佐久間 康成

Chemotherapy-induced nausea and vomiting is a serious adverse side-effect of anthracycline-based chemotherapy regimens, in patients with breast cancer. A combination of three drugs, 5-hydroxytryptamine (5-HT3) receptor antagonist, aprepitant and dexamethasone, is recommended for antiemetic therapy. Palonosetron (PALO), a novel 5-HT3 receptor antagonist has been identified to be effective against delayed nausea and vomiting. In this study, the results of PALO for patients who received anthracycline-based chemotherapy were compared with that of granisetron (GRA) using a crossover study design. This study evaluated the efficacy of antiemetics in the first cycle of chemotherapy, as well as the second and third cycles. A total of 21 patients and 19 patients were assigned to PALO and GRA treatment groups during the first cycle of chemotherapy, respectively. The patients switched to the other antiemetic drug for the second chemotherapy cycle (PALO followed by GRA or GRA followed by PALO). The patients could select PALO or GRA antiemetics for the third cycle, according to their preference. A total of 21 patients selected PALO and 18 patients selected GRA in the third cycle, and one patient was withdrawn from the study as their third cycle questionnaire was not obtained. No significant differences between PALO and GRA were identified in first and second cycles. However, during the third cycle, a significant difference was observed in acute-phase complete control of emetic events between the PALO and GRA groups, which was defined as no emetic episode, no additional antiemetic treatment and no more than mild nausea, between PALO and GRA. These results demonstrated that changing antiemetics may affect the efficacy of antiemetics. This study indicates that alteration of antiemetic regimens, including drug combination and order, may improve the efficacy of antiemetic treatment.

INTRODUCTION: We report a patient with a rapidly progressing recurrence of hepatocellular carcinoma (HCC) with a portal vein tumor thrombus after radiofrequency ablation of the original lesion, then treated with transcatheter arterial infusion. Radical hepatic resection demonstrated a complete pathological response. PRESENTATION OF CASE: A 60-year old male with alcoholic cirrhosis and gastric varices was diagnosed with HCC measuring 12mm in segment 8. He underwent laparoscopic radiofrequency ablation, but recurred three months later. The lesion progressed rapidly and the right portal vein was occluded. He then underwent transcatheter arterial infusion with miriplatin and iodized oil, which was effective in reducing the size of the main lesion and portal vein tumor thrombus. Right anterior sectionectomy was then performed. Pathologically, there were no viable HCC cells in either the main lesion or the portal vein thrombus. He is alive two years and nine months after surgery without recurrence. DISCUSSION: A rapidly progressing HCC recurrence with portal vein tumor thrombus is usually associated with a poor prognosis. No effective treatments have been reported in this situation except hepatic resection. In this patient the tumor was effectively reduced after three courses of transarterial miriplatin and subsequent radical hepatic resection. This is the first report to achieve a complete pathological response for such an aggressive recurrence after initial radiofrequency ablation. CONCLUSION: This strategy may result in long-term survival of patients with rapidly progressing recurrent HCC with portal vein thrombus, and further study is warranted.

STUDY DESIGN: Case series. PURPOSE: To determine the utility of "PainVision" apparatus for the assessment of low back pain. OVERVIEW OF LITERATURE: A newly developed device, the PainVision PS-2100 (Nipro, Osaka, Japan), has been used to assess the perception of pain in a quantitative manner. In the current study, we aimed to evaluate the efficacy of PainVision for the assessment of low back pain. METHODS: We assessed 89 patients with low back pain. The numeric rating scale (NRS) score, McGill Pain Questionnaire (MPQ) score and the degree of pain calculated by PainVision were measured twice at 4-week intervals in each patient. An electrode was patched on the forearm surface of the patients and the degree of pain was automatically calculated (degree of pain=100×[current producing pain comparable with low back pain-current at perception threshold/current at perception threshold]). Correlations between NRS and MPQ scores and the degree of pain were determined using Spearman's rank correlation test. RESULTS: There was a strong correlation between the NRS and MPQ scores at each time point (rs =0.60, p<0.0001). The degree of pain also showed a moderate correlation with NRS and MPQ scores at each time point (rs =0.40, p<0.03). The change in the degree of pain over 4 weeks showed a moderate correlation with changes in the NRS and MPQ scores (rs =0.40, p<0.01). CONCLUSIONS: PainVision as self-reported questionnaires is a useful tool to assess low back pain.

PURPOSE: Cytomegalovirus (CMV) infection is known to be the most frequently viral infection among patients after liver transplantation. This is especially true in pediatric living-donor liver transplantation because the recipients have often not been infected with CMV and postoperative primary infection with CMV frequently occurs. PATIENTS AND METHODS: Of 93 patients who underwent pediatric liver transplantation at our department, 33 patients (36.3%) were diagnosed with CMV infection using the antigenemia method (C7-HRP). Retrospective review and statistical analysis were conducted to confirm risk factors of post-transplantation CMV infection. RESULT: Positive lymphocytes were diagnosed between postoperative days 8 and 111 after transplantation. Ganciclovir or foscavir were administrated to 21 patients. The other 10 patients who had one positive lymphocyte were observed and the cell disappeared on follow-up examination. We did not observe any cases of positive lymphocytes with C7-HRP in patients who received a graft from a CMV antibody-negative donor. Independent predictors associated with CMV infection in the multivariable analysis were administration of OKT3 and grafts from CMV antibody-positive donors. CONCLUSION: In CMV infection after pediatric liver transplantation, cases with CMV antibody-positive donors and with OKT3 administration for acute rejection are considered high risk, and cases with CMV antibody-negative donors are considered low risk.

The use of donors with coagulation FIX deficiency is controversial, and there are no current protocols for peri-transplant management. We herein describe the first reported case of a pediatric LDLT from an asymptomatic donor with mild coagulation FIX deficiency. A 32-yr-old female was evaluated as a donor for her 12-month-old daughter with biliary atresia. The donor's pretransplant coagulation tests revealed asymptomatic mild coagulation FIX deficiency (FIX activity 60.8%). Freeze-dried human blood coagulation FIX concentrate was administered before the dissection of the liver and 12 h afterwards by bolus infusion (40 U/kg) and was continued on POD 1. The bleeding volume at LDLT was 590 mL. On POD 1, 3, 5, and 13, the coagulation FIX activity of the donor was 121.3%, 130.6%, 114.6%, and 50.2%, respectively. The donor's post-transplant course was uneventful, and the recipient is currently doing well at 18 months after LDLT. The FIX activity of the donor and recipient at nine months after LDLT was 39.2% and 58.0%, respectively. LDLT from donors with mild coagulation FIX deficiency could be performed effectively and safely using peri-transplant short-term coagulation FIX replacement and long-term monitoring of the plasma FIX level in the donor.

We performed an immunohistochemical analysis of the expression of zinc-finger E-box binding homeobox 1 (ZEB1), a master regulator of epithelial-mesenchymal transition (EMT), and determined its relationship with E-cadherin in 157 non-small cell lung carcinomas (93 adenocarcinomas, 36 squamous cell carcinomas, 18 large cell carcinomas, and 10 pleomorphic carcinomas). Although the expression of E-cadherin was low in the subset of adenocarcinomas (10%) and squamous cell carcinomas (11%), ZEB1 expression was only observed in one case of squamous cell carcinoma and none of the adenocarcinomas. In contrast, the low expression of E-cadherin (50% and 90%, respectively) and the positive expression of ZEB1 (11% and 50%, respectively) were more frequently observed in poorly differentiated carcinomas (large cell carcinomas and pleomorphic carcinomas). Overall, the expression of ZEB1 was inversely correlated with that of E-cadherin. Furthermore, the distribution of ZEB1-positive cancer cells was more restricted than in the area in which the expression of E-cadherin was lost, and the former was detected within the latter. We concluded that the expression of ZEB1 was not necessarily associated with the low expression of E-cadherin in lung adenocarcinomas and squamous cell carcinomas. The expression of ZEB1 correlated with an undifferentiated and/or sarcomatoid morphology that may occur in the late stage of EMT.

OBJECTIVES: The effects of glucocorticoid during culture on human islet cells have been controversial. Exendin-4 (EX) enhances the insulin secretion and significantly improves clinical outcomes in islet cell transplantation. In this study, we examined the effects of glucocorticoids and EX on human islet cells during pretransplant culture. METHODS: Methylprednisolone (MP) and/or EX were added to the standard culture medium for clinical islet cell transplantation. Islets were cultured for 24 hours with 3 different conditions (control, no additives; MP alone; and MP + EX). β-Cell fractional viability, cellular composition, multiple cytokine/chemokine production, multiple phosphorylation proteins, and glucose-induced insulin secretion were evaluated. RESULTS: Viable β-cell survival in MP and MP + EX group was significantly higher than in the control group. Exendin-4 prevented MP-induced reduction of insulin secretion. Methylprednisolone supplementation to the culture medium decreased cytokine and chemokine production. Moreover, extracellular signal-regulated kinase 1/2 phosphorylation was significantly increased by MP and MP + EX. CONCLUSIONS: Glucocorticoid supplementation into culture media significantly decreased the cytokine/chemokine production and increased the extracellular signal-regulated kinase 1/2 phosphorylation, resulting in the improvement of human β-cell survival. In addition, EX maintained the insulin secretion suppressed by MP. The supplementation of MP and EX together could be a useful strategy to create suitable human islets for transplantation.

STUDY DESIGN: Experimental animal study. PURPOSE: To evaluate pain-related behavior and changes in nuclear factor-kappa B (NF-kB), receptor activator of NF-kB (RANK), and ligand (RANKL) in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. OVERVIEW OF LITERATURE: The pathological mechanisms underlying pain from lumbar-disc herniation have not been fully elucidated. RANKL are transcriptional regulators of inflammatory cytokines. Our aim was to evaluate pain-related behavior and RANKL expression in DRG after sciatic-nerve compression and application of NP in rats. METHODS: MECHANICAL HYPERALGESIA AND RANKL EXPRESSION WERE ASSESSED IN THREE GROUPS OF RATS: NP+sciatic nerve compression (2 seconds), sham-operated, and controls (n=20 each). Mechanical hyperalgesia was measured every other day for 3 weeks using von Frey filaments. RANKL expression in L5 DRGs was examined at five and ten days after surgery using immunohistochemistry. RESULTS: Mechanical hyperalgesia was observed over the 12-day observation period in the NP+nerve compression group, but not in the control and sham-operated animal groups (p<0.05). RANKL immunoreactivity was seen in the nuclei of L5 DRG neurons, and its expression was significantly upregulated in NP+nerve compression rats compared with control and sham-operated rats (p<0.01). CONCLUSIONS: The exposure of sciatic nerves to mechanical compression and NP produces pain-related behavior and up-regulation of RANKL in DRG neurons. RANKL may play an important role in mediating pain after sciatic nerve injury with exposure to NP.

アルコール摂取(多飲)は急性膵炎、慢性膵炎の成因として最も頻度が高い。他の成因と異なり、アルコール性膵炎は断酒・禁煙で発症・進展の予防が可能で、生活指導が重要な疾患である。その一方で「アルコール性」を規定するエタノール摂取量の明確な基準はなく、その発症・進展の機序についても不明な点が多い。慢性膵炎臨床診断基準2009では慢性膵炎をアルコール性と非アルコール性に分類し、発症前、発症早期に治療介入ができるように慢性膵炎疑診、早期慢性膵炎の診断基準を設定した。急性膵炎でも高リスク群であるアルコール多飲者の実際の発症率は低率で、遺伝子異常(SPINK1、PRSS1など)など、他の要因が深く関与していることが想定されている。アルコール性急性膵炎、慢性膵炎の診断・治療は、他の成因によるものと大きく変わるところはなく、介入治療は改訂アトランタ分類2012による膵炎局所合併症の新分類に応じた適切な時期・手技で行うことが推奨される。(著者抄録)

胆道手術におけるドレーン挿入の功罪を臨床試験の結果から検討した.膿瘍・穿孔などの合併症がない胆嚢摘出術では,開腹・腹腔鏡下ともにドレーンの挿入は創感染,呼吸器感染といった術後の合併症を増やし,それに見合う利点がないとされる.胆道切開や胆管切除・吻合でも同様に,ドレーンの利点が乏しいという結果が得られている.ルーチンワークとして行われがちなドレーンの挿入であるが,evidence-based medicine(EBM)に基づき再考すべきである.(著者抄録)

STUDY DESIGN: Quantitative and immunohistological analysis of the efficacy of an IκB kinase-β (IKKβ) inhibitor in an injured intervertebral disc (IVD) model. OBJECTIVE: To elucidate the efficacy of an IKKβ inhibitor on inflammatory cytokine levels in injured IVDs or on neuropeptide levels in the dorsal root ganglia (DRG) neurons innervating injured IVDs in rats. SUMMARY OF BACKGROUND DATA: Multiple studies have suggested that upregulation of inflammatory cytokines in damaged IVDs causes discogenic low back pain. The efficacy of blocking individual inflammatory cytokines is limited; however, inflammatory cytokine stimuli often require IKKβ to activate nuclear factor-k B. METHODS: Sprague-Dawley rats were divided into 3 groups: sham, saline (disc-injury plus saline), and IKKβ (disc-injury plus anti-IKKβ). To induce injury, IVDs were repeatedly punctured.Experiment 1: Four, 7, and 14 days postinjury, coccygeal (Co) 5/6, Co6/7, and Co7/8 IVDs were resected and tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels were quantified by enzyme-linked immunosorbent assay. Experiment 2: The neurotracer Fluoro-Gold was injected into injured L5-L6 IVDs and uninjured sham group IVDs to detect DRG neurons. One week postsurgery, L1-L6 DRGs were immunolabeled with the neuropeptide calcitonin gene-related peptide. The proportions of Fluoro-Gold-labeled calcitonin gene-related peptide-immunoreactive DRG neurons were assessed. RESULTS: Experiment 1: IVD levels of tumor necrosis factor-α (through 2 wk), IL-1β (at 4 d), and IL-6 (at 4 d) were significantly higher in the saline group than in the sham group, and significantly lower in the IKKβ group than in the saline group (P < 0.05). Experiment 2: The percentage of calcitonin gene-related peptide-immunoreactive Fluoro-Gold-labeled DRG neurons was significantly higher in the saline group than in the sham group, and significantly lower in the IKKβ group than in the saline group (P < 0.05). CONCLUSION: Injury-induced upregulation of inflammatory cytokines within IVDs and increased levels of neuropeptides within DRG neurons can be suppressed by inhibiting IKKβ. LEVEL OF EVIDENCE: N/A.

PURPOSE: To examine the effects of conservative and surgical treatments for nocturnal leg cramps in patients with lumbar spinal stenosis (LSS). Nocturnal leg cramps is frequently observed in patients with peripheral neuropathy. However, there have been few reports on the relationship between nocturnal leg cramps and LSS, and it remains unknown whether conservative or surgical intervention has an impact on leg cramps in patients with LSS. MATERIALS AND METHODS: The subjects were 130 LSS patients with low back and leg pain. Conservative treatment such as exercise, medication, and epidural block was used in 66 patients and surgical treatment such as decompression or decompression and fusion was performed in 64 patients. Pain scores and frequency of nocturnal leg cramps were evaluated based on self-reported questionnaires completed before and 3 months after treatment. RESULTS: The severity of low back and leg pain was higher and the incidence of nocturnal leg cramps was significantly higher before treatment in the surgically treated group compared with the conservatively treated group. Pain scores improved in both groups after the intervention. The incidence of nocturnal leg cramps was significantly improved by surgical treatment (p=0.027), but not by conservative treatment (p=0.122). CONCLUSION: The findings of this prospective study indicate that the prevalence of nocturnal leg cramps is associated with LSS and severity of symptoms. Pain symptoms were improved by conservative or surgical treatment, but only surgery improved nocturnal leg cramps in patients with LSS. Thus, these results indicate that the prevalence of nocturnal leg cramps is associated with spinal nerve compression by LSS.

STUDY DESIGN: Animal study. OBJECTIVE: To investigate pain-related expression of NaV1.7 in dorsal root ganglia (DRG) innervating intervertebral discs. SUMMARY OF BACKGROUND DATA: The pathophysiology of discogenic low back pain is not fully understood. Prostaglandins and cytokines produced by degenerated discs can cause pain, but nonsteroidal anti-inflammatory and steroid medications are often ineffective at pain reduction. Tetrodotoxin-sensitive, voltage-gated sodium (NaV) channels are associated with sensory transmission in primary sensory nerves, and the NaV1.7 channel has emerged as an attractive analgesic target. The purpose of this study was to investigate pain-related expression of NaV1.7 in DRG innervating intervertebral discs. METHODS: Using a rodent model of disc puncture, we labeled DRG neurons innervating L5-L6 discs with FluoroGold neurotracer (n = 20). Half of the rats (n = 10) underwent intervertebral disc puncture using a 23-gauge needle (puncture group), and the other half underwent non-puncture sham surgery (non-puncture group). Seven and 14 days after surgery, DRGs from the L1 to L6 levels were harvested, sectioned, and immunostained for NaV1.7, and the proportion of NaV1.7-immunoreactive DRG neurons was evaluated. RESULTS: NaV1.7 was expressed in DRG neurons innervating intervertebral discs from L1 to L5. The ratio of NaV1.7-expressing DRG neurons to total FG-labeled neurons was 7.2% and 7.6% at 1 and 2 weeks after surgery, respectively, in the non-puncture group and 16.2% and 16.3% at 1 and 2 weeks, respectively, in the puncture group. The upregulation of NaV1.7 after puncture was significant at both 1 and 2 weeks after surgery (P < 0.01). CONCLUSION: We found that disc injury increases NaV1.7 expression in DRG neurons innervating injured discs. NaV1.7 may be a therapeutic target for pain control in patients with lumbar disc degeneration.

Rational treatment for neoplasms of the duodenal papilla (NDPs) is still controversial, especially for early stage lesions. Total papillectomies are indicated in patients expected to have adenomas, adenocarcinoma in an adenoma, or mucosal adenocarcinomas with no lymph node metastases. However, the preoperative pathological evaluation of NDPs is still challenging and often inaccurate, mainly because of the complicated anatomical structures involved and the possibility of an adenocarcinoma in an adenoma. Herein, we introduce a new method of total papillectomy, the extraduodenal papillectomy (ExDP). In this method, papillectomy is undertaken from outside of the duodenum, instead of resection from the inside through a wide incision of the duodenal wall as is done in conventional transduodenal papillectomy (TDP). The advantages of ExDP are precise and deeper cutting of the sphincter and shorter exploration time of the tumor compared to conventional TDP. We demonstrate three representative patients, all of whom had an uneventful postoperative course. One of them subsequently underwent a pylorus preserving pancreatoduodenectomy after detailed postoperative pathological evaluation. Including that patient, no recurrence has occurred with 37-46 months of follow-up. In conclusion, ExDP is regarded as a "total biopsy" for early stage borderline lesions and a feasible, less demanding alternative method for the treatment of NDPs.

PURPOSE: Bupivacaine is commonly used for the treatment of back pain and the diagnosis of its origin. Nonunion is sometimes observed after spinal fusion surgery; however, whether the nonunion causes pain is controversial. In the current study, we aimed to detect painful nonunion by injecting bupivacaine into the disc space of patients with nonunion after anterior lumbar interbody fusion (ALIF) surgery for discogenic low back pain. MATERIALS AND METHODS: From 52 patients with low back pain, we selected 42 who showed disc degeneration at only one level (L4-L5 or L5-S1) on magnetic resonance imaging and were diagnosed by pain provocation on discography and pain relief by discoblock (the injection of bupivacaine). They underwent ALIF surgery. If the patients showed low back pain and nonunion 2 years after surgery, we injected bupivacaine into the nonunion disc space. Patients showing pain relief after injection of bupivacaine underwent additional posterior fixation using pedicle screws. These patients were followed up 2 years after the revision surgery. RESULTS: Of the 42 patient subjects, 7 showed nonunion. Four of them did not show low back pain; whereas 3 showed moderate or severe low back pain. These 3 patients showed pain reduction after injection of bupivacaine into their nonunion disc space and underwent additional posterior fixation. They showed bony union and pain relief 2 years after the revision surgery. CONCLUSION: Injection of bupivacaine into the nonunion disc space after ALIF surgery for discogenic low back pain is useful for diagnosis of the origin of pain.

Although cisplatin (CDDP) is a key drug in the treatment of esophageal squamous cell carcinoma (ESCC), acquired chemoresistance remains a major problem. Combination therapy may represent one strategy to overcome this resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of cancer cells, and its inhibition by small molecules, either alone or in combination, has shown promise in the treatment of solid malignancies. In the present study, we evaluated the synergistic effects of combining CDDP with the HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) on two CDDP-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150. The results obtained demonstrated the synergistic inhibitory effects of CDDP and 17-AAG on the growth of KYSE30 and KYSE150 cells. Cell growth and cell number were more effectively reduced by the combined treatment with CDDP and 17-AAG than by the treatment with either CDDP or 17-AAG alone. Western blotting revealed that the combined action of CDDP and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3, which demonstrated that the reduction in both cell growth and cell number was mediated by apoptosis. Time-course experiments showed that reduction in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis. The results of the present study demonstrate that 17-AAG synergizes with CDDP and induces apoptosis in CDDP-resistant ESCC cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect. Combination therapy with CDDP and an HSP90 inhibitor may represent a promising strategy to overcome CDDP resistance in ESCC.

PURPOSE: This retrospective study evaluates the clinical course and outcomes of patients who underwent surgery for strangulated hernias. METHODS: Among 520 groin hernias from 2001 to 2012, 51 inguinal and 42 femoral hernias were strangulated and operated emergently at a tertiary referral center. Perioperative factors, patient profiles, and time interval to surgery (T total = time from onset to surgery, T 1 = time from onset to initial evaluation, T 2 = time from the first hospital to the tertiary center, T 3 = time from admission at the tertiary center to surgery, T total = T 1 + T 2 + T 3) were analyzed in patients with strangulation, then compared between two groups, the bowel resection (BR) group and the non-bowel resection (NBR) group. RESULTS: T 1, T 2 and T total in the bowel resection group were significantly longer than those in the non-bowel resection group (P < 0.05). Patients who presented initially to the tertiary center (T 2 = 0) had a significantly lower resection rate than patients transported from other hospitals (24 vs. 44 %, P = 0.048). There was no significant difference in morbidity between the BR and NBR groups (35 vs. 24 %, P = 0.231). CONCLUSIONS: The elapsed time from onset to surgery, especially T 1 and T 2, is the most important prognostic factor in patients with strangulated groin hernias. Early diagnosis and transportation are essential for good outcomes.