoter. An increased protein expression of endogenous MnSOD and GPx also positively correlated with the level of p53 induction in TR9-7 cells. However, catalase (CAT) protein expression remained unaltered after p53 induction. We also examined the expression of MnSOD, GPx, and CAT in a panel of normal or LFS fibroblasts, containing either WT or mutant p53. We found increased MnSOD enzymatic activity, MnSOD mRNA expression, and MnSOD and GPx protein in LFS fibroblasts carrying a WT p53 allele when compared with homozygous mutant p53 isogenic cells. The CAT protein level was unchanged in these cells. We observed both the release of cytochrome C and Ca2+ from the mitochondria into the cytoplasm and an increased frequency of apoptotic cells after p53 induction in the TR9-7 cells that coincided with an increased expression of MnSOD and GPx, and the level of reactive oxygen species. The increase in apoptosis was reduced by the antioxidant N-acetylcysteine. These results identify a novel mechanism of p53-dependent apoptosis in which p53-mediated up-regulation of MnSOD and GPx, but not CAT, produces an imbalance in antioxidant enzymes and oxidative stress.

Gastric leakage is a challenging complication of sleeve gastrectomy. Multimodal approaches, including drainage, clipping, and stenting of the leak, are occasionally insufficient. We report successful management of refractory gastric leakage using percutaneous transesophageal gastro-tubing (PTEG). Drainage and stenting proved inadequate for treating sleeve leakage near the esophagogastric junction in two patients. PTEG was finally performed, and enteral feeding was started on the following day. The patients were discharged within 1 week. The PTEG-tube was removed after confirming oral food intake. Both patients continue to do well without recurrence. PTEG was developed for patients who are unsuitable for percutaneous endoscopic gastrostomy. PTEG provides decompression and permits enteral feeding in patients refractory to other endoscopic treatments. PTEG is an option for managing intractable sleeve leakage without surgery.

DCCTの報告は1型糖尿病患者が正常値に近い血糖コントロールを長期に続ければ細小血管障害の発症および進展を防止することを示した。現在では, 強化インスリン療法が1型糖尿病の標準的治療と考えられている。しかし, 強化インスリン療法では低血糖が従来法より3倍多く発生するという欠点も指摘されている。もし, 患者が自己の血糖値を予測できるならば, 低血糖の予防にも厳格な血糖管理にも有利である。今回, 我々は, サマーキャンプに参加した小学4年から中学3年までの1型糖尿病患児28名を対象に, 血糖値予測が可能か否かにつき検討した。患児は, 毎食前と21時に血糖値を予測した後, 簡易血糖測定器にて自己血糖測定を行った。血糖測定値と血糖予測値は正規分布を示さず, 各々の自然対数Ln (mBG) とLn (pBG) は正規分布を示した。Ln (mBG) とLn (pBG) は正相関した (y=0.359x+3.239, r=0.495)。また, 予測値が実測値の±20%, ±30%以内に入ったものはそれぞれ393例中124例 (31.5%), 175例 (44.5%) であった。2日目から4日目までの測定時点別にLn (mBG) とLn (pBG) を検討したところ, Ln (mBG) とLn (pBG) に有意差を認めたものではLn (mBG) が他の日の同じ時間帯に比し大きく変動していた。1型糖尿病患児の血糖値予測が正しい確率は低く, 特に血糖値が非常に高いか低い場合や血糖値が大きく変動した場合は, さらにその確率は低かった。

p73 is a candidate tumor suppressor gene with substantial DNA and protein homology to the p53 tumor suppressor gene. We have investigated two hypotheses: (a) p73 is mutated in diverse types of human cancer, and (b) p73 is functionally redundant with p53 in carcinogenesis so that mutations would be exclusive in these two genes. The entire coding region and intronic splice junctions of p73 were examined in 54 cancer cell lines. Three lung cancer cell lines contained mutations that affected the amino acid sequence. One amino acid substitution was in a region with homology to the specific DNA binding region of p53 and two microdeletions were outside the region of homology. Two of the cell lines with p73 mutations also carried p53 mutations. Although our results are inconsistent with the two hypotheses tested, p73 mutations may contribute infrequently to the molecular pathogenesis of human lung cancer.

We describe a case of gas-producing infection following a perianal abscess. A 61-year-old man was admitted to our hospital complaining of perineal pain and was found to have a perianal abscess. He was diabetic but had not received treatment for the disease. Although the perianal abscess was drained and antibiotic treatment started, severe swelling of the scrotum, with crepitation, redness, and partial necrosis progressed rapidly. Computed tomography revealed subcutaneous gas formation in the scrotum. A culture study revealed Clostridium, Enterococcus, and numerous other types of bacteria. The patient was diagnosed with Fournier's gangrene caused by infection with Clostridium in combination with other species of bacteria. The infection was refractory to drainage and antibiotic therapy. Thus, repeated extensive debridement of all necrotic tissue in the scrotum was required until healthy granulation was present in the wound. Our case shows that, in patients with Fournier's gangrene caused by infection with Clostridium in combination with other species of bacteria, the mainstay of treatment should be open drainage and aggressive surgical debridement of all necrotic tissue, followed by broad-spectrum antibiotic therapy.

Mutations in the transforming growth factor beta type II receptor (TGFbeta RII) gene have been detected in several human cancers exhibiting microsatellite instability. To extend analyses of this gene, we previously investigated the exon-intron organization of the TGFbeta RII gene and defined seven exons and flanking intron sequences. In this study, we further determined the nucleotide sequences surrounding these seven exons and designed eight sets of intron-based primers to examine the entire coding region of the TGFbeta RII gene. Using these primers, we screened genomic DNA sequences from 30 sporadic colorectal cancers for mutations of the TGFbeta RII gene. TGFbeta RII mutations were detected in two of 30 tumors and both displayed microsatellite instability. One had a deletion in a polyadenine tract in exon 3 and the other had a point mutation in the kinase domain located in exon 7. There were no mutations in exons 1, 2, 4, 5 and 6. These results further implicate the polyadenine tract and kinase domain as mutational hotspots in the TGFbeta RII gene in cells with genomic instability and suggest that TGFbeta RII gene mutations occur rarely in cells lacking genomic instability.

8-Hydroxydeoxyguanosine (oh8dG) is a promutagenic DNA lesion produced by oxygen radicals, and a high level of 8-hydroxyguanine in breast cancers was previously demonstrated by the gas chromatography-mass-spectrometry method. To confirm the previous observation, the oh8dG levels of DNA of 22 breast cancers and corresponding adjacent non-cancerous breast tissues were analyzed by high performance liquid chromatography-electrochemical detector (HPLC-ECD) system, and the correlation of the oh8dG levels in breast cancer DNAs with clinical and immunohistochemical parameters was examined. However, the levels of oh8dG in DNA of breast cancers are not significantly different from those of corresponding non-cancerous breast tissues (P = 0.084) by the HPLC-ECD method. Furthermore, the oh8dG levels in breast cancers were not associated with p53 and erbB-2 immunoreactions, with expression of estrogen and progesterone receptors, and with clinical stage and histological grade. Thus, in contrast to the previous data, the present study using the HPLC-ECD method does not indicate an increase of oh8dG levels in breast cancers.

Diesel exhaust particles (DEP) cause tumors in the respiratory tracts of experimental animals. It was previously shown that DEP produced superoxide and hydroxyl radical. To examine whether oxygen radicals are involved in mouse lung tumorigenesis induced by DEP, formation of an oxidative DNA damage, 8-hydroxydeoxyguanosine (oh8dG), by DEP was investigated. Furthermore, the role of high dietary fat and beta-carotene on this process was studied. After intratracheal instillation of DEP, a significant increase of oh8dG in mouse lung DNA was observed. High dietary fat enhanced the formation of oh8dG in lung DNA. Intake of beta-carotene suppressed the formation of oh8dG in lung DNA, but the protective effect of beta-carotene against this process was not statistically significant. These results suggest that formation of oh8dG in lung DNA was induced by oxygen free radicals produced by DEP. Thus, it is possible that oh8dG is a promutagenic lesion in DEP-induced lung tumorigenesis in mice and high dietary fat enhances this process through the generation of oh8dG in mouse lung DNA.

当院では糖尿病患者教育指導の一環として簡易血糖測定機を用いた血糖自己測定指導を検査技師が実施している。従来の呈色法を用いた血糖測定機 (呈色型血糖測定機, 以下呈色型と略す) のほかに, バイオセンサーを用いた固定化酵素電極法による血糖測定機 (バイオセンサー型血糖測定機, 以下バイオセンサー型と略す) を導入したところ, 血糖自己測定の指導数も増加した。バイオセンサー型は次のような特徴が認められた。バイオセンサー型は呈色型に比べ扱いやすく, 高齢者でも操作が可能であった。測定に必要な血液量も少なく, 採血部位も限定されなかった。そのため, 呈色型からバイオセンサー型への使用変更者も多かった。来院時検査における血糖測定値とも良く相関し, 精度的にも優れていた。しかし, 電極チップのセット不備や残存消毒液による血液の希釈など操作法についての問題点も残った。

Although the serotonin (5-hydroxytryptamine (5-HT)) 2A receptor has been reported to be associated with pain, no relationship has been found between single nucleotide polymorphisms in the 5-HT2A receptor gene and analgesic requirements. To clarify the mechanism of individual differences in analgesic requirements, we investigated the relationship between the 5-HT2A 102T/C gene polymorphism and analgesic requirements in 135 patients who underwent major open abdominal surgery and were managed with continuous epidural analgesia with opioids after surgery. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. We found that the 102T/C polymorphism had significant main effects with regard to analgesic requirements. In addition, significant interaction effects were found between the 102T/C polymorphism and sex in terms of analgesic requirements. Among female subjects, patients with the T/T genotype of the 102T/C polymorphism had more analgesic requirements than those with the other genotypes. This finding suggests that the linkage disequilibrium block, which includes the 102T/C polymorphism of the 5-HT2A receptor gene, is involved in individual differences in analgesic requirements in women.

Opioid analgesics are commonly used for the treatment of acute as well as chronic, moderate to severe pain. Well-known, however, is the wide interindividual variability in sensitivity to opioids that exists, which has often been a critical problem in pain treatment. To date, only a limited number of studies have addressed the relationship between human genetic variations and sensitivity to opioids, and such studies are still in their early stages. Therefore, revealing the relationship between genetic variations in many candidate genes and individual differences in sensitivity to opioids will provide valuable information for appropriate individualization of opioid doses required for adequate pain control. Although the methodologies for such association studies can be diverse, here we summarize protocols for investigating the association between genetic polymorphisms and sensitivity to opioids in human volunteers and patients undergoing painful surgery.

Mutation in the epidermal growth factor receptor (EGFR) is frequently seen in non-small cell lung cancers (NSCLCs), especially in Asian females with adenocarcinoma. The frequency of mutation and the factors associated requires to be elucidated by analyzing a large number of consecutive clinical samples. We summarized the result of the EGFR mutation analysis for 1,176 patients performed at the time of diagnosis or relapse. The PNA-LNA PCR clamp, a highly sensitive detection method for the EGFR mutation, was employed. For fresh cases a portion of samples isolated to establish the diagnosis of lung cancer was used. For cases with a relapsed disease archival tissue were tested. The variables associated with the EGFR mutation after removing the confound factors were investigated by the logistic analysis using the samples collected in our university (n = 308) where detailed information on patients were available. The frequency of the EGFR mutation and its subtypes were investigated using all samples (n = 1,176). The EGFR mutation was significantly associated with adenocarcinoma (p = 0.006) and light-smoking (p < 0.0001), but not gender. The deletions in exon 19 were more frequently associated with male gender while exon 21 deletions were with female gender (p = 0.0011). The overall frequency of the EGFR mutation was 31%. Our result suggests that the female predominance in the EGFR mutation rate is a reflection of a higher frequency of adenocarcinoma in females. The gender difference in the mutation subtypes may provide a clue for the mechanism of the occurrence of the EGFR mutation.

Inhibitor of growth 2 (ING2) is associated with chromatin remodeling and regulation of gene expression by binding to a methylated histone H3K4 residue and recruiting HDAC complexes to the region. The aim of our study is to investigate the regulation of ING2 expression and the clinical significance of upregulated ING2 in colon cancer. Here, we show that the ING2 mRNA level in colon cancer tissue increased to more than twice than that in normal mucosa in the 45% of colorectal cancer cases that we examined. A putative NF-kappaB binding site was found in the ING2 promoter region. We confirmed that NF-kappaB could bind to the ING2 promoter by EMSA and luciferase assays. Subsequent microarray analyses revealed that ING2 upregulates expression of matrix metalloproteinase 13 (MMP13), which enhances cancer invasion and metastasis. ING2 regulation of MMP13 expression was confirmed in both ING2 overexpression and knock down experiments. MMP13 expression was further induced by coexpression of ING2 with HDAC1 or with mSin3A, suggesting that the ING2-HDAC1-mSin3A complex members regulates expression of MMP13. In vitro invasion assay was performed to determine functional significance of ING2 upregulation. ING2 overexpressed cells exhibited greater invasive potential. Taken together, upregulation of ING2 was associated with colon cancer and MMP13-dependent cellular invasion, indicating that ING2 expression might be involved with cancer invasion and metastasis.

A 28-year-old man with no previous history of abdominal surgery presented at a local hospital with abdominal pain. He was diagnosed to have an intestinal obstruction and was treated conservatively. However, the symptoms persisted, and he was thereafter referred to this hospital. Plain abdominal radiographs demonstrated small-bowel gas. A computed tomographic scan of the abdomen disclosed wall thickening of an edematous, fluid-filled ileum. An exploratory laparotomy was performed to determine the cause of the intestinal obstruction. The ileum had herniated into the intersigmoid fossa, 100 cm proximal to the ileocecal valve, and the patient was diagnosed to have an intersigmoid hernia. Since the incarcerated portion of the small bowel was viable, reduction of the hernia and closure of the defect in the sigmoid mesocolon were performed. The postoperative course was uneventful. A sigmoid mesocolon hernia is an uncommon condition. This report presents a case of intersigmoid hernia and a review of 60 cases of sigmoid mesocolon hernia reported in Japan.

Aims: The association between SNPs of the human OPRM1 gene encoding the µ-opioid receptor and postoperative analgesic requirements in surgical patients remains controversial. Here, we evaluate whether any of the five tag SNPs (A118G, IVS2+G691C, IVS3+G5953A, IVS3+A8449G and TAA+A2109G) representing the four linkage disequilibrium blocks of the OPRM1 gene influences postoperative analgesic requirements. Materials & methods: We studied 138 adult Japanese patients who underwent major open abdominal surgery under combined general and epidural anesthesia and received continuous postoperative epidural analgesia with opioids. Results: The 118G homozygous (GG) patients required 24-h postoperative analgesics more than 118A homozygous (AA) and heterozygous (AG) patients. Tag SNP haplotypes also were associated with 24-h postoperative analgesic requirements. Conclusions: These results suggest that OPRM1 gene tag SNP genotypes and haplotypes can primarily contribute to prediction of postoperative analgesic requirements in individual patients undergoing major open abdominal surgery.

To evaluate the effects of fidarestat (SNK-860) on vibration perception threshold, as measured by C64 quantitative tuning fork (64Hz) analysis, as well as its effects on subjective symptoms in patients with diabetic polyneuropathy. Open-label, prospective study conducted at 12 hospitals in the central area of Honshu, Japan. Fidarestat was administered at a dosage of 1mg once daily after breakfast for 28 weeks. Vibration perception threshold of upper and lower extremities was determined using a C64 quantitative tuning fork, and measured at baseline and after 12 and 28 weeks of treatment. Subjective symptoms, including numbness, spontaneous pain and hypoaesthesia, were evaluated every 4 weeks. Subjective symptoms were evaluated in 22 patients, and vibration perception threshold data were available for 19 patients. Vibration perception threshold at baseline was negatively correlated with the severity of the following subjective symptoms: numbness in the upper limbs, and numbness, coldness and hot flushes, smarting pain causing difficulty walking and hypoaesthesia in the lower limbs. During treatment with fidarestat, vibration perception threshold increased significantly in the upper (p = 0.0017) and lower (p = 0.0001) limbs. The following symptoms were also significantly improved: severity of numbness in the lower limbs, heaviness in the foot, coldness and hot flushes in the lower limbs, smarting pain causing difficulty walking, sensation as if walking on sand, sensation as if walking on an uneven road, spontaneous pain in the lower limbs, and dizziness. Adverse events occurred in four patients. Administration of fidarestat after breakfast was effective in significantly alleviating some symptoms of diabetic polyneuropathy. The C64 quantitative tuning fork analysis is useful in the diagnosis of diabetic polyneuropathy, and as a measure of the severity of the neuropathological symptoms of this condition.

The ING1 gene is involved in the regulation of the cell cycle, senescence, and apoptosis and is a novel candidate tumor suppressor gene. ING2, another gene in the ING family, was identified and cloned. The functions of ING1 and ING2 largely depend on the activity of p53. To determine whether an alteration in these genes plays a role in carcinogenesis and tumor progression in lung cancer, we screened 30 human lung cancer cell lines and 31 primary lung cancer tumors for mutations in these genes using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing. Our findings failed to uncover any mutations in these genes. We also examined the expression of ING1 and ING2 in lung cancer cell lines that either had or lacked a p53 mutation, and in a control bronchial epithelium cell line, using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). ING1 expression was up-regulated in all 7 lung cancer cell lines that had a p53 mutation, while the expression of ING2 was down-regulated in 6 of 7 lung cancer cell lines that had a p53 mutation. These results suggest that the ING1 and ING2 genes have different roles in lung carcinogenesis and progression, and the ING2 gene may be an independent tumor suppressor candidate on p53.

Immune responses have been reported to decline following surgical stress, leading to an increased susceptibility to infection or to the growth of tumors. In this study, we report that pre-operative treatment with the biological response modifier (BRM) polysaccharide Kureha (PSK) can inhibit the decline of immunocompetence during the perioperative period. BALB/c mice were laparotomized, the intestinal tracts were exposed to room air for 1.5 h, and then the abdomens were closed. Six hours after the operation, the spleen and serum were collected. The concentrations of IL-6 in the serum and of IFNgamma and IL-4 in the supernatant of splenocyte cultures were measured. In the surgical stress group that received surgical stress and the PSK treatment, the serum IL-6 concentration was significantly elevated in the group with surgical stress. PSK treatment controlled the stress-induced elevation. IFNgamma concentrations were measured in the supernatant of Concanavalin A (Con A) stimulated splenocyte cultures. It was lower in the group with surgical stress than in the cultures derived from the non-treated group. The IFNgamma concentration in the group with surgical stress plus PSK treatment was significantly higher than the level in the group with surgical stress alone. The IL-4 concentration was significantly lower in the surgical stress group than in the control group, however, the concentration tended to be higher in the surgical stress plus PSK treatment group than in the group with surgical stress alone. The IFNgamma/IL-4 ratio in the group with surgical stress was lower than the ratio in the non-treated group. The ratio in the group with surgical stress plus PSK treatment was significantly higher than the ratio in the group with surgical stress alone. These results suggest that PSK restores the abnormality of the biological responses induced by surgical stress and corrects the reduced Th1/Th2 cytokine balance to a normal level.

196 Background: The oxaliplatin-based regimen FOLFOX is widely used to treat patients with advanced colorectal cancer (CRC). However, dose-limiting toxicity after continuous oxaliplatin administration can lead to peripheral neuropathy. Several agents, including opioids, that have been employed to treat oxaliplatin-induced peripheral neuropathy (OIPN) have been examined in clinical settings regarding their protective and therapeutic effects. However, the pharmacotherapy of these agents has not yet been established. Therefore, we investigated the efficacy and tolerability of oxycodone for OIPN and subsequently with FOLFOX therapy in CRC patients. Methods: This was a single-center retrospective study of 64 CRC patients who underwent FOLFOX therapy at the Toho University Sakura Medical Center (Sakura, Japan). Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group), whereas the additional 35 patients (non-OXY group) were not given oxycodone during the FOLFOX treatment course. The incidence and severity of OIPN and the number of FOLFOX cycles were measured and compared between the two groups. Neurological toxicities were assessed according to the Common Terminology Criteria for Advanced Events, version 3.0. Results: All study patients had OIPN. Most patients experienced grade 1 or 2 sensory neuropathy. Grade 3 sensory neuropathy was observed in two patients in the non-OXY group. All patients in the OXY group completed the scheduled FOLFOX therapy, whereas FOLFOX therapy was discontinued in ten patients in the non-OXY group due to severe peripheral neuropathy. The median numbers of FOLFOX cycles in the OXY and non-OXY groups were 13 (range, 6–46) and 7 (range, 2–18), respectively (P 2 (range, 408.7–3385.3 mg/m2) in the OXY group and 483.0 mg/m2 (range 76.2–1414.1 mg/m2) in the non-OXY group (P

The transforming growth factor-beta (TGF-beta) binds the type II TGF-beta growth factor receptor (RII) to inhibit the growth of most epithelial tissues. Most human colon and gastric cancers with microsatellite instability (MI) have frameshift mutations in polynucleotide repeats within the RII coding region; these mutations truncate the receptor protein and disable the serine/threonine kinase to produce TGF-beta resistance. To further investigate the type, frequency and tissue distribution of RII mutations, we selected 24 human cancer cell lines from various tissues which were previously reported to be resistant to the inhibitory effects of TGF-beta. We developed protocols for non-isotopic SSCP analysis of PCR products from genomic DNA samples, and we tested them for microsatellite instability. PCR-SSCP analysis followed by DNA sequencing identified deletion mutations in the exon 3 poly-adenine tract in three colon tumor cell lines: LS174T and SW48 had a single base deletion and LS411 had a two base deletion. Among the 24 previously unreported cell lines, only these three demonstrated microsatellite instability. These and other recent data indicate that RII mutations are essentially confined to colon and gastric cancers with microsatellite instability. The narrow spectrum of tissues containing RII mutations illustrates the complexity of genetic checkpoints in human carcinogenesis.

The transforming growth factor-beta type II receptor (RII) is commonly mutated in colon and gastric cancers with microsatellite instability (MI). We utilized our series of lung cancers with MI and rare alleles of the H-ras1 gene to determine the association between MI and RII mutations and searched the entire RII coding region in 33 lung cancers with MI by polymerase chain reaction-single-strand conformation polymorphism analysis. We found no mutations, and these data support other recent evidence that RII mutations rarely occur except in colon and gastric tumors with MI.

We examined for germ-line p53 mutations and microsatellite instability in three gastric cancer patients who had family histories of gastric cancer aggregation. Although no germ-line p53 mutation was detected in these three cases, the replication error (RER) phenotype was observed in two of them. One base deletion in the sequence of ten repeating adenines of the type II transforming growth factor-beta receptor gene was detected in one of these two cases. Furthermore, there were young patients of 50 years and downward in their families. Therefore, it is possible that inherited disorders in mismatch repair systems contribute to high susceptibility to gastric cancers in these families.