Publications by authors named "Manabu Muto"

233 Publications

Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in 40-69-years subjects.

Esophagus 2021 Jun 12. Epub 2021 Jun 12.

Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8397, Japan.

Background: Visceral fat obesity can be defined quantitatively by abdominal computed tomography, however, the usefulness of measuring visceral fat area to assess the etiology of gastrointestinal reflux disease has not been fully elucidated.

Methods: A total of 433 healthy subjects aged 40-69 years (234 men, 199 women) were included in the study. The relationship between obesity-related factors (total fat area, visceral fat area, subcutaneous fat area, waist circumference, and body mass index) and the incidence of reflux erosive esophagitis was investigated. Lifestyle factors and stomach conditions relevant to the onset of erosive esophagitis were also analyzed.

Results: The prevalence of reflux erosive esophagitis was 27.2% (118/433; 106 men, 12 women). Visceral fat area was higher in subjects with erosive esophagitis than in those without (116.6 cm vs. 64.9 cm, respectively). The incidence of erosive esophagitis was higher in subjects with visceral fat obesity (visceral fat area ≥ 100 cm) than in those without (61.2% vs. 12.8%, respectively). Visceral fat obesity had the highest odds ratio (OR) among obesity-related factors. Multivariate analysis showed that visceral fat area was associated with the incidence of erosive esophagitis (OR = 2.18), indicating that it is an independent risk factor for erosive esophagitis. In addition, daily alcohol intake (OR = 1.54), gastric atrophy open type (OR = 0.29), and never-smoking history (OR = 0.49) were also independently associated with the development of erosive esophagitis.

Conclusions: Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in subjects aged 40-69 years.
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http://dx.doi.org/10.1007/s10388-021-00859-5DOI Listing
June 2021

Repeated talaporfin sodium photodynamic therapy for esophageal cancer: safety and efficacy.

Esophagus 2021 Jun 9. Epub 2021 Jun 9.

Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Talaporfin sodium photodynamic therapy (tPDT) is an effective salvage treatment for local failure after chemoradiotherapy for esophageal cancer. Repeated tPDT could also be indicated for local recurrence or residue after the first salvage tPDT. However, the safety and efficacy of repeated tPDT have not been elucidated.

Methods: We reviewed 52 patients with esophageal cancer who were treated with the first tPDT at Kyoto University Hospital between October 2015 and April 2020.

Results: Among 52 patients, repeated tPDT after the first tPDT was indicated for 13 patients (25%), of which six had residual tumor, four had local recurrence after complete response (CR) after the first tPDT at the primary site, and six had metachronous lesion. The total session of repeated tPDT was 25; 16 were for primary sites and nine were for metachronous sites. Among them, six patients (46.2%) achieved local (L)-CR and nine lesions (56.3%) achieved lesion L-CR. By session, 10 sessions (40%) achieved L-CR. There were no severe adverse events except for one patient; this patient showed grade 3 esophageal stenosis and perforation after the third tPDT on the same lesion that was previously treated with porfimer sodium photodynamic therapy four times.

Conclusion: Repeated tPDT could be an effective and safe treatment for local failure even after salvage tPDT for esophageal cancer.
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http://dx.doi.org/10.1007/s10388-021-00853-xDOI Listing
June 2021

Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan.

Cancer Med 2021 May 15. Epub 2021 May 15.

Department of Gastroenterology, Kobe City Medical Center General Hospital, Kobe, Japan.

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.
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http://dx.doi.org/10.1002/cam4.3927DOI Listing
May 2021

Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations.

Gastric Cancer 2021 May 7. Epub 2021 May 7.

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown.

Methods: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed.

Results: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression.

Conclusions: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.
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http://dx.doi.org/10.1007/s10120-021-01191-8DOI Listing
May 2021

Autoimmune polyendocrine syndrome type 3, characterized by autoimmune thyroid disease, type 1 diabetes mellitus, and isolated ACTH deficiency, developed during adjuvant nivolumab treatment.

Asia Pac J Clin Oncol 2021 Apr 18. Epub 2021 Apr 18.

Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Autoimmune polyendocrine syndrome (APS) is one of the life-threatening immune-related adverse events (irAEs). We firstly report a case of APS induced by adjuvant nivolumab therapy. Clinicians should be aware of the potential risks of developing severe irAEs when applying adjuvant immunotherapy.
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http://dx.doi.org/10.1111/ajco.13573DOI Listing
April 2021

Incidence and treatment outcomes of metachronous gastric cancer occurring after curative endoscopic submucosal dissection of undifferentiated-type early gastric cancer: Japan Clinical Oncology Group study-post hoc analysis of JCOG1009/1010.

Gastric Cancer 2021 Mar 31. Epub 2021 Mar 31.

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background And Aims: A drawback of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is the development of metachronous gastric cancer (MGC). While MGC after ESD for differentiated-type (D-) EGC was well understood, little is known about MGC occurring after ESD for undifferentiated-type (UD-) EGC, because ESD had not been indicated. We evaluated the incidence and treatment outcomes of MGC after ESD of UD-EGC.

Methods: This study is a post hoc analysis of JCOG1009/1010, a multicenter trial to evaluate the efficacy and safety of ESD for UD-EGC. The patients who underwent curative ESD of index solitary UD-EGC were analyzed. Surveillance endoscopy was performed biannually for the first 3 years and thereafter annually. We assessed the time to MGC occurrence after ESD, lesion characteristics, and treatment outcomes of MGC. Time to MGC occurrence was estimated by cumulative incidence function, with death and total gastrectomy as competing risks.

Results: A total of 198 patients were included in this study. During a median follow-up period of 5.8 years, 4 patients (2%) developed MGC. Median time to MGC occurrence was 4.5 years (range: 3.1-5.4). Five-year cumulative incidence of MGC was 1.0% (95% CI: 0.2-3.3%). Two MGCs were histologically D-EGC, and the remaining two were UD-EGC. The median tumor size of MGCs was 1.0 cm (range: 0.7-1.7), and the depth of invasion (M/SM1/SM2) was 2/1/1, respectively. Three patients achieved curative resection with repeated ESD.

Conclusions: MGC does not occur commonly after curative ESD of UD-EGC, and repeated ESD could contribute to stomach preservation.
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http://dx.doi.org/10.1007/s10120-021-01183-8DOI Listing
March 2021

Current status of diagnostic and therapeutic colonoscopy in Japan: The Japan Endoscopic Database Project.

Dig Endosc 2021 Mar 27. Epub 2021 Mar 27.

JED (Japan Endoscopy Database) Project Committee, Japan Gastroenterological Endoscopy Society, Tokyo, Japan.

Objectives: The Japan Endoscopy Database Project was initiated to develop the world's largest endoscopy data repository. This study describes the first phase of the colonoscopy project in Japan.

Methods: Data were aggregated offline by integrating information from the endoscopy database software from January 2015 through March 2017. The study population included all patients who underwent colonoscopy at eight centers.

Results: A total of 31,395 patients who underwent 38,497 colonoscopy procedures were registered. The majority of procedures were performed for screening (n = 14,156), followed by fecal immunochemical test positivity (n = 3960), abdominal symptoms (n = 3864), post-colorectal surgery surveillance (n = 3431), post-endoscopic treatment surveillance (n = 3757), thorough pre-treatment examination (n = 2822), and therapeutic purposes (n = 6507). In the screening group, advanced cancers, early cancers, and adenomas were diagnosed endoscopically in 2.1%, 1.3%, and 28.7% of cases, respectively, while in the fecal immunochemical test-positive group, they were diagnosed in 2.5%, 1.9%, and 41.6% of cases, respectively. The incidence of complications was 0.177% and 0.152% in the screening and fecal immunochemical test-positive groups, respectively. The therapeutic procedures included 1446 cold forceps polypectomy procedures, 4770 cold snare polypectomy procedures, 368 hot biopsies, 2998 hot snare polypectomy procedures, 9775 endoscopic or piecemeal endoscopic mucosal resections, and 1660 endoscopic submucosal dissections. A total of 173 procedure-related complications (0.82%) occurred in 21,017 therapeutic procedures performed in 15,744 patients.

Conclusions: The first phase of the Japan Endoscopy Database Project established the proportions of the diagnostic and therapeutic colonoscopy procedures, and complication rates in real-world settings.
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http://dx.doi.org/10.1111/den.13980DOI Listing
March 2021

A randomized, double-blind, phase II study of oral histone deacetylase inhibitor resminostat plus S-1 versus placebo plus S-1 in biliary tract cancers previously treated with gemcitabine plus platinum-based chemotherapy.

Cancer Med 2021 03 26;10(6):2088-2099. Epub 2021 Feb 26.

Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan.

Purpose: Effective second-line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S-1. In the phase I study, addition of resminostat to S-1 was suggested to have promising efficacy for pre-treated BTCs. This study investigated the efficacy and safety of resminostat plus S-1 in second-line therapy for BTCs.

Methods: Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1-5 and 8-12) and S-1 group (80-120 mg orally per day by body surface area; days 1-14) over a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety.

Results: Among 101 patients enrolled, 50 received resminostat+S-1 and 51 received placebo+S-1. Median PFS was 2.9 months for resminostat+S-1 vs. 3.0 months for placebo+S-1 (HR: 1.154, 95% CI: 0.759-1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653-1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment-related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S-1 than in the placebo+S-1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%).

Conclusions: Resminostat plus S-1 therapy improved neither PFS nor OS for patients with pre-treated BTCs. Addition of resminostat to S-1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI-183883).
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http://dx.doi.org/10.1002/cam4.3813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957161PMC
March 2021

Diagnostic yield of conventional endoscopy with endoscopic ultrasonography for submucosal invasion of superficial esophageal squamous cell carcinoma: a post hoc analysis of multicenter prospective confirmatory study (JCOG0508).

Esophagus 2021 Jul 28;18(3):604-611. Epub 2021 Jan 28.

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Endoscopic ultrasonography (EUS) is reportedly the reliable modality to predict the depth of esophageal squamous cell carcinoma (ESCC), however, most previous studies are retrospective or single-centered. We aimed to evaluate the diagnostic ability of conventional endoscopy and EUS using the data from a multicenter prospective study of endoscopic resection (ER) followed by chemoradiotherapy for cSM1-2N0M0 ESCC (JCOG0508).

Methods: All lesions were evaluated as cSM cancer with both conventional endoscopy and EUS before enrollment and judged as cSM1 or cSM2 in real time. We compared the clinical and pathological diagnoses for tumor depth and assessed the positive predictive value (PPV) for pSM (pSM/cSM) as the primary endpoint. We also investigated the clinical factors affecting the pathological depth of SM.

Results: 175 lesions were examined, and clinical diagnosis was SM1 in 114 and SM2 in 61 lesions. The pathological diagnoses of the epithelium, lamina propria mucosa, muscularis mucosae, SM1, and SM2 were 3, 31, 55, 17, and 69. The PPV for pSM was 49.1% (86/175) in all lesions, 34.2% (39/114) in cSM1 lesions, and 77.0% (47/61) in cSM2 lesions. Multivariable analysis demonstrated that cSM2 (vs. cSM1, OR 6.79) was an independent clinical factor associated with pSM.

Conclusions: While the accurate depth diagnosis in cSM ESCC was difficult to make, the clinical diagnosis of SM2 with both conventional endoscopy and EUS was significantly associated with pSM. Furthermore, diagnostic ER could be recommended to confirm the pathological diagnosis especially in cSM1 lesions with both conventional endoscopy and EUS.
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http://dx.doi.org/10.1007/s10388-021-00815-3DOI Listing
July 2021

Cancer of unknown primary with EGFR mutation successfully treated with targeted therapy directed by clinical next-generation sequencing: a case report.

BMC Cancer 2020 Dec 2;20(1):1177. Epub 2020 Dec 2.

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan.

Background: Cancer of unknown primary (CUP) is usually treated with nonselective and empirical chemotherapy; however, its prognosis is generally poor, with a median survival of less than a year. Thus, clinicians eagerly await the development of more effective treatment strategies. In recent years, advances in next-generation sequencing (NGS) have made it possible to analyze comprehensively the genome of individual cancers. NGS has identified many genomic alterations, some of which are potential molecular targets of specific agents. We report a case of CUP that was successfully treated with targeted therapy directed by the genomic data obtained from an NGS-based multiplex assay.

Case Presentation: A 52-year-old Asian woman with right hip joint pain underwent fluorodeoxyglucose-positron emission tomography/computed tomography, which showed multiple metastatic tumors in her right hip joint, thyroid gland, lung, and vertebrae. Brain magnetic resonance imaging showed multiple cerebral metastases. Additional tests, including pathology examination and conventional epidermal growth factor receptor (EGFR) gene mutation analysis (single-strand conformation polymorphism assay), could not identify the primary origin of the tumors, so the patient was diagnosed with CUP. After empirical chemotherapy for CUP, an NGS-based multiplex assay performed using a resected specimen of thyroid tumor detected the EGFR mutation c.2573 T > G p.Leu858Arg (L858R). Her treatment was changed to erlotinib, an EGFR tyrosine-kinase inhibiter, which dramatically shrank the tumors and decreased her serum carcinoembryonic antigen level. She achieved long-term disease control and survived for 2 years and 9 months from the first diagnosis.

Conclusion: This case might support the strategy that NGS-based multiplex assays could identify actionable molecular targets for individual patients with CUP.
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http://dx.doi.org/10.1186/s12885-020-07640-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709432PMC
December 2020

Nivolumab versus chemotherapy in Japanese patients with advanced esophageal squamous cell carcinoma: a subgroup analysis of a multicenter, randomized, open-label, phase 3 trial (ATTRACTION-3).

Esophagus 2021 Jan 10;18(1):90-99. Epub 2020 Nov 10.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: The efficacy and safety of nivolumab versus chemotherapy was evaluated in the Japanese subpopulation from the overall intent-to-treat (ITT) population of the ATTRACTION-3 trial conducted in patients with advanced esophageal squamous cell carcinoma (ESCC) as second-line treatment.

Methods: Data from Japanese patients enrolled in the multicenter, randomized, open-label, phase 3 ATTRACTION-3 trial were analyzed. The primary endpoint was overall survival (OS). Secondary endpoints included duration of response (DOR), objective response rate (ORR), disease control rate (DCR), and safety. Exploratory subgroup analyses evaluated the association between OS and stratification factors/baseline variables.

Results: Overall, 274 (nivolumab, 136; chemotherapy, 138) of the 419 patients in ATTRACTION-3 were enrolled from Japan: response-evaluable population (107; 108) and safety population (135; 138). OS tended to be longer in the nivolumab group versus the chemotherapy group (median: 13.4 months vs. 9.4 months; HR, 0.77; 95% CI 0.59-1.01). Median DOR was longer in the nivolumab group (7.6 months) versus the chemotherapy group (3.6 months). ORRs were similar between the nivolumab [22.4% of patients (24/107)] and chemotherapy groups [22.2% (24/108); odds ratio, 0.98; 95% CI 0.52-1.87]. DCR was lower in the nivolumab group [41.1% (44/107)] versus the chemotherapy group [66.7% (72/108)]. OS in the exploratory analysis consistently favored the nivolumab group versus the chemotherapy group. Overall, nivolumab demonstrated favorable efficacy and safety versus chemotherapy in the Japanese subpopulation, and the trend was similar to that observed in the overall ATTRACTION-3 ITT population.

Conclusion: Nivolumab represents a new standard second-line treatment option for Japanese patients with advanced ESCC.
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http://dx.doi.org/10.1007/s10388-020-00794-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794205PMC
January 2021

A nonrandomized, single-arm confirmatory trial of expanded endoscopic submucosal dissection indication for undifferentiated early gastric cancer: Japan Clinical Oncology Group study (JCOG1009/1010).

Gastric Cancer 2021 Mar 8;24(2):479-491. Epub 2020 Nov 8.

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: While endoscopic submucosal dissection (ESD) is recognized as a minimally invasive standard treatment for differentiated early gastric cancers (EGCs), it has not been indicated for undifferentiated EGC (UD-EGC) because of a relatively high risk of lymph node metastasis (LNM). However, patients with surgically resected mucosal (cT1a) UD-EGC ≤ 2 cm in size with no lymphovascular invasion or ulceration are reported to be at a very low risk of LNM. This multicenter, single-arm, confirmatory trial was conducted to evaluate the efficacy and safety of ESD for UD-EGC.

Methods: The key eligibility criteria were endoscopically diagnosed cT1a/N0/M0, single primary lesion, size ≤ 2 cm, no ulceration and histologically proven components of undifferentiated adenocarcinoma on biopsy. Based on the histological findings after ESD, additional gastrectomy was indicated if the criteria for curative resection were not satisfied. The subjects of the primary analysis were patients with UD-EGC as the dominant component. The primary endpoint was 5-year overall survival (OS) of patients with UD-EGC.

Results: Three hundred 46 patients were enrolled from 49 institutions. The proportion of en bloc resection was 99%. No ESD-related Grade 4 adverse events were noted. Delayed bleeding and intraoperative and delayed perforation occurred in 25 (7.3%), 13 (3.8%), and 6 (1.7%) patients, respectively. Among the 275 patients who were the subjects of the primary analysis, curative resection was achieved in 195 patients (71%), and 5-year OS was 99.3% (95% CI: 97.1-99.8).

Conclusions: ESD can be a curative and less invasive treatment for UD-EGC for patients meeting the eligibility criteria of this study.
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http://dx.doi.org/10.1007/s10120-020-01134-9DOI Listing
March 2021

A management of neutropenia using granulocyte colony stimulating factor support for chemotherapy consisted of docetaxel, cisplatin and 5-fluorouracil in patients with oesophageal squamous cell carcinoma.

Jpn J Clin Oncol 2021 Feb;51(2):199-204

Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan.

Background: An exploratory study was designed to evaluate the efficacy of granulocyte colony stimulating factor support for chemotherapy consisting of docetaxel, cisplatin and 5-fluorouracil chemotherapy in patients with oesophageal cancer.

Methods: The inclusion criteria were as follows: (1) oesophageal squamous cell carcinoma, (2) a schedule to receive three courses of induction chemotherapy (docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, 5-fluorouracil 750 mg/m2 days 1-5, every 3 weeks), (3) stage IB-III, (4) 20-75 years old, (5) 0-1 performance status, (6) preserved organ functions and (7) written informed consent. The endpoints were to evaluate the efficacy of granulocyte colony stimulating factor support including secondary prophylactic usage for docetaxel, cisplatin and 5-fluorouracil chemotherapy. Patients who previously had 'febrile neutropenia', or 'Grade 3 or 4 infection accompanied by grade 3 or 4 neutropenia' prophylactically received granulocyte colony stimulating factor support from day 7.

Results: A total of 91 patients were included in the analysis. Granulocyte colony stimulating factor support was given to 81.3%. The incidence of grade 4 neutropenia and febrile neutropenia were 81.3 and 32.9%, respectively. The dose of anticancer agents was reduced in 48.4%. There were no treatment-related deaths. The relative dose intensity of docetaxel, cisplatin and 5-fluorouracil were 92.7 ± 9.8%, 86.0 ± 15.6% and 91.8 ± 10.0%, respectively. In the secondary prophylactic granulocyte colony stimulating factor support group, the neutrophil count significantly increased between day 7 and day 13 as compared with the non-prophylactic granulocyte colony stimulating factor support group (P < 0.05 for each day).

Conclusions: Granulocyte colony stimulating factor support including secondary prophylactic usage may be feasible for maintaining the intensity of docetaxel, cisplatin and 5-fluorouracil chemotherapy in patients with oesophageal cancer.
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http://dx.doi.org/10.1093/jjco/hyaa190DOI Listing
February 2021

[How Does Aging Contribute to Cancer?]

Gan To Kagaku Ryoho 2020 Sep;47(9):1281-1286

Dept. of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University.

Advances in sequencing technology have been reported to show cancer driver mutations with aging in a variety of normal tissues at very small clone sizes. In the normal esophagus, prior to carcinogenesis, clones that had acquired driver mutations in esophageal cancer, mainly NOTCH1 mutations, during early life appeared multi-centrically. With aging, the number of driver mutations increased and the clones expanded. In the elderly, most of the normal esophagus was replaced by clones with driver mutations. In contrast, in normal colorectal epithelium, about 1% of crypts contain driver mutations even in the 50s. In normal hepatocytes, age-related mutations are rarely detected. These results suggest that the frequency of detection of driver mutations in normal tissues varies greatly among tissues. The panorama of aging and cancer remains veiled.
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September 2020

Near-focus magnification and second-generation narrow-band imaging for early gastric cancer in a randomized trial.

J Gastroenterol 2020 Dec 6;55(12):1127-1137. Epub 2020 Oct 6.

Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Magnifying endoscopy with narrow-band imaging (NBI) is effective for the diagnosis of early gastric cancer (EGC). However, magnifying endoscopy is not yet popular globally because of the required level of skill and lack of availability. To overcome these problems, dual-focus endoscopy (standard- and near-focus (NF) modes) has been developed. In this study, we evaluated the diagnostic performance of NF with second-generation (2G)-NBI (NF-NBI) for the diagnosis of EGC.

Methods: This was a secondary analysis of a multicenter randomized controlled trial of 4523 high-risk patients who underwent gastroscopies at 13 institutions in Japan. Patients were randomly assigned to white-light imaging (WLI) followed by 2G-NBI or to 2G-NBI followed by WLI. Lesions suspicious for EGC, newly detected by non-magnifying WLI or 2G-NBI, were subsequently observed with NF-NBI. All detected lesions were biopsied or resected. The diagnostic performance of NF-NBI was compared with the final histology.

Results: A total of 870 detected lesions (145 EGC, 725 non-EGC) were analyzed. Overall diagnostic performance for EGC using NF-NBI was accuracy 87.7%, sensitivity 60.7%, specificity 93.1%, positive predictive value 63.8%, and negative predictive value 92.2%. There were no significant differences in diagnostic performance between lesions detected by WLI or 2G-NBI. For lesions diagnosed with high (333 lesions) and low (537 lesions) confidences, accuracy was 92.2% and 84.9%, sensitivity was 64.7% and 58.5%, and specificity was 90.5% and 88.8%, respectively.

Conclusion: The diagnostic performance of NF-NBI is good and acceptable for diagnosis of EGC in combination with either WLI or 2G-NBI.
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http://dx.doi.org/10.1007/s00535-020-01734-3DOI Listing
December 2020

BRCA2 Reversion Mutation Identified by Liquid Biopsy After Durable Response to FOLFIRINOX in BRCA2-Associated Pancreatic Cancer.

Pancreas 2020 Nov/Dec;49(10):e101-e103

Department of Therapeutic Oncology Graduate School of Medicine Kyoto University Kyoto, Japan Clinical Genetics Unit Kyoto University Hospital Kyoto, Japan Department of Diagnostic Pathology Kyoto University Hospital Kyoto, Japan Department of Medical Oncology Kindai University Faculty of Medicine Osaka, Japan Department of Genome Biology Kindai University Faculty of Medicine Osaka, Japan Department of Therapeutic Oncology Graduate School of Medicine Kyoto University Kyoto, Japan.

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http://dx.doi.org/10.1097/MPA.0000000000001672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598072PMC
October 2020

Successful management of hyperammonemia with hemodialysis on day 2 during 5-fluorouracil treatment in a patient with gastric cancer: a case report with 5-fluorouracil metabolite analyses.

Cancer Chemother Pharmacol 2020 11 3;86(5):693-699. Epub 2020 Oct 3.

Department of Gastroenterology, Hirakata Kohsai Hospital, Osaka, Japan.

Purpose: Hyperammonemia is an important adverse event associated with 5-fluorouracil (5FU) from 5FU metabolite accumulation. We present a case of an advanced gastric cancer patient with chronic renal failure, who was treated with 5FU/leucovorin (LV) infusion chemotherapy (2-h infusion of LV and 5FU bolus followed by 46-h 5FU continuous infusion on day 1; repeated every 2 weeks) and developed hyperammonemia, with the aim of exploring an appropriate hemodialysis (HD) schedule to resolve its symptoms.

Methods: The blood concentrations of 5FU and its metabolites, α-fluoro-β-alanine (FBAL), and monofluoroacetate (FA) of a patient who had hyperammonemia from seven courses of palliative 5FU/LV therapy for gastric cancer were measured by liquid chromatography-mass spectrometry.

Results: On the third day of the first cycle, the patient presented with symptomatic hyperammonemia relieved by emergency HD. Thereafter, the 5FU dose was reduced; however, in cycles 2-4, the patient developed symptomatic hyperammonemia and underwent HD on day 3 for hyperammonemia management. In cycles 5-7, the timing of scheduled HD administration was changed from day 3 to day 2, preventing symptomatic hyperammonemia. The maximum ammonia and 5FU metabolite levels were significantly lower in cycles 5-7 than in cycles 2-4 (NH3 75 ± 38 vs 303 ± 119 μg/dL, FBAL 13.7 ± 2.5 vs 19.7 ± 2.0 μg/mL, FA 204.0 ± 91.6 vs 395.9 ± 12.6 ng/mL, mean ± standard deviation, all p < 0.05). After seven cycles, partial response was confirmed.

Conclusion: HD on day 2 instead of 3 may prevent hyperammonemia in 5FU/LV therapy.
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http://dx.doi.org/10.1007/s00280-020-04158-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595983PMC
November 2020

Comprehensive genomic profiling for patients with chemotherapy-naïve advanced cancer.

Cancer Sci 2021 Jan 21;112(1):296-304. Epub 2020 Nov 21.

Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan.

Comprehensive genomic profiling (CGP) testing by next-generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies. However, whether CGP testing at the time of first-line chemotherapy could be clinically useful is not clear. We conducted this single-center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy-naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne companion diagnostic (F1CDx) assay. The primary outcome was the detection rate of at least one actionable/druggable cancer genomic alteration. Actionable/druggable cancer genomic alterations were determined by the F1CDx report. An institutional molecular tumor board determined the molecular-based recommended therapies. A total of 197 patients were enrolled from October 2018 to June 2019. CGP success rate was 76.6% (151 of 197 patients), and median turnaround time was 19 days (range: 10-329 days). Actionable and druggable cancer genomic alterations were reported in 145 (73.6%) and 124 (62.9%) patients, respectively. The highest detection rate of druggable genomic alterations in gastrointestinal cancers was 80% in colorectal cancer (48 of 60 patients). Molecular-based recommended therapies were determined in 46 patients (23.4%). CGP testing would be a useful tool for the identification of a potentially effective first-line chemotherapy.
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http://dx.doi.org/10.1111/cas.14674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780032PMC
January 2021

Association of Chemoradiotherapy With Thoracic Vertebral Fractures in Patients With Esophageal Cancer.

JAMA Netw Open 2020 09 1;3(9):e2013952. Epub 2020 Sep 1.

Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Importance: The association of chemoradiotherapy (CRT) with a thoracic vertebral fracture in patients with esophageal cancer is unknown.

Objective: To determine whether CRT is associated with thoracic vertebral fractures in patients with esophageal cancer.

Design, Setting, And Participants: This retrospective cohort study included patients with clinical stages I to III thoracic esophageal cancer who visited the Kyoto University Hospital, Kyoto, Japan, from January 1, 2007, to December 31, 2013. Data were analyzed from April 6, 2018, to June 4, 2020.

Exposures: Chemoradiotherapy (CRT group) or surgery or endoscopic treatment (non-CRT group).

Main Outcomes And Measures: The main outcome of this study was the cumulative incidence rate of thoracic vertebral fractures in 36 months. The incidence rate was calculated taking censoring into account. Possible risk factors, including CRT, were explored in the multivariable analysis. The association of irradiated doses with fractured vertebrae was also evaluated.

Results: A total of 315 patients (119 for the CRT group and 196 for the non-CRT group) were included. The median age of patients was 65 (range, 32-85) years. Fifty-six patients (17.8%) were female and 259 (82.2%) were male. The median observation time was 40.4 (range, 0.7-124.1) months. Thoracic vertebral fractures were observed in 20 patients (16.8%) in the CRT group and 8 patients (4.1%) in the non-CRT group. The 36-month incidence rate of thoracic vertebral fractures was 12.3% (95% CI, 7.0%-19.1%) in the CRT group and 3.5% (95% CI, 1.3%-7.5%) in the non-CRT group (hazard ratio [HR], 3.41 [95% CI, 1.50-7.73]; P = .003). The multivariable analysis showed that the HR of the thoracic vertebral fracture in the CRT group to non-CRT group was 3.91 (95% CI, 1.66-9.23; P = .002) with adjusting for sex, 3.14 (95% CI, 1.37-7.19; P = .007) with adjusting for age, and 3.10 (95% CI, 1.33-7.24; P = .009) with adjusting for the history of vertebral or hip fractures. The HR of the thoracic vertebral fracture for a 5-Gy increase in the mean radiation dose to the single vertebra was 1.19 (95% CI, 1.04-1.36; P = .009).

Conclusions And Relevance: This study found that chemoradiotherapy was associated with thoracic vertebral fractures in patients with esophageal cancers. A reduced radiation dose to thoracic vertebrae may decrease the incidence of fractures.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489848PMC
September 2020

[Precision Medicine Provided by National Health Insurance].

Gan To Kagaku Ryoho 2020 Aug;47(8):1158-1163

Dept. of Clinical Oncology, Kyoto University Hospital.

From June 2019, 2 different comprehensive genomic profiling(CGP)test panels were covered by National Health Insurance System in Japan. However, the indication of CGP was solid cancer patients refractory to standard chemotherapy or those without standard of care, while other countries indicate CGP to chemotherapy naIve advanced cancer patients. To be covered by National Health Insurance System, certified core hospital for genomic medicine should hold expert panel with affiliated hospitals. We develop a unique system for expert panel collaborated with SYSMEX Corporation to streamline medical staffs' effort. To provide precision medicine to cancer patients, we have to maximize the merit of CGP and solve several issues.
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August 2020

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial).

Medicine (Baltimore) 2020 Aug;99(32):e21457

Center for Innovative Cancer Treatment.

Introduction: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol.

Methods/design: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response.

Discussion: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab.

Trial Registration: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.
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http://dx.doi.org/10.1097/MD.0000000000021457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592999PMC
August 2020

Premature mortality due to stomach cancer in Japan: a nationwide analysis from 1980 to 2015.

Ann Epidemiol 2020 07 3;47:19-24. Epub 2020 Jun 3.

Department of Preventive Medicine and Community Health, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Purpose: Premature mortality offers an alternative approach for monitoring the burden of mortality; however, little is known about its measures for stomach cancer. In the present study, we investigated temporal changes in premature mortality because of stomach cancer in the Japanese population from 1980 to 2015.

Methods: Mortality data for stomach cancer were obtained from the World Health Organization mortality database. Years of life lost (YLL) was calculated using Japanese life tables. The average lifespan shortened was calculated and defined as the ratio of YLL in relation to the expected lifespan.

Results: Over a 35-year time frame, the age-standardized rates adjusted to the World Standard Population for deaths from stomach cancer substantially decreased in both sexes. The results from the average YLL (AYLL) measure showed that lifespan of stomach cancer patients was prolonged by about 3 and 5 years in men and women, respectively. The average lifespan shortened measure showed that stomach cancer led to a loss of 18.5% of lifespan among men and of 21.9% among women in 1980, but these numbers were reduced to 13.6% and 14.5%, respectively, in 2015.

Conclusions: Our study demonstrated decreasing trends in premature mortality for stomach cancer in Japan over a 35-year period.
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http://dx.doi.org/10.1016/j.annepidem.2020.05.012DOI Listing
July 2020

E487K-Induced Disorder in Functionally Relevant Dynamics of Mitochondrial Aldehyde Dehydrogenase 2.

Biophys J 2020 08 10;119(3):628-637. Epub 2020 Jul 10.

Medical Sciences Innovation Hub Program, RIKEN Cluster for Science, Technology and Innovation Hub, Yokohama, Kanagawa, Japan; Department of Biomedical Data Intelligence, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Research and Development Group for In Silico Drug Discovery, Center for Cluster Development and Coordination, Foundation for Biomedical Research and Innovation at Kobe 6-3-5, Minatojima-Minamimachi Kobe, Hyogo, Japan. Electronic address:

Mitochondrial aldehyde dehydrogenase 2 (ALDH2), which is a homotetramer assembled by two equivalent dimers, is an important enzyme that metabolizes ethanol-derived acetaldehyde to acetate in a coenzyme-dependent manner. The highly reactive acetaldehyde exhibits a toxic effect, indicating that the proper functioning of ALDH2 is essential to counteract aldehyde-associated diseases. It is known that the catalytic activity of ALDH2 is drastically impaired by a frequently observed mutation, E487K, in a dominant fashion. However, the molecular basis of the inactivation mechanism is elusive because of the complex nature of the dynamic behavior. Here, we performed microsecond-timescale molecular dynamics simulations of the proteins complexed with coenzymes. The E487K mutation elevated the conformational heterogeneity of the dimer interfaces, which are relatively distal from the substituted residue. Dynamic network analyses showed that Glu487 and the dimer interface were dynamically communicated, and the dynamic community further spanned throughout all of the subunits in the wild-type; however, this network was completely rearranged by the E487K mutation. The perturbation of the dynamic properties led to alterations of the global conformational motions and destabilization of the coenzyme binding required for receiving a proton from the catalytic nucleophile. The insights into the dynamic behavior of the dominant negative mutant in this work will provide clues to restore its function.
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http://dx.doi.org/10.1016/j.bpj.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399495PMC
August 2020

Protocol for a single-arm confirmatory trial of adjuvant chemoradiation for patients with high-risk rectal submucosal invasive cancer after local resection: Japan Clinical Oncology Group Study JCOG1612 (RESCUE study).

BMJ Open 2020 07 14;10(7):e034947. Epub 2020 Jul 14.

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Introduction: Intestinal resection with lymph node dissection is the current standard treatment for high-risk lower rectal submucosal invasive cancer after local resection; however, surgery affects patients' quality of life due to stoma placement or impaired anal sphincter function. A recent study demonstrated that adjuvant chemoradiation yields promising results.

Methods And Analysis: This study aims to confirm the non-inferiority of adjuvant chemoradiation, consisting of capecitabine and concurrent radiotherapy (45 Gy in 25 fractions), measured by 5-year relapse-free survival (RFS), over standard surgery in patients with high-risk lower rectal submucosal invasive cancer after local resection. The primary endpoint is 5 year RFS. The secondary endpoints are 10 years RFS, 5-year and 10-year overall survival, 5-year and 10-year local RFS, 5-year and 10-year proportion of anus-preservation without stoma, Wexner score, low anterior resection syndrome score, adverse events and serious adverse events. During the 5-year trial period, 210 patients will be accrued from 65 Japanese institutions.

Ethics And Dissemination: The National Cancer Center Hospital East Certified Review Board approved this study protocol in October 2018. The study is conducted in accordance with the precepts established in the Declaration of Helsinki and Clinical Trials Act. Written informed consent will be obtained from all eligible patients prior to registration. The primary results of this study will be published in an English article. In addition, the main results will be published on the websites of Japan Clinical Oncology Group (www.jcog.jp) and jRCT (https://jrct.niph.go.jp/). As to data curation, it has not been prepared yet.

Trial Registration Number: jRCT1031180076.
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http://dx.doi.org/10.1136/bmjopen-2019-034947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365419PMC
July 2020

Long-term outcome of endoscopic resection for intramucosal esophageal squamous cell cancer: a secondary analysis of the Japan Esophageal Cohort study.

Endoscopy 2020 11 24;52(11):967-975. Epub 2020 Jun 24.

Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan.

Background: Prospectively collected long-term data of patients undergoing endoscopic resection for superficial esophageal squamous cell carcinoma (ESCC) are limited. The aim of this study was to determine the prospectively collected long-term outcomes of endoscopic resection for ESCC as a secondary analysis of the Japan Esophageal Cohort (JEC) study.

Methods: Patients who underwent endoscopic resection of intramucosal ESCC at 16 institutions between September 2005 and May 2010 were enrolled in the JEC study. All patients underwent endoscopic examination with iodine staining at 3 and 6 months after resection, and every 6 months thereafter. We investigated clinical courses after endoscopic resection, survival rates, and cumulative incidence of metachronous ESCC.

Results: 330 patients (mean age 67.0 years) with 396 lesions (mean size 20.4 mm) were included in the analysis. Lesions were diagnosed as high-grade intraepithelial neoplasia in 17.4 % and as squamous cell carcinoma in 82.6 % (limited to epithelium in 28.4 %, to lamina propria in 55.4 %, and to muscularis mucosa in 16.2 %). En bloc resection was achieved in 291 (73.5 %). The median follow-up period was 49.4 months. Local recurrences occurred in 13 patients (3.9 %) and were treated by endoscopic procedures. Lymph node metastasis occurred in two patients (0.6 %) after endoscopic resection. The 5-year overall, disease-specific, and metastasis-free survival rates were 95.1 %, 99.1 %, and 94.6 %, respectively. The 5-year cumulative incidence rate of metachronous ESCC was 25.7 %.

Conclusions: Our study demonstrated that endoscopic resection is an effective treatment for intramucosal ESCC, with favorable long-term outcomes.
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http://dx.doi.org/10.1055/a-1185-9329DOI Listing
November 2020

[Incidence of Proteinuria among Japanese Colorectal Cancer Patients after Receiving Ramucirumab-Cohort Study Using Claim Database].

Gan To Kagaku Ryoho 2020 Jun;47(6):917-922

Medicines Development Unit Japan, Eli Lilly Japan K. K.

We evaluated the incidence of proteinuria after receiving ramucirumab for the patients with advanced colorectal cancer using claim database. Among 1,706 evaluable patients, incidence proportion of proteinuria was 21.8% and incidence rate (/100 person-years)was 75.3. In patients with history of proteinuria or previous bevacizumab use, incidence rate was high and many patients tend to occur proteinuria in the early stage after initiating ramucirumab prescription. Appropriate management by periodical monitoring from the early stage after initiating ramucirumab prescription is important.
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June 2020

Effectiveness of planned surveillance for detecting second primary head and neck cancers after endoscopic resection of esophageal squamous cell carcinoma.

Jpn J Clin Oncol 2020 Sep;50(10):1162-1167

Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Second primary head and neck cancers after endoscopic resection of esophageal squamous cell carcinoma adversely affect patients' outcomes and the quality of life; however, an adequate surveillance schedule remains unclear.

Methods: We analyzed 330 patients with early esophageal squamous cell carcinoma who underwent endoscopic resection and were registered in the multicenter cohort study to evaluate adequate surveillance for detection of second primary head and neck cancers. Gastrointestinal endoscopists examined the head and neck regions after 3-6 months of endoscopic resection for esophageal squamous cell carcinoma and subsequently every 6 months. An otolaryngologist also examined the head and neck regions at the time of endoscopic resection for esophageal squamous cell carcinoma and at 12 months intervals thereafter.

Results: During the median follow-up period of 49.4 months (1.3-81.2 months), 33 second primary head and neck cancers were newly detected in 20 patients (6%). The tumor site was as follows: 22 lesions in the hypopharynx, eight lesions in the oropharynx, two lesions in larynx and one lesion in the oral cavity. The 2-year cumulative incidence rate of second primary head and neck cancers was 3.7%. Among them, 17 patients with 29 lesions were treated by transoral surgery. One patient with two synchronous lesions was treated by radiotherapy. Two lesions in two patients were not detected after biopsy. All patients were cured with preserved laryngeal function.

Conclusions: Surveillance by gastrointestinal endoscopy every 6 months and surveillance by an otolaryngologist every 12 months could detect second primary head and neck cancers at an early stage, thereby facilitating minimally invasive treatment.
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http://dx.doi.org/10.1093/jjco/hyaa087DOI Listing
September 2020

Chemotherapy for patients with unresectable or metastatic small bowel adenocarcinoma: a systematic review.

Int J Clin Oncol 2020 Aug 24;25(8):1441-1449. Epub 2020 May 24.

Department of Health Informatics, Kyoto University School of Public Health, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.

Background: There is no standard chemotherapy available for unresectable or metastatic small bowel adenocarcinoma (SBA) because of its rarity. This systematic review aims to assess the efficacy and safety of chemotherapy for patients with unresectable or metastatic SBA.

Methods: In accordance with the PRISMA statements, literature search was conducted using PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. The included studies were prospective randomized, nonrandomized, or observational studies. Risk of bias was assessed the ROBINS-I tool.

Results: Seven prospective single-arm Phase II studies were included in this review. Six of them were assessed as having a moderate risk of bias and one as having a serious risk of bias. A meta-analysis was not performed, because the studies were single-arm. Systemic chemotherapy based on fluoropyrimidine regimens achieved favorable outcomes with acceptable adverse effects as a first therapy; however, the regimens differed in each study. The object response rate was 18-50%, and the disease control rate was 29-87%. With 5-fluorouracil, adriamycin, and mitomycin-C regimen, one treatment-related death occurred. A second line of therapy including chemotherapy with nab-paclitaxel also showed favorable efficacy. The object response rate was 20%, and the disease control rate was 50%.

Conclusions: Systemic chemotherapy based on fluoropyrimidine regimens was mainly used for unresectable or metastatic SBA. While it may achieve favorable outcomes with acceptable adverse effects, further evidence is needed.
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http://dx.doi.org/10.1007/s10147-020-01703-zDOI Listing
August 2020

Association of local complete response with prognosis after salvage photodynamic therapy for esophageal squamous cell carcinoma.

Dig Endosc 2021 Mar 17;33(3):355-363. Epub 2020 Jul 17.

Department of Clinical Oncology, Kyoto University, Kyoto, Japan.

Objectives: Photodynamic therapy (PDT) is an effective salvage endoscopic treatment for local failure at the primary site after chemoradiotherapy (CRT) in esophageal cancer patients. However, the contribution of local control by salvage PDT to the prognosis is unclear. We investigated whether complete response at primary site by salvage PDT could improve the prognosis.

Methods: Between January 2008 and March 2016, 34 patients received salvage PDT for local failure of esophageal cancer limited to stage T1-2 after definitive CRT or radiotherapy. Local complete response (L-CR) rate, adverse events, overall survival (OS), and progression-free survival (PFS) were assessed retrospectively.

Results: Local complete response rates after PDT were 68% (23/34; 95% CI, 50-83%) in all patients: 81% (17/21; 95% CI, 58-95%) for stage T1 and 46% (6/13; 95% CI, 19-75%) for stage T2 patients. Grade 3 esophageal stricture occurred in one patient. The median follow-up was 26.0 months (range, 3.7-93.6 months); 21 patients died. The median survival times were 54.3 months in patients who achieved L-CR after PDT (L-CR group) and 19.8 months in those who did not (non-CR group). The 2-year OS rates were 79% (95% CI, 54-92%) in the L-CR group and 40% (95% CI, 11-68%) in the non-CR group (P = 0.0389; log-rank test). The median PFS was 21.2 months in the L-CR group and 1.9 months in the non-CR group (P < 0.001; log-rank test).

Conclusion: Achieving L-CR by salvage PDT for local failure after CRT in esophageal cancer was associated with good prognosis.
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http://dx.doi.org/10.1111/den.13730DOI Listing
March 2021