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Background This study aimed to assess the safety and efficacy of carbon-ion radiotherapy (CIRT) for salvage of previously X-ray-irradiated (XRT) locally recurrent rectal cancer (LRRC). Methods Between September 2005 and December 2017, 77 patients with LRRC were treated with CIRT re-irradiation. All the patients had received prior XRT with a median dose of 50.0 Gy (range 20–74 Gy), principally for neoadjuvant or adjuvant recurrence prophylaxis in 34 patients and for recurrence in 43 patients. The total CIRT dose of 70.4 Gy (RBE) (gray relative biologic effectiveness) was administered in 16 fixed fractions during 4 weeks (4.4 Gy [RBE] per fraction). Results All the patients completed the scheduled treatment course. None of the patients received resection after CIRT. Acute grade 3 toxicities occurred for eight patients (10 %), including five grade 3 pelvic infections (2 involving pain and 1 involving neuropathy). Late grade 3 toxicities occurred for 16 patients (21 %): 13 with late grade 3 pelvic infections, 9 with gastrointestinal toxicity, 1 with skin toxicity, 2 with pain, and 4 with neuropathy. No grade 4+ toxicity was noted. The overall local control rates (infield + out-of-field recurrence) were 69 % at 3 years and 62 % at 5 years. In the planning target volume (PTV), the infield recurrence rates were 90 % and 87 % respectively. The control rates for regional recurrence were 85 % at 3 years and 81 % at 5 years. The median overall survival time was 47 months. The survival rates were 61 % at 3 years and 38 % at 5 years. Conclusion Carbon-ion re-irradiation of previously X-ray-irradiated locally recurrent rectal cancer appears to be safe and effective, providing good local control and survival advantage without unacceptable morbidity.

There are no clinical reports of long‐term follow‐up after carbon‐ion radiotherapy (CIRT) using a dose of 51.6 Gy (relative biological effectiveness [RBE]) in 12 fractions for localized prostate cancer, or of a comparison of clinical outcomes between passive and scanning beam irradiation. A total of 256 patients with localized prostate cancer who received CIRT at a dose of 51.6 Gy (RBE) in 12 fractions using two different beam delivery techniques (passive [n = 45] and scanning [n = 211]), and who were followed for more than 1 year, were analyzed. The biochemical relapse‐free (bRF) rate was defined by the Phoenix definition, and the actuarial toxicity rates were evaluated using the Kaplan‐Meier method. Of the 256 patients, 41 (16.0%), 111 (43.4%), and 104 (40.6%) were classified as low, intermediate, and high risk, respectively, after a median follow‐up of 7.0 (range 1.1‐10.4) years. Androgen deprivation therapy was performed in 212 patients (82.8%). The 5‐year bRF rates of the low‐, intermediate‐, and high‐risk patients were 95.1%, 90.9%, and 91.1%, respectively. The 5‐year rates of grade 2 late gastrointestinal and genitourinary toxicities in all patients were 0.4% and 6.3%, respectively. No grade ≥3 toxicities were observed. There were no significant differences in the rates of bRF or grade 2 toxicities in patients who received passive irradiation versus scanning irradiation. Our long‐term follow‐up results showed that a CIRT regimen of 51.6 Gy (RBE) in 12 fractions for localized prostate cancer yielded a good therapeutic outcome and low toxicity rates irrespective of the beam delivery technique., A 51.6 Gy (relative biological effectiveness) carbon‐ion radiotherapy regimen in 12 fractions for localized prostate cancer with long‐term follow‐up yielded a good therapeutic outcome and low toxicity rates in both passive and scanning beam irradiation without significant difference.

Highlights • Carbon-ion re-irradiation for pancreatic cancer; feasibility and efficacy. • Adjuvant chemotherapy improve local control of re-irradiation using carbon ions. • Carbon-ion radiotherapy for recurrent pancreatic cancer; reasonable option., Background and purpose Patients who receive carbon-ion radiotherapy (C-ion RT) for primary pancreatic cancer may experience locoregional recurrence; however, the treatment options for such patients are limited. We aimed to investigate the feasibility and efficacy of carbon-ion re-irradiation for patients with pancreatic cancer who experienced recurrence after initial C-ion RT. Materials and methods Twenty-one patients with recurrent pancreatic cancer who underwent repeat C-ion RT between December 2010 and November 2016 at our institute were retrospectively evaluated. The sites of post-initial C-ion RT failure were in-field central in 16 patients (76.2%) and marginal in 5 (23.8%). The median doses of initial and repeat C-ion RT were both 52.8 Gy (relative biological effectiveness [RBE]). Thirteen patients (61.9%) received concurrent chemotherapy with re-irradiation, while 11 (52.4%) received adjuvant chemotherapy. Results The median follow-up period after re-irradiation was 11 months. The 1-year local control, progression-free survival, and overall survival rates were 53.5%, 24.5%, and 48.7%, respectively. Toxicity data was obtained from the patients’ charts. Only 1 patient (4.8%) developed grade 3 acute toxicities and none developed grade ≥3 late toxicities. Univariate analysis indicated that patients who received adjuvant chemotherapy had significantly improved local control rates compared with those who did not; the 1-year local control rates were 80.0% and 0.0%, respectively (P = 0.0469). Conclusion Repeating C-ion RT may be a reasonable option with tolerable toxicity for patients with recurrent pancreatic cancers. Adjuvant chemotherapy appears to improve the local control rate. This is the first study to examine re-irradiation using C-ion for recurrent pancreatic cancer after initial C-ion RT.

Purpose Carbon ion beams have several physical and biological advantages compared with conventional radiation for cancer therapy. The objective of this study is to evaluate the safety and effectiveness of 2-fraction carbon ion radiation therapy (CIRT) in patients with hepatocellular carcinoma (HCC). Methods and Materials Between December 2008 and March 2013, 57 patients with localized HCC were treated with CIRT at a total dose of 45 Gy (relative biological effectiveness) in 2 fractions and retrospectively analyzed after long-term observation. The main endpoints of this study were treatment-related toxicity and local tumor control. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Changes in the Child-Pugh score from before to after CIRT were also examined to evaluate hepatic toxicity. Local control was defined as no progression of the irradiated lesion according to the modified Response Evaluation Criteria in Solid Tumors. Results The median age of the patients was 75 years (range, 49-89 years). Of these patients, 41 had a newly diagnosed lesion, and 16 had residual or recurrent lesions after previous treatments. The median follow-up duration was 54 months (range, 7-103 months). All surviving patients were followed for more than 51 months. Two patients experienced grade 3 acute skin reactions, but no other grade 3 or higher toxicities were observed in any organ. No patient exhibited an increase in the Child-Pugh score of 2 or more points after CIRT. The local tumor control rates at 1, 3, and 5 years were 98%, 91%, and 91% after CIRT, respectively. All lesions that failed to respond to previous treatments were successfully controlled by CIRT. The 1-, 3-, and 5-year overall survival rates were 97%, 67%, and 45%, respectively. Conclusions Two-fraction CIRT was a well-tolerated and effective treatment for patients with HCC.

Highlights • High LET and high RBE of carbon ion made it a promising tool for treating pancreatic cancers. • Dose averaged LET minimum within the GTV is significantly associated with local control. • Outcome of CIRT in pancreatic cancers can be improved by modulating dose averaged LET within the GTV., Background and purpose High linear energy transfer (LET) radiation carbon-ion radiotherapy (C-ion RT) is one of the most promising modalities for treating unresectable primary pancreatic cancers. However, how LET contributes to a therapeutic effect is not clear. To assess whether there is an enhanced effect of high LET radiation on tumour control, we aimed to determine the impact of dose-averaged LET on local control (LC) of primary pancreatic tumours. Materials and methods A retrospective analysis of 18 patients with primary pancreatic carcinomas treated with definitive C-ion RT with concurrent chemotherapy in 2013 was conducted. The dose of irradiation was 55.2 Gy (RBE). The relationship between dose-averaged LET and LC of primary tumours was evaluated. Results All patients had histologically confirmed adenocarcinoma. The median follow-up duration was 22 months. The actuarial LC and overall survival (OS) at 18 months were 62.5% and 70.1%, respectively. There were no cases of grade ≥3 late toxicities observed. Local recurrences developed in four patients (22%), all of which were infield central recurrences. Although there were no significant differences in gross tumour volume (GTV) dose coverage, patients with higher minimum dose-averaged LET (LETmin) values within the GTV had better LC (dose-averaged LETmin ≥44 keV/microm; 18-months LC 100.0% vs 34.3%; p = 0.0366). Conclusion Dose-averaged LETmin within the GTV was significantly associated with LC of primary pancreatic cancers. Our data suggest that outcomes for patients with unresectable primary pancreatic cancers receiving C-ion RT can be improved by modulating the dose-averaged LET within the GTV.

There are no studies on the risk factors of radiation pneumonitis (RP) after carbon-ion radiotherapy at a dose of 50 Gy (relative biological effectiveness (RBE)) in a single fraction. The objective of this study was to identify factors associated with RP after radiotherapy, including dose–volume parameters. Ninety-eight patients without a history of thoracic radiotherapy who underwent treatment for solitary lung tumors between July 2013 and April 2016 were retrospectively analyzed. Treatment was planned using Xio-N. The median follow-up duration was 53 months, and the median clinical target volume was 32.3 mL. Three patients developed grade 2 RP, and one patient developed grade 3 interstitial pneumonitis. None of the patients developed grade 4 or 5 RP. The dose-volume parameters of the normal lung irradiated at least with 5–30 Gy (RBE), and the mean lung dose was significantly lower in patients with grade 0–1 RP than in those with grade 2–3 RP. Pretreatment with higher SP-D and interstitial pneumonitis were significant factors for the occurrence of symptomatic RP. The present study showed a certain standard for single-fraction carbon-ion radiotherapy that does not increase the risk of RP, however, further validation studies are needed.

Purpose We investigated the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for locally recurrent rectal cancer (LRRC). Patients and methods Data from patients with LRRC treated with C-ion RT from November 2003 to December 2014 at three institutions were retrospectively analyzed. The endpoints of this clinical trial were overall survival (OS), local control (LC), and acute/late toxicity. Results A total of 224 patients' data were collected. The prescribed dose was 70.4 Gy (relative biological effectiveness [RBE]-weighted absorbed dose) or 73.6 Gy (RBE) in 16 fractions. The median follow-up period from the initiation of C-ion RT was 62 months (range 6–169 months). The OS rates were 73% (95% confidence interval [CI], 67%–79%) at 3 years and 51% (95%CI 44%–58%) at 5 years. The LC rates were 93% (95%CI 88%–96%) at 3 years, and 88% (95%CI 82%–93%) at 5 years. Grade 3 acute toxicity was observed in three patients: gastrointestinal toxicity (n = 1) and pelvic infection (n = 2). Grade 3 late toxicity was observed in 12 patients: skin reaction (n = 2), gastrointestinal toxicity (n = 2), neuropathy (n = 1), and pelvic infection (n = 7). There was no grade 4 or 5 acute or late toxicity. Conclusions This first multi-institutional analysis of C-ion RT for LRRC indicated relatively favorable outcomes with limited toxicities.

Purpose/Objective(s) 70% of patients able to receive surgical resection for pancreatic adenocarcinoma may ultimately experience recurrence; 25-35% have disease in the remnant pancreas or tumor bed. Surgical re-resection carries notable risks for morbidity, while success with photon irradiation has been limited. Carbon-ion radiotherapy (CIRT) has demonstrated unique promise in the treatment of locally advanced pancreatic cancer (LAPC). An initial cohort from 2011-2015 was published in 2017; here, we provide an update on CIRT safety and efficacy for post-surgical salvage of locally recurrent pancreatic cancer, with 60 cases from 2007 to 2020. Materials/Methods Patients with locoregional recurrence following resection of pancreatic cancer were eligible. CIRT was conducted using 48.0 to 55.2 Gy (RBE) in 12 fractions, delivered over 3 weeks. Inclusion criteria included: 1) unresectable disease due to tumor invasion or patient refusal of re-resection; 2) absence of distant metastasis, 3) ECOG performance of 0 to 2. Patients with disease invading the GI tract, previous radiotherapy, or metallic stent placement were excluded. Results A total of 60 patients treated between January 2007 and 2020 were retrospectively reviewed. Median age was 65, with pancreatic head primary in 34 cases and body/tail in 26 cases. 34 cases underwent pancreaticoduodenectomy, with 26 distal pancreatectomies. 14 cases recurred in the residual pancreas, while 46 cases recurred in surrounding tissue. 16 cases received 48 – 52.8 Gy (RBE) via dose escalation, with 44 cases receiving 55.2 Gy (RBE). Grade 3 hematologic toxicity was seen in 3 cases, with no other G3+ acute or late toxicity was noted. 2-year local control was achieved in 56% for 48-52.8 Gy (RBE) and 61% for 55.2 Gy (RBE) cohorts. 2-year survival was 48% in the high dose cohort, with median survival time (MST) of 23 months. Conclusion CIRT for postoperative recurrence of pancreatic cancer compared favorably to conventional chemoradiation salvage (2-year survival 38%, 16-month MST), with acceptable toxicity. CIRT may be a viable treatment alternative when re-resection is difficult.

Long-term outcomes after surgical resection of bile duct cancer remain unsatisfactory, and survival, particularly after tumor recurrence, is poor. Gemcitabine and cisplatin combination (GC) therapy is the standard first-line treatment; however, second-line approaches are yet to be established. Radiotherapy may prolong the survival of patients with advanced biliary tract cancer, and particle radiotherapy delivers a more concentrated dose than conventional radiotherapy to deeper tumors. The present report describes the long-term survival of a 65-year-old man with distal bile duct cancer of pathological stage IIA (T2N0M0; depth of invasion, 5.5 mm) following multimodal treatment. Following subtotal stomach-preserving pancreatoduodenectomy, multiple hepatic recurrences were identified 9 months later, and GC therapy was initiated. The tumors were no longer evident 18 months later, and GC therapy was discontinued at the patient's request. A computed tomography (CT) scan performed 30 months after surgery identified a new solitary hepatic recurrence and duke pancreatic monoclonal antigen type-2 (DUPAN-2) levels were increased. Further GC therapy was declined. Carbon ion radiotherapy (CIRT) at a dose of 60 Gy [relative biological effectiveness (RBE)-weighted absorbed dose] was then delivered in four fractions over 4 days [15 Gy (RBE)/day]. Tumor size decreased on CT, and fluorodeoxyglucose-positron emission tomography/CT revealed a decline in the standardized uptake value of the tumor after 2 months, with decreased DUPAN-2 levels. Following regrowth of the hepatic recurrence, CIRT was repeated at a dose of 66 Gy (RBE) in four fractions over 4 days [16.5 Gy (RBE)/day] and stable disease was maintained for 19 months. After 19 months, CT revealed tumor regrowth and another new metastatic lesion was identified in the left kidney. The patient received systematic chemotherapy again and died of the disease 81 months after the initial surgery. In conclusion, CIRT is a potential treatment option to control solitary recurrence of biliary tract cancer.

Carbon ion beams constitute the primary delivery method of heavy ion radiotherapy. It offers improved dose distribution, and enables concentration of dose within target volumes with minimal extraneous exposure of normal tissue, while delivering superior biological effect in comparison with photon and proton technologies. Here, we review the application of this technology to various gastrointestinal cancers.

Aim Evaluation of the therapeutic efficacy of carbon-ion radiation therapy for isolated lymph node recurrence following curative resection of esophageal cancer. Materials and methods Ten cases with lymph node recurrence after esophageal cancer surgery were treated with carbon-ion radiation therapy. A total of 48.0 Gy [relative biologic effectiveness (RBE)] was delivered over 3 weeks with a daily dose of 4.0 Gy (RBE). Results The median follow-up duration was 27.1 months (range=3-92.0 months) after carbon-ion radiation therapy. The local control rates at 2, 3 and 5 years were 92.4%. The overall survival rates at 2, 3 and 5 years were 70.0%, 58.3% and 21.9%. The median survival period was 45.3 months after carbon-ion radiation therapy. There were no toxicities of grade 3 or higher. Conclusion Carbon-ion radiation therapy may be a safe and effective treatment option for isolated lymph node recurrence after radical surgery for esophageal cancer.

The efficacy and safety of carbon ion radiotherapy (C-ion RT) for locoregional recurrence after surgery for pancreatic cancer were retrospectively evaluated. The results for 30 patients showed that C-ion RT was performed safely with relatively long overall survival, good local control, and minimal toxicity.

Purpose The aim of this multi-institutional study was to evaluate the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for locally advanced pancreatic cancer (LAPC). Methods and Materials Patients with LAPC treated with C-ion RT from April 2012 to December 2014 at 3 institutions were retrospectively analyzed. Patients with pathologically-confirmed invasive ductal adenocarcinoma of the pancreas were eligible. The prescribed dose was 52.8 Gy (relative biological effectiveness weighted absorbed dose; RBE) or 55.2 Gy (RBE) in 12 fractions. Overall survival (OS), distant metastasis-free survival (DMFS), local recurrence (LR), and toxicity were evaluated. Results In total, 72 patients were included in this study. Tumors in the head of the pancreas were seen in 30 patients (42%), while those in the body or tail of the pancreas were seen in 42 patients (58%). Fifty-six patients (78%) received concurrent chemotherapy. The OS rates were 73% (95% confidence interval [CI], 62%-84%) at 1 year, and 46% (95% CI, 31%-61%) at 2 years with a median OS of 21.5 months (95% CI, 11.8-31.2 months). The 1- and 2-year DMFS rates were 41% (95% CI, 29%-52%) and 28% (95% CI, 16%-40%), respectively. The 1- and 2-year cumulative incidences of LR were 16% (95% CI, 9%-26%) and 24% (95% CI, 14%-36%), respectively. Nineteen patients (26%) experienced acute grade 3 or 4 hematological toxicities. Two patients (3%) had grade 3 anorexia. Late gastrointestinal (GI) grade 3 toxicity was observed in 1 patient (1%). No patients developed late grade 4 or 5 toxicity. Conclusions The first multi-institutional analysis of C-ion RT for LAPC indicated relatively favorable outcomes with limited toxicities, especially for tumors not in close proximity to GI tract.

Background: The purpose of the present study was to evaluate the efficacy and safety of single-fraction carbon-ion radiotherapy (CIRT) in patients with non-small cell lung cancer. Methods: Patients with histologically confirmed non-small cell lung cancer, stage T1-2N0M0, and treated with single-fraction CIRT (50Gy (relative biological effectiveness)) between June 2011 and April 2016 were identified in our database and retrospectively analyzed. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Results: The study included 57 patients, 22 (38.6%) of whom had inoperable cancer. The median age was 75 years (range: 42&ndash, 94 years), and the median follow-up time was 61 months (range: 6&ndash, 97 months). The 3- and 5-year overall survival rates were 91.2% and 81.7%, respectively. All survivors were followed up for more than three years. The 3- and 5-year local control rates were 96.4% and 91.8%, respectively. No case of &ge, grade 2 pneumonitis was recorded. Conclusions: This study suggests that single-fraction CIRT for T1-2N0M0 non-small cell lung cancer patients is feasible and can be considered as one of the treatment choices, especially in medically inoperable patients.

The expression of genes can be influenced by the balance of histone acetylation and/or histone demethylation, with an imbalance of these processes possibly observed in many cancers. The histone demethylase LSD1 inhibitor activity is associated with selective transcriptional regulation and alterations in the gene expression. However, the exact mechanisms underlying the antitumor effects of LSD1 inhibitors are not fully understood. The antitumor effects of NCL1, an LSD1 inhibitor, in esophageal squamous cell cancer (ESCC) cell lines were evaluated. A comprehensive analysis of the changes in the gene expression in ESCC cell lines induced by NCL1 was carried out using a microarray analysis. A loss-of-function assay using a siRNA analysis was performed to examine the oncogenic function of the gene. NCL1 strongly inhibited the cell growth of T.Tn and TE2 ESCC cells and induced apoptosis. According to the microarray analysis, 81 genes in the T.Tn cells and 149 genes in the TE2 cells were up- or down-regulated 2-fold or more by NCL1 exposure. Among these genes, 27 were contained in both cell lines and exhibited similar expression patterns. PHLDB2, one of the genes down-regulated by NCL1, was overexpressed in the ESCC tumor tissues. Moreover, a high expression level of PHLDB2 was found to be significantly correlated with poor prognosis. The present observations of the comprehensive analysis of the gene expression levels provide insight into the mechanisms underlying the antitumor effects of LSD1 inhibitors in ESCC patients.

Short gastric vessel division (SGVD) has been performed as a part of fundoplication for achalasia. However, whether or not SGVD is necessary is still unknown. Forty-six patients with achalasia who underwent a laparoscopic surgery with or without SGVD were analyzed. A questionnaire was administered to assess the postoperative improvement. Regarding improvement of dysphagia and postoperative reflux, there were no significant differences between SGVD (+) group and SGVD (−) group (P = 0.588 and P = 0.686, respectively). Nineteen patients (95%) in the SGVD (+) group and 24 (92%) in the SGVD (−) group answered that the surgery was satisfactory (P = 0.756). In the SGVD (+) group, the pre- and postsurgical body weight increase was +7.3%. In the SGVD (−) group, it was 8.2%. There was no significant difference of body weight increase between the 2 groups (P = 0.354). SGVD is not always required in laparoscopic surgery for achalasia.

Gastrointestinal stromal tumors (GISTs) rarely arise in the esophagus, where carcinoma is the most common malignant neoplasm and leiomyoma is the most common benign tumor. Because of their rarity, the clinical course and treatment of esophageal GISTs are poorly understood. These lesions are generally thought to carry a poor prognosis, making the differential diagnosis of other common mesenchymal neoplasms essential, for both prognostic and therapeutic reasons. We report a case of successfully resected giant esophageal GIST, thought to be the largest resected GIST reported in Japan. The patient was a 65-year-old woman, in whom upper gastrointestinal endoscopy found a 180-mm submucosal tumor in the lower thoracic esophagus, extending just below the aortic arch. We diagnosed esophageal GIST, and the patient underwent middle and lower esophagectomy via left thoracotomy, followed by gastric tube reconstruction. The tumor was resected completely. Histopathological and immunohistochemical staining confirmed that the tumor was a high-risk lesion, and treatment with imatinib was initiated. Computed tomography showed liver metastasis 5 months later, but the patient is doing well 24 months after surgery.

Objective: The aim of this study was to identify alternative compounds to the tumor suppressor miR-375 using the connectivity map (CMAP) and to validate the antitumor effects of the identified drugs in esophageal squamous cell carcinoma (ESCC). Methods: Gene profiling of miR-375-treated TE2 and T.Tn cells was applied in order to search the CMAP database. Among the compounds identified using the CMAP, we focused on 8 drugs [(-)-epigallocatechin-3-gallate, metformin, rosiglitazone among others], excluding 2 drugs among the top 10 compounds. We evaluated whether these compounds possess tumor-suppressive functions in ESCC. Results: A cytotoxicity assay showed that the sensitivity of TE2 and T.Tn cells treated with the 8 compounds was evaluated based on IC50 values of 42.9 µM to 3.8 mM. A cell cycle analysis revealed that the percentage of TE2 and T.Tn cells incubated with 6 compounds in the G0/G1 phase or the G2/M phase increased by approximately 40-80%. A TUNEL assay showed that the percentages of apoptotic cells treated with almost all compounds were significantly increased (p < 0.05) compared with the control cells. Conclusion: The CMAP database is a useful tool for identifying compounds affecting the same molecular pathways, particularly products that are difficult to apply via practical approaches, such as microRNAs.

Purpose To evaluate the efficiency of automated function imaging (AFI) on transthoracic echocardiogram (TTE) for detecting left ventricular (LV) wall motion (LVWM) abnormalities, we compared longitudinal peak systolic strain (LPSS) measurements using AFI with naked eye TTE evaluations by experienced cardiologists and non-experienced residents. Materials and methods A total of 352 segments of LV myocardium from 22 consecutive subjects with LVWM abnormalities based on American Heart Association classifications (11 male, mean age 58±14years) on previous TTE (Vivid-7, GE) were evaluated. LPSS was measured using stored AFI data. Naked eye evaluation of LVWM was performed by 2 experienced cardiologists and 2 non-experienced residents. Results AFI successfully tracked 342 (97%) of all segments (mean LPSS −14.8±8.1%). A significant strong negative correlation was observed between LV ejection fraction using method of disks and global LPSS (R=−0.8974). Temporary AFI criteria of LPSS were normal 2. Of 342 segments, 239, 87, and 16 segments were diagnosed as normal, hypokinesis, and akinesis, respectively. Level of agreement and kappa coefficients between qualitative evaluation of LVWM by AFI temporary criteria and qualitative evaluation of LVWM by experienced cardiologist 2 (0.784 and 0.479, respectively) were inferior to those comparing experienced cardiologists (0.845 and 0.595) but superior comparing experienced cardiologist with non-experienced resident (0.696 and 0.323), and between the 2 non-experienced-residents (0.682 and 0.347). Conclusion Qualitative evaluation of LVWM using temporary AFI criteria had a 97% success rate and agreed well with findings of an experienced cardiologist. AFI can be a useful tool for training residents.

An epiphrenic diverticulum is a pulsion pseudodiverticulum of the distal esophagus that is frequently associated with esophageal motility disorders. Therefore, a simple diverticulectomy leads to a poor outcome. High-resolution impedance manometry (HRIM), introduced recently, enables easier evaluation of both esophageal pressure and bolus transit dynamics. We report the case of a 40-year-old female diagnosed with an epiphrenic diverticulum with hypertensive lower esophageal sphincter pressure by use of HRIM. She underwent a laparoscopic transhiatal diverticulectomy with a long myotomy and Dor’s fundoplication and was discharged with no complications. Four weeks after the operation, HRIM was performed again, and showed no accumulation of water in the esophagus and improvement of bolus transit. We herein report the usefulness of HRIM for evaluation of esophageal motility disorders for patients with an epiphrenic diverticulum.

The purpose of this research is to determine the correlation between IGFBP-4/IGF-I expression and the clinical status of esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining for IGFBP-4 and IGF-I was performed in 61 clinical samples. The correlation between IGFBP-4/IGF-I staining and clinicopathological features was examined statistically. In addition, we compared the mRNA expression levels of IGFBP-4 and IGF-I between ESCC cancer tissues and the normal esophageal epithelium using a quantitative real-time RT-PCR. According to the results of immunohistochemical staining, IGFBP-4 expression in the region of normal epithelial cells showed an increase of 52.5 % compared to expression in the tumor cells. There was no statistically significant correlation between IGFBP-4/IGF-I and clinicopathological features. The correlation between IGF-I and IGFBP-4 was not significant either. RT-PCR assay showed IGF-I expression in ESCC tissue has a tendency to be higher than that of normal esophageal epithelium. On the other hand, IGFBP-4 expression levels in cancer tissue were lower in comparison with normal epithelium. These results were not significant. There were the differences of IGFBP-4 expression between the region of ESCC and the region of normal epithelium cells. One suggested possibility is that IGF-independent action of IGFBP-4 might have taken part in these results. We need further exploratory experiments to elucidate the details of the actual function of IGFBP-4 expression in ESCC.

Background The safety and effectiveness of carbon-ion radiotherapy (CIRT) for isolated para-aortic lymph node (PALN) metastasis was evaluated retrospectively. Methods CIRT for isolated PALN metastasis from CRC was performed in 34 cases from June 2006 to August 2015 in our institute. A median dose of 52.8 Gy(RBE) (range, 48-52.8 Gy(RBE)) was delivered with a median daily dose of 4.4 Gy(RBE) (range, 4.0-4.4 Gy(RBE)). Results The median follow-up duration for all patients was 24.4 months (range, 7-82.8 months). There were 13 cases (38.2%) who achieved complete response after treatment. The local control rates at 2 and 3 years were 70.1% and 70.1%, respectively. The overall survival rates at 2 and 3 years were 83.3% and 63.0%, respectively. The 3-year survival rates for Stage I-III were 68.7%, while those for Stage IV was 0%. The overall survival of cases with rectal cancer or with high CA19-9 values pre-CIRT tended to be worse. The median survival period was 41.7 months. Twelve of the 34 patients survived for more than 3 years. There were no adverse effects of Grade 3 or higher. Conclusions CIRT for isolated PALN recurrence after curative resection for CRC appears effective and safe, and it is considered a promising therapy.

Adenocarcinoma arising from heterotopic gastric mucosa (HGM) is exceedingly rare. This report presents the case of a 57-year-old male who presented with the chief complaint of dysphagia. Endoscopy and computed tomography revealed a locally advanced tumor of the cervical esophagus and swollen mediastinal lymph nodes. He underwent chemoradiotherapy followed by esophagectomy with three-field lymph node dissection. The resected tumor was a circumferentially scarred lesion located 1.5 cm from the proximal margin. The tumor was identified to be a well-differentiated adenocarcinoma arising from HGM with invasion to the muscularis propria. Postoperative chemoradiotherapy was performed because positive surgical margins were observed in the resected tissue. The patient has remained alive for more than 4 years after surgery, without any evidence of recurrence.

症例は29歳，女性．2009年1月から軽度の右下腹部痛を自覚していたが，増強したため同年7月当院内科を受診した．腹部超音波検査，造影CT検査上，上行結腸内に血管ごと嵌入する回盲部に連続する腫瘤影を認め，大腸癌等の大腸腫瘍に伴う腸重積と考えられた．大腸内視鏡検査および注腸検査では，回盲部から上行結腸にかけて内腔を占める1型腫瘍を認め，同腫瘍が先進部となって順行性に重積しているのを確認し，生検結果では高分化型腺癌と診断された．以上より，大腸癌による腸重積と診断し，準緊急的に結腸右半切除術D3郭清を施行した．腫瘍は盲腸に存在し，最終診断はpSE，pN2，H0，P0，M0，CY0，fStageIIIBであった．術後補助化学療法を施行し，現在術後1年で無再発生存中である．腸重積にて発見された若年性大腸癌は極めて稀であり，若干の考察を加え，報告する．

症例は45歳の男性で，繰り返す下血を主訴に精査加療目的にて来院した．下部消化管内視鏡施行時に小腸からの出血を疑われ，小腸全体の精査および加療目的で2008年6月内科を紹介受診した．カプセル内視鏡および経肛門的ダブルバルーン小腸内視鏡でBauhin弁より1.5m程口側に陥凹面を形成する粘膜下腫瘍様病変を認めた．生検で腺癌が認められたため，原発性小腸癌の術前診断で回腸部分切除術を施行した．切除標本の肉眼所見で表面に陥凹を有する1.2×0.8cmの黄色の隆起性病変を認め，病理組織学的検査所見で回腸カルチノイドと診断された．本邦では回腸カルチノイドはまれであり，若干の文献的検討を加え，報告する．

膿尿を尿路感染症診断の手がかりとされることが多い。しかし，筆者らは最近，膿尿を認めない症例を経験した。 そこで膿尿を認めない尿路感染症の臨床的特徴を明らかにする目的で検討を行った。 対象は最近5年間に入院した上部尿路感染症の129例 (男:女=88:41，年齢中央値4.12ヵ月)。膿尿の有無で2群に分け，年齢，性別，発熱から検尿までの時間，最高体温，最高白血球数，最高CRP，および膀胱尿管逆流現象の有無について比較検討した。 その結果，膿尿を認めない18例 (14%) と膿尿を認めた111例 (86%) の二群間で，上記項目について統計学的有意差は認められなかった (p>0.05)。ただし，起炎菌に関しては膿尿を認めた例でE. coliが，認めない例でEnterococcusが有意に多かった。 以上より，膿尿を診断の手がかりとすると，膿尿を呈さない1割強の尿路感染症および基礎疾患としての膀胱尿管逆流現象を見逃す可能性があるため，細菌尿の確認を必ず行うべきであると思われた。

Purpose Investigation of the treatment potential of carbon-ion radiation therapy in pelvic recurrence of rectal cancer. Methods and Materials A phase 1/2 dose escalation study was performed. One hundred eighty patients (186 lesions) with locally recurrent rectal cancer were treated with carbon-ion radiation therapy (CIRT) (phase 1/2: 37 and 143 patients, respectively). The relapse locations were 71 in the presacral region, 82 in the pelvic sidewalls, 28 in the perineum, and 5 near the colorectal anastomosis. A 16-fraction in 4 weeks dose regimen was used, with total dose ranging from 67.2 to 73.6 Gy(RBE); RBE-weighted absorbed dose: 4.2 to 4.6 Gy(RBE)/fraction. Results During phase 1, the highest total dose, 73.6 Gy(RBE), resulted in no grade >3 acute reactions in the 13 patients treated at that dose. Dose escalation was halted at this level, and this dose was used for phase 2, with no other grade >3 acute reactions observed. At 5 years, the local control and survival rates at 73.6 Gy(RBE) were 88% (95% confidence interval [CI], 80%-93%) and 59% (95% CI, 50%-68%), respectively. Conclusion Carbon-ion radiation therapy may be a safe and effective treatment option for locally recurrent rectal cancer and may serve as an alternative to surgery.

UNLABELLED We followed up a girl with primary aldosteronism for 8 y, which was diagnosed at 6 y of age when she was referred to us for evaluation of heart murmur and growth failure. The diagnosis of bilateral adrenal hyperplasia was made by selective adrenal venous sampling. Following potassium supplement, her retarded growth was corrected dramatically, and she attained a normal adult height. Puberty developed normally and menarche occurred at 12 y of age. Blood pressure was also controlled adequately. Myocardial hypertrophy associated with aortic damage was noted at 13 y of age. Chronic renal failure developed with proteinuria and enlarged renal cysts. CONCLUSION Serum electrolytes should be included in the evaluation of children with impaired growth. Although primary aldosteronism is a rare occurrence in children, the condition appears to deserve special attention not only from the viewpoint of growth failure and hypokalaemia but from the occurrence of late organ damage to the kidney and heart.

Multicystic dysplastic kidney (MCDK) is one of the most common congenital abnormalities of the kidney and urinary tract (CAKUT), although its pathophysiology remains unknown. Familial occurrence of MCDK suggests that mutations in genes associated with nephrogenesis are involved in the pathogenesis in at least some cases. Hepatocyte nuclear factor 1β (HNF1β) is a member of the homeodomain-containing super family of transcription factors, and is known to regulate tissue-specific gene expression in a number of organs including the kidneys, pancreas and liver. It has been recently postulated to be associated with CAKUT, including MCDK. We recently encountered a family with a deletion mutant of HNF1β, of which the 2nd son, the proband, developed bilateral MCDK resulting in renal loss of function in infancy while the 1st son developed unilateral MCDK. Their father has two normal kidneys. This family confirmed that mutations in the HNF1β gene are strongly associated with the development of MCDK. Furthermore, the fact that no clear phenotype-genotype correlation exists suggests that gene(s) other than HNF1β are also involved in nephrogenesis and the development of MCDK.

T1 esophageal squamous cell carcinoma (ESCC) has a low, but still present, risk of lymph node (LN) metastasis. Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is often applied for T1 ESCC. To achieve successful treatment by EMR/ESD, the risk of LN metastases, LN recurrence, and hematological recurrence need to be better understood. The aim of this study was to determine the precise risk for metastasis in T1 ESCC.We divided 295 patients with T1 ESCC who underwent surgery and/or ESD/EMR into 6 categories (m1, m2, m3, sm1, sm2, and sm3). Their risks of LN metastasis, LN recurrence, hematological recurrence, and the outcome were determined.The rates of LN metastasis and LN recurrence were 0% in m1 and m2, 9% in m3, 16% in sm1, 35% in sm2, and 62% in sm3 cases. The incidence of hematological recurrence was 0% in m1, m2, m3, and sm1 cases; 9% in sm2 cases; and 13% in sm3 cases. The overall risk of metastasis was 9% in m3, 16% in sm1, 38% in sm2, and 64% in sm3 patients. The 5-year disease-specific survival rates were 100% in m1, m2, and m3; 90.9% in sm1; 78.8% in sm2; and 68.6% in sm3 patients. Statistically, both lymphatic and venous invasion were selected as predictive markers for metastasis. In m3 patients, positivity for either of these had an odds ratio for metastasis of 7.333 (P = 0.093).Our study provides a precise assessment of the comprehensive risk of metastasis and feasible predictive markers for T1 ESCC.

Background/aims There are few second-line regimens available for esophageal cancer. The use of fractionated docetaxel and nedaplatin as second-line chemotherapy was examined in this study. Methodology Eligibility criteria were follows: histologically-proven squamous cell carcinoma, surgically unresectable disease, failure to respond to chemotherapy with 5-FU and cisplatin and no more than 2 prior chemotherapy regimens. A total of 12 patients were enrolled in this study. To reduce toxicities, fractionated docetaxel (50 mg/m² in day 1 and 8) and nedaplatin (50 mg/m² in day 8) were administered as second-line chemotherapy. Results Stable disease (SD) was observed in 4 cases (33%) and the disease control rate was 33%. Regarding toxicities, leukopenia was the most frequently observed (8 cases, 67%); however, there were no cases of grade 4 nonhematological toxicity. The 1-year overall survival was 26.7% and the median survival time was 7.8 months (95% CI=3.328-12.272 months). The 1-year progression-free survival was 0% and the median progression-free time was 2.0 months (95% CI=1.319-2.681). Conclusions Combination chemotherapy using fractionated docetaxel and nedaplatin is safe and effective and appears to be a feasible regimen to use as second-line chemotherapy for FP-resistant advanced esophageal squamous cell carcinoma.

Background The correlation between the number of pathologic metastatic LNs in patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiotherapy (NACRT) and surgical outcome has rarely been reported. We evaluated the correlation between the number of pathologic metastatic lymph nodes (LNs) and the surgical outcome in ESCC after NACRT. Methods Eighty-eight patients with ESCC who underwent NACRT followed by surgery were evaluated. The clinical response of NACRT was evaluated and surgical specimens of the primary tumor and resected LNs were analyzed clinicopathologically. Results Fewer pathologic metastatic LNs was associated with better survival. According to the number of metastatic LNs, the difference in the median survival was the largest between the groups when patients were divided into those with 2 and 3 metastatic LNs (χ2: 13.694, P

A 52-year-old man visited our hospital to have a general checkup. Routine gastrointestinal endoscopy showed a twisted lumen with a corkscrew appearance in the distal oesophagus. No other abnormality was identifi ed (fi gure A). Our patient did not have any symptoms of dysphagia or retrosternal pain. A single-contrast barium examination of his oesophagus confi rmed a spiral staircase peristalsis and an absence of peristalsis in the oesophageal body. CT of the mediastinum was done, and virtual endoscopy of the oesophagus showed the typical features of corkscrew oesophagus (fi gure B). Although manometry might be necessary to diagnose corkscrew oesophagus, we did not recommend this to our patient because his corkscrew oesophagus had been diagnosed, without any previous symptoms. In the future, our patient will need to be treated with drugs such as muscle relaxants and anxiolytic agents, in conjunction with either antirefl ux therapy or surgical myotomy. Currently, we only advise him not to consume cold fl uids to prevent the development of symptoms.

A prospective study was performed to investigate the validity of renal failure index (RFI) or fractional excretion of sodium (FENa) in preterm infants. The subjects were 128 newborn infants, 72 with oliguria and 56 without renal dysfunction (control). Oliguric infants were divided into two categories: acute renal failure (ARF) and prerenal failure (PRF), according to creatinine clearance (Ccr). Furthermore, all subjects were divided into four groups according to gestation, that is, 38 infants with gestational age of 25-28 weeks (group 1), 28 with 29-30 weeks (group 2), 38 with 31-36 weeks (group 3) and 24 of > 37 weeks (group 4). As a result, differentiation between ARF and PRF was valid when the RFI or FENa was used in infants of > 29 weeks gestation (groups 2, 3 and 4). Although infants of > 31 weeks gestation (groups 3 and 4) who present with an RFI > 3 or an FENa > 3% may be diagnosed as having ARF, infants in group 2 with an RFI of > 8 or an FENa of > 6% may be diagnosed as having ARF. For the infants in group 1, the application of RFI or FENa for diagnosis of ARF may be limited because of some overlap among the groups.

We attempted to clarify the renal physiologic response to arginine vasopressin (AVP) in the 12 sick neonates: three with respiratory distress syndrome (RDS), three with meconium aspiration syndrome, two with transient tachypnea of the newborn, two with neonatal asphyxia, and two low birthweight infants during the first 2 days of life. Plasma atrial natriuretic factor (ANF), urinary AVP, osmolality, free water clearance and creatinine clearance (Ccr) were measured at 8 to 16 hours of life (stage 1) and 24 to 32 hours of life (stage 2). Urinary AVP was expressed as the ratio of AVP to Ccr (urine AVP/Ccr). These subjects were divided into two groups: group A represented five infants with a urine AVP/Ccr ratio of 2000 or higher and group B, seven infants with a ratio of less than 2000 at stage 1. Hyponatremia occurred in two infants of group A at stage 2. Number of infants on mechanical ventilation was four in group A and one in group B. There were no significant differences in gestational age, birthweight, Apgar scores at 1 and 5 minutes, blood gas pH and mean arterial blood pressure between groups A and B. A good correlation was observed between logarithm of urine AVP/Ccr ratio and urinary osmolality (p < 0.01). A negative correlation was observed between logarithm of urine AVP/Ccr ratio and free water clearance (p < 0.01). Body weight of infants of group A at stage 2 was greater than at stage 1 (p < 0.05). Higher plasma ANF concentrations were observed in infants of group A at stage 2 when compared with those at stage 1 (p < 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

69 Background: Recently, abscopal effect, by which systemic anti-tumor effect by local radiation therapy (RT) was elicited, has been reported. This phenomenon was thought to be mediated by stress protein gp96, a key molecule in antigen-presenting. We tested the enhancement of dendritic cell (DC) therapy by various stress, such as radiation or modulated electro-hyperthermia (mEHT) in DC therapy for squamous cell carcinoma (SCC). Methods: Mouse SCC cells, SCCVII, were inoculated into the left femur (primary tumor) of C3H/He mice subcutaneously, and also similarly inoculated into non-treated chest subcutaneous tissue (secondary tumor). Only the primary tumor was exposed to 4 or 10 Gy of RT or 5-10 watts of mEHT. Then DCs was injected only into the primary tumor. Following that, tumor volumes of the primary and secondary tumor were measured. Next, the population of immune-related T-cells in tumor-draining lymph nodes (TDLN) and gp96 expression in the primary tumor were evaluated. Results: With intratumoral injection of DCs and RT, primary tumor growth was markedly suppressed. Furthermore, secondary tumor growth was also suppressed. On the other hand, the combination of DCs and mEHT could inhibit tumor growth at both the primary and the secondary tumor. As for the population of T-cells, the population of CD3+, CD 4+ and CD 8+T-cells in the TDLN was markedly elevated and that of FoxP3 was reduced my mEHT. Gp96 expression, a stress protein, was strongly enhanced after RT and mEHT. Conclusions: Stress, such as RT or hyperthermia can enhance the efficacy of DC therapy and can induce a strong antitumor effect by stimulating the expression of stress protein, gp96. These combination therapies can be a strong systemic immunotherapy for esophageal SCC.

We attempted to determine the plasma endothelin-1-like immunoreactivity (ET-1) levels and to evaluate its physiological significance in 29 neonates: 5 with respiratory distress syndrome (RDS), 3 with transient tachypnoea of the newborn (TTN), 4 with neonatal asphyxia, 5 with bronchopulmonary dysplasia (BPD) following RDS, 7 healthy preterm infants and 5 healthy full-term infants. Plasma ET-1 levels in infants with RDS were significantly higher than those in healthy full-term infants through the 1st week of life. Plasma ET-1 levels in infants with neonatal asphyxia were high on the first 2 days of life and then gradually decreased to those of healthy full-term infants. Plasma levels in infants with TTN were the same as those in healthy full-term infants. Plasma ET-1 levels in infants with BPD were high when compared with those in healthy preterm infants during the first 2 months of life. This study showed that plasma levels were markedly elevated for a long time in the infants with respiratory distress. We speculate that plasma ET-1 may be a specific marker for pulmonary endothelium injury in infants with respiratory distress.

Urinary endothelin-1-like immunoreactivity (ET-1-LI) excretion was determined in 31 neonates, six sick infants with renal dysfunction secondary to neonatal asphyxia and 25 healthy infants, during the first week of life to clarify its evolutional change and the origin of the urinary ET-1-LI in the newborn period. Urinary ET-1-LI concentrations in the healthy infants maintained the same level during the first week of life (n = 35, 36 +/- 22 pg/mg creatinine, mean +/- SD). There was no difference in urinary ET-1-LI excretion in infants between 30 and 41 weeks of gestation. Urinary ET-1-LI concentrations in the sick infants were significantly elevated through the first week of life when compared with those of healthy infants. Fractional excretion of sodium and endothelin clearance were more elevated in the sick infants than in the healthy infants. A good correlation was observed between urinary ET-1-LI concentrations and urinary N-acetyl-beta-D-glucosaminidase index (r = 0.72, p < 0.01). These results suggest that the origin of urinary endothelin-1 may be the renal tissue and that ET-1 may be a nonspecific marker of renal injury in neonates.

To elucidate the effects of birth stress on immunoreactive endothelin-1 (irET-1) concentrations in fetal blood, we determined irET-1 levels in cord plasma in different modes of delivery associated with or without complications such as asphyxia. The irET-1 concentrations in both the umbilical artery and vein were significantly higher than those found in maternal venous blood at delivery, although there was no significant difference between preterm and full-term infants. When plasma irET-1 concentrations of healthy infants born by vaginal delivery and by cesarean section without labor were compared, the former had significantly (p less than 0.05) higher levels than the latter (15.4 +/- 4.9 pg/mL versus 11.1 +/- 3.1 pg/mL). Furthermore, umbilical venous plasma obtained from vaginally delivered infants complicated by asphyxia showed significantly (p less than 0.001) higher irET-1 levels (28.2 +/- 9.4 pg/mL) than those of nonasphyxiated infants (14.2 +/- 4.5 pg/m). These data suggest that birth stress, especially asphyxia, may contribute to the increase in fetal circulating irET-1 levels.

We determined plasma endothelin-1-like immunoreactivity and atrial natriuretic factor concentrations in preterm and full-term newborn infants during the first month of life. Plasma endothelin-1-like immunoreactivity levels were far greater than those of maternal blood in the newborn infants. The highest plasma endothelin-1-like immunoreactivity levels were observed on the first day of life (8.7 +/- 3.7 pmol/l) and gradually decreased with age. There was no significant difference in plasma endothelin-1-like immunoreactivity levels between preterm and full-term infants. A good correlation was observed between plasma endothelin-1-like immunoreactivity levels and atrial natriuretic factor concentrations (p < 0.01). These results suggest that circulating endothelin may regulate the cardiovascular system in the newborn period.