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Integrating artificial intelligence (AI) applications into colonoscopy practice is being accelerated as deep learning technologies emerge. In this field, most of the preceding research has focused on polyp detection and characterization, which can mitigate inherent human errors accompanying colonoscopy procedures. On the other hand, more challenging research areas are currently capturing attention: the automated prediction of invasive cancers. Colorectal cancers (CRCs) harbor potential lymph node metastasis when they invade deeply into submucosal layers, which should be resected surgically rather than endoscopically. However, pretreatment discrimination of deeply invasive submucosal CRCs is considered difficult, according to previous prospective studies (e.g.

To elucidate the advantages and limitations of existing artificial intelligence technologies for colonoscopy by evaluating the currently available eight prospective studies (two for automated polyp detection and six for automated polyp characterization). AI is expected to mitigate the inherent risk of human error causing a polyp to be missed or mischaracterized by assisting polyp detection and characterization (i.e., pathological prediction). Some of the prospective studies clearly demonstrate the potential for AI to improve adenoma detection rates, which is considered one of the most important quality indicators for colonoscopies, or achieve a > 90% negative predictive value in differentiating diminutive (≤ 5 mm) rectosigmoid adenomas which is considered as a threshold required for optical diagnosis. However, it is also important to consider the negative impacts of AI, such as the deskilling effect on healthcare providers, which has yet to be sufficiently addressed. We believe that AI can become standard practice in colonoscopy procedures within several years, given its rapid spread and its expected low implementation cost. However, considering the limited evidence supporting the use of AI for colonoscopy, additional studies should be done to explore the long-term efficacy and safety of AI in colonoscopy and implement robust endpoints such as colorectal cancer incidence and mortality.

The prevalence of nonsuicidal self-injury (NSSI) in adults is lower than that in adolescents and it is more prevalent in patients with psychiatric disorders. Sleep disturbances such as nightmares are associated with NSSI after accounting for depression; thus, persons with major NSSI sometimes present at medical institutions during the night seeking emergency treatment. Gingival tissues comprise the most frequent target of self-injury of the oral cavity using oral hygiene tools. Most NSSI in the oral cavity is minor because such tools are blunt. Major NSSI such as autoamputation of the tongue is rare. We describe two patients who partially autoamputated the apex of their own tongues using edged tools. Case 1 was a 55-year-old female with depression who had defaulted from psychiatric intervention. She had cut off her tongue using a Japanese kitchen knife and presented with the dry, necrotic amputated portion and blood oozing from the remainder of her tongue. We debrided and sutured the remainder of the tongue without reattaching the amputated portion. Her postoperative course was uneventful, and she was free of adverse events such as functional disability and wound infection. Case 2 was a 69-year-old female with schizophrenia who had defaulted from psychiatric intervention and had cut off her tongue using scissors. The amputated portion of the tongue was lost and the remainder, which was oozing blood, was debrided and sutured. She defaulted on a follow-up appointment. Neither of these patients had suicidal intent. The prevalence of NSSI across all age groups has recently increased, and the risk that self-injury will become normalized has become a concern. Thus, dentists as well as oral and maxillofacial surgeons should be aware of the possibility that patients will present with major NSSI requiring emergency treatment.

Background and study aims Decisions concerning additional surgery after endoscopic resection of T1 colorectal cancer (CRC) are difficult because preoperative prediction of lymph node metastasis (LNM) is problematic. We investigated whether artificial intelligence can predict LNM presence, thus minimizing the need for additional surgery. Patients and methods Data on 690 consecutive patients with T1 CRCs that were surgically resected in 2001 – 2016 were retrospectively analyzed. We divided patients into two groups according to date: data from 590 patients were used for machine learning for the artificial intelligence model, and the remaining 100 patients were included for model validation. The artificial intelligence model analyzed 45 clinicopathological factors and then predicted positivity or negativity for LNM. Operative specimens were used as the gold standard for the presence of LNM. The artificial intelligence model was validated by calculating the sensitivity, specificity, and accuracy for predicting LNM, and comparing these data with those of the American, European, and Japanese guidelines. Results Sensitivity was 100 % (95 % confidence interval [CI] 72 % to 100 %) in all models. Specificity of the artificial intelligence model and the American, European, and Japanese guidelines was 66 % (95 %CI 56 % to 76 %), 44 % (95 %CI 34 % to 55 %), 0 % (95 %CI 0 % to 3 %), and 0 % (95 %CI 0 % to 3 %), respectively; and accuracy was 69 % (95 %CI 59 % to 78 %), 49 % (95 %CI 39 % to 59 %), 9 % (95 %CI 4 % to 16 %), and 9 % (95 %CI 4 % – 16 %), respectively. The rates of unnecessary additional surgery attributable to misdiagnosing LNM-negative patients as having LNM were: 77 % (95 %CI 62 % to 89 %) for the artificial intelligence model, and 85 % (95 %CI 73 % to 93 %; P Conclusions Compared with current guidelines, artificial intelligence significantly reduced unnecessary additional surgery after endoscopic resection of T1 CRC without missing LNM positivity.

EGFR signaling has been implicated in hypoxia-associated resistance to radiation or chemotherapy. Non–small cell lung carcinomas (NSCLC) with activating L858R or ΔE746-E750 EGFR mutations exhibit elevated EGFR activity and downstream signaling. Here, relative to wild-type (WT) EGFR, mutant (MT) EGFR expression significantly increases radiosensitivity in hypoxic cells. Gene expression profiling in human bronchial epithelial cells (HBEC) revealed that MT-EGFR expression elevated transcripts related to cell cycle and replication in aerobic and hypoxic conditions and downregulated RAD50, a critical component of nonhomologous end joining and homologous recombination DNA repair pathways. NSCLCs and HBEC with MT-EGFR revealed elevated basal and hypoxia-induced γ-H2AX–associated DNA lesions that were coincident with replication protein A in the S-phase nuclei. DNA fiber analysis showed that, relative to WT-EGFR, MT-EGFR NSCLCs harbored significantly higher levels of stalled replication forks and decreased fork velocities in aerobic and hypoxic conditions. EGFR blockade by cetuximab significantly increased radiosensitivity in hypoxic cells, recapitulating MT-EGFR expression and closely resembling synthetic lethality of PARP inhibition. Implications: This study demonstrates that within an altered DNA damage response of hypoxic NSCLC cells, mutant EGFR expression, or EGFR blockade by cetuximab exerts a synthetic lethality effect and significantly compromises radiation resistance in hypoxic tumor cells. Mol Cancer Res; 15(11); 1503–16. ©2017 AACR.

To achieve DNA sequencing with solid-state nanopores, the speed of the DNA in the nanopore must be controlled to obtain sequence-specific signals. In this study, we fabricated a nanopore-sensing system equipped with a DNA motion controller. DNA strands were immobilized on a Si probe, and approach of this probe to the nanopore vicinity could be controlled using a piezo actuator and stepper motor. The area of the Si probe was larger than the area of the membrane, which meant that the immobilized DNA could enter the nanopore without the need for the probe to scan to determine the location of the nanopore in the membrane. We demonstrated that a single-stranded DNA could be inserted into and removed from a nanopore in our experimental system. The number of different ionic-current levels observed while DNA remained in the nanopore corresponded to the number of different types of homopolymers in the DNA.

Several studies have shown that colonoscopy is associated with a reduction in colorectal cancer mortality. This benefit is based on the detection and resection of any neoplastic polyps; however, polyps can be missed during screening colonoscopy and endoscopists may not be able to differentiate between neoplastic and non-neoplastic polyps. Polyp miss rates as high as 20 % have been reported for high definition resolution colonoscopy 1 , while a large prospective trial of optical biopsy of small colon polyps using narrow-band imaging (NBI) showed that the accuracy of physicians was only 80 % in diagnosing detected polyps as adenomas, even after a physician training program 2 . To overcome these limitations, computer-aided diagnosis (CAD) is attracting more attention because it may help endoscopists to avoid missing and mischaracterizing polyps. CAD for colonoscopy is generally designed to extract various features from a colonoscopic image/movie and output the predicted polyp location or pathology based on machine learning. The term “machine learning” refers to a fundamental function of artificial intelligence, whereby a computer can be trained to learn (in this case, recognize or characterize polyps) through repetition and experience (exposure to a large number of annotated polyp images). Ideally, the output of CAD is expressed in real time on the monitor, immediately assisting the endoscopist’s decision-making.

Background and study aims Invasive cancer carries the risk of metastasis, and therefore, the ability to distinguish between invasive cancerous lesions and less-aggressive lesions is important. We evaluated a computer-aided diagnosis system that uses ultra-high (approximately × 400) magnification endocytoscopy (EC-CAD). Patients and methods We generated an image database from a consecutive series of 5843 endocytoscopy images of 375 lesions. For construction of a diagnostic algorithm, 5543 endocytoscopy images from 238 lesions were randomly extracted from the database for machine learning. We applied the obtained algorithm to 200 endocytoscopy images and calculated test characteristics for the diagnosis of invasive cancer. We defined a high-confidence diagnosis as having a ≥ 90 % probability of being correct. Results Of the 200 test images, 188 (94.0 %) were assessable with the EC-CAD system. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were 89.4 %, 98.9 %, 94.1 %, 98.8 %, and 90.1 %, respectively. High-confidence diagnosis had a sensitivity, specificity, accuracy, PPV, and NPV of 98.1 %, 100 %, 99.3 %, 100 %, and 98.8 %, respectively. Conclusion: EC-CAD may be a useful tool in diagnosing invasive colorectal cancer.

Background and study aims Real-time diagnosis of colorectal polyps is needed to prevent unnecessary resection of benign polyps. The vessels in hyperplastic polyps sometimes mimic the characteristic meshed capillary network of neoplastic lesions on non-magnified narrow-band imaging (NBI). Endocytoscopy in conjunction with NBI (EC-NBI) enables more detailed vessel observation. The current study evaluated whether EC-NBI can accurately diagnose small colorectal lesions with visible vessels on non-magnified NBI. Patients and methods This retrospective study was conducted from January to December 2016. During colonoscopy, lesion images were obtained using NBI and EC-NBI. On EC-NBI, lesions were classified as having “clear,” “unclear,” or “invisible” blood vessel margins. All specimens were resected and pathologically examined, and the association between vessel margin findings and pathological diagnosis was assessed. The lesion surface to vessel depth was measured in clear, unclear, and invisible lesions. Results Among 114 adenomas, 108 were clear, while six were unclear. Among 36 hyperplastic polyps, eight were clear, while 28 were unclear. A micro-network (MN) pattern was seen in 106 of 114 adenomas, and four of 36 hyperplastic polyps. The sensitivity, specificity, correct diagnostic rate, and positive and negative predictive values of clear blood vessel margins or a MN pattern as an adenoma index were 98.2 %, 69.4 %, 91.3 %, 91.1 %, and 92.6 %, respectively. EC-NBI correctly diagnosed 69.4 % (25/36) of hyperplastic polyps. The lesion surface–blood vessel distance was greater in unclear versus clear lesions (P Conclusions EC-NBI may effectively differentiate hyperplastic polyps with visible vessels from adenomas. Blood vessel depth affects visibility.

For nanopore sensing of various-sized molecules with high sensitivity, the size of the nanopore should be adjusted according to the size of each target molecule. For solid-state nanopores, a simple and inexpensive nanopore fabrication method utilizing dielectric breakdown of a membrane is widely used. This method is suitable for fabricating a small nanopore. However, it suffers two serious problems when attempting to fabricate a large nanopore: the generation of multiple nanopores and the non-opening failure of a nanopore. In this study, we found that nanopore fabrication by dielectric breakdown of a SiN membrane under high-pH conditions (pH ≥ 11.3) could overcome these two problems and enabled the formation of a single large nanopore up to 40 nm in diameter within one minute. Moreover, the ionic-current blockades derived from streptavidin-labelled and non-labelled DNA passing through the fabricated nanopore were clearly distinguished. The current blockades caused by streptavidin-labelled DNA could be identified even when its concentration is 1% of the total DNA.

Immune checkpoint inhibitors (ICIs), including nivolumab, have exhibited substantial benefits in the treatment of several types of cancers. However, treatment with ICIs is often accompanied by immune-related adverse events (irAEs), and a clear understanding of the precise indications and management of irAEs is important for harnessing the full potential of these agents. While skin- or gastrointestinal-associated irAEs have been relatively well studied, there are few reports regarding nivolumab-induced cholangitis. We retrospectively reviewed data from patients with advanced or recurrent non-small cell lung cancer who were treated with nivolumab between December 2015 and December 2018 at Tottori University in Japan. Among the 59 patients, we identified four patients who experienced nivolumab-induced cholangitis. Of these four patients, stable disease (SD) was observed in two patients (50%), while partial response (PR) was achieved in two patients (50%) under nivolumab treatment. Patients were treated with corticosteroid alone (n=2) or in combination with mycophenolate mofetil (MMF) (n=2); these treatments resulted in improvements in nivolumab-induced cholangitis in three patients. In conclusion, the present retrospective study identified four cases of nivolumab-induced cholangitis. The combination of corticosteroid and MMF was effective in two cases with grade 4 nivolumab-induced cholangitis. Further reports are needed to establish the optimal management of patients with this irAE.

Real-time characterization of colorectal lesions during colonoscopy is important for reducing medical costs, given that the need for a pathological diagnosis can be omitted if the accuracy of the diagnostic modality is sufficiently high. However, it is sometimes difficult for community-based gastroenterologists to achieve the required level of diagnostic accuracy. In this regard, we developed a computer-aided diagnosis (CAD) system based on endocytoscopy (EC) to evaluate cellular, glandular, and vessel structure atypia in vivo. The purpose of this study was to compare the diagnostic ability and efficacy of this CAD system with the performances of human expert and trainee endoscopists. We developed a CAD system based on EC with narrow-band imaging that allowed microvascular evaluation without dye (ECV-CAD). The CAD algorithm was programmed based on texture analysis and provided a two-class diagnosis of neoplastic or non-neoplastic, with probabilities. We validated the diagnostic ability of the ECV-CAD system using 173 randomly selected EC images (49 non-neoplasms, 124 neoplasms). The images were evaluated by the CAD and by four expert endoscopists and three trainees. The diagnostic accuracies for distinguishing between neoplasms and non-neoplasms were calculated. ECV-CAD had higher overall diagnostic accuracy than trainees (87.8 vs 63.4%; $$P=0.01$$ ), but similar to experts (87.8 vs 84.2%; $$P=0.76$$ ). With regard to high-confidence cases, the overall accuracy of ECV-CAD was also higher than trainees (93.5 vs 71.7%; $$P

Background: Chronic obstructive pulmonary disease is a smoking-related disease, and is categorized into the emphysema and airway dominant phenotypes. We examined the relationship between emphysematous changes and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma. Patients and Methods: The medical records for 250 patients with lung adenocarcinoma were retrospectively reviewed. All patients were categorized into the emphysema or non-emphysema group. Results: Wild-type EGFR was detected in 136 (54%) and mutant EGFR in 48 (19%). Emphysematous changes were observed in 87 (36%) patients. EGFR mutation was highly frequent in the non-emphysema group (p=0.0014). Multivariate logistic regression analysis showed that emphysema was an independent risk factor for reduced frequency of EGFR mutation (Odds Ratio=3.47, p=0.005). Conclusion: Our data showed a relationship between emphysematous changes and EGFR mutation status. There might be mutually exclusive genetic risk factors for carcinogenesis and development of emphysematous changes.

Background Oxidative stress plays an important role in the pathogenesis of bronchial asthma. Antioxidant nutrition and supplementation have been used to reduce oxidative stress. However, a clinical trial with antioxidant supplementation showed no beneficial effects in patients with asthma. On the other hand, physical activity is related to the prognosis of chronic obstructive pulmonary disease (COPD) and is also related to oxidant status. We investigated the relationships between oxidative stress, serum levels of vitamins, dietary vitamin intake, daily activities, and pulmonary functions in patients with asthma. Methods Eighteen patients with bronchial asthma were enrolled in this study. Reactive oxidative stress was assessed by measuring organic hydroperoxides (diacron reactive oxygen metabolites: dROM) in sera and by measuring H2O2 levels in exhaled breath condensates. The biological antioxidant capacity in serum was evaluated by measuring antioxidant potential capacity against ferric ion. We also assessed pulmonary functions, fraction of exhaled nitric oxide, serum levels of vitamins, dietary vitamin intake, and physical activities. Results There were no relationships between the index of oxidative stress (dROM and H2O2 in exhaled breathe condensates) and pulmonary functions, serum levels of vitamins, daily vitamin intakes, and activity levels in patients with asthma. Conclusion The status of transient oxidative stress may not be related to daily activities, vitamin levels, and pulmonary functions in patients with asthma in a real-life setting. However, our results were obtained in the short-term period from a small number of subjects, so a large longitudinal study is required to ascertain the relationships between oxidative stress, physical activity and vitamin intake in patients with asthma.

A 73-year-old man with a history of lethargy, fever and dyspnea was admitted to Tottori University Hospital. A computed tomography (CT) scan revealed splenomegaly and diffusely spreading ground-glass opacities (GGOs) in both lungs. A video-assisted thoracoscopic surgery (VATS)-guided lung biopsy revealed intravascular proliferation of large atypical lymphoid cells in the arteries, veins and alveolar walls. The patient was diagnosed with intravascular large B-cell lymphoma (IVLBCL); he received 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) immunochemotherapy and has remained in complete remission for >1 year. Although IVLBCL is a rare disease, it should be considered in the differential diagnosis of pulmonary diffuse lesions that present with GGOs on CT scans.

Background and study aims: Magnifying narrow-band imaging (NBI) is useful for examination of colorectal lesions, and endocytoscopy (EC) allows diagnostic evaluation of structural atypia, nuclear atypia, and vascular structures of colorectal tumors. The aim of this study was to examine surface microvessels in deep invasive colorectal cancer using EC with a new NBI video processor system. Patients and methods: We retrospectively assessed 132 colorectal neoplastic lesions: 81 adenomas, 18 intramucosal cancers, 4 submucosal slightly invasive cancers, and 29 submucosal deep invasive cancers. Detailed vascular findings commonly seen in submucosal deep invasive carcinomas included > 2-fold vasodilatation seen in adenomas, abnormal tortuosity and branching, loss of the micro-network pattern, caliber change in > 2 places in a single blood vessel, and blood vessels not visible in a line because they appear like a string of beads (beaded sign). Results: Univariate analysis revealed 4 vascular findings that were strongly predictive of submucosal deep invasion: vasodilatation (odds ratio [OR] 9.31; 95 % confidence interval [CI] 3.57 – 24.30), loss of the micro-network pattern (OR 61.60; 95 % CI 17.87 – 212.29), caliber change (OR 35.7; 95 % CI 9.16 – 139.14), and the beaded sign (OR 45.90; 95 % CI 5.50 – 382.73). Conclusions: Detailed assessment of ultra-magnified microvessels could improve the diagnostic performance for submucosal deep invasive cancer. Study registration: UMIN-CTR000014033

Currently, depressed type T1 colorectal cancer is often detected and its malignant potential is being revealed. However, few reports have focused on the morphology of T2 colorectal cancer types. The aim of the present retrospective study was to clarify the characteristics of colorectal T2 cancer types derived from depressed type T1 cancer. The present study included 195 patients with colorectal T2 cancer surgically resected at a referral hospital between April 2001 and April 2009. A total of 48 lesions (25%) with lymph node metastasis and 4 (2%) with distant metastasis were found. The lesions were classified by their form during endoscopy into four categories: Group A, depressed type (the periphery consists of normal mucosa); group B, laterally spreading type; group C, protruded type; group D, ulcerative type (the periphery consists of neoplastic mucosa). Tumor size, lymphatic and venous involvement, lymph node metastasis, and distant metastasis were compared between the four categories. The distribution of patients were as follows: Group A, 73 (37%), group B, 26 (13%), group C, 24 (12%) and group D, 72 (37%). The average tumor size for each category was 23, 51, 30 and 36 mm for groups A, B, C and D, respectively. The number of positive findings for lymphatic involvement, venous involvement, lymph node metastasis and distant metastasis for each category were: Group A, 50 (69%), 54 (74%), 19 (26%) and 1 (1%); group B, 14 (54%), 12 (46%), 8 (31%) and 0 (0%); group C, 14 (58%), 8 (33%), 6 (25%) and 0 (0%); group D 35 (49%), 41 (57%), 16 (22%) and 3 (4%). Group A demonstrated a significantly smaller tumor size (P

Background & Aims Precise optical diagnosis of colorectal polyps could improve the cost-effectiveness of colonoscopy and reduce polypectomy-related complications. However, it is difficult for community-based non-experts to obtain sufficient diagnostic performance. Artificial intelligence-based systems have been developed to analyze endoscopic images; they identify neoplasms with high accuracy and low interobserver variation. We performed a multi-center study to determine the diagnostic accuracy of EndoBRAIN, an artificial intelligence-based system that analyzes cell nuclei, crypt structure, and microvessels in endoscopic images, in identification of colon neoplasms. Methods The EndoBRAIN system was initially trained using 69,142 endocytoscopic images, taken at 520-fold magnification, from patients with colorectal polyps who underwent endoscopy at 5 academic centers in Japan from October 2017 through March 2018. We performed a retrospective comparative analysis of the diagnostic performance of EndoBRAIN vs that of 30 endoscopists (20 trainees and 10 experts); the endoscopists assessed images from 100 cases produced via white-light microscopy, endocytoscopy with methylene blue staining, and endocytoscopy with narrow-band imaging. EndoBRAIN was used to assess endocytoscopic, but not white-light, images. The primary outcome was the accuracy of EndoBrain in distinguishing neoplasms from non-neoplasms, compared with that of endoscopists, using findings from pathology analysis as the reference standard. Results In analysis of stained endocytoscopic images, EndoBRAIN identified colon lesions with 96.9% sensitivity (95% CI, 95.8%–97.8%), 100% specificity (95% CI, 99.6%–100%), 98% accuracy (95% CI, 97.3%–98.6%), a 100% positive-predictive value (95% CI, 99.8%–100%), and a 94.6% negative-predictive (95% CI, 92.7%–96.1%); these values were all significantly greater than those of the endoscopy trainees and experts. In analysis of narrow-band images, EndoBRAIN distinguished neoplastic from non-neoplastic lesions with 96.9% sensitivity (95% CI, 95.8–97.8), 94.3% specificity (95% CI, 92.3–95.9), 96.0% accuracy (95% CI, 95.1–96.8), a 96.9% positive-predictive value, (95% CI, 95.8–97.8), and a 94.3% negative-predictive value (95% CI, 92.3–95.9); these values were all significantly higher than those of the endoscopy trainees, sensitivity and negative-predictive value were significantly higher but the other values are comparable to those of the experts. Conclusions EndoBRAIN accurately differentiated neoplastic from non-neoplastic lesions in stained endocytoscopic images and endocytoscopic narrow-band images, when pathology findings were used as the standard. This technology has been authorized for clinical use by the Japanese regulatory agency and should be used in endoscopic evaluation of small polyps more widespread clinical settings. UMIN clinical trial no: UMIN000028843.

Endocytoscopy, a next-generation endoscopic system, facilitates observation at a maximum magnification of ×520. To our knowledge, no study has reported high-precision diagnosis of colorectal low-grade adenoma, endoscopically. We aimed to reveal which endocytoscopic findings may be used as indicators of low-grade adenoma and to assess whether a "resect and discard" strategy using endocytoscopy is feasible.Lesions diagnosable with endocytoscopy were examined retrospectively between May 2005 and July 2017. A normal pit-like structure in endocytoscopic images was considered a normal pit (NP) sign and used as an indicator of low-grade adenoma. The primary outcome was the diagnostic accuracy of the NP sign for low-grade adenoma. We evaluated agreement rates between endocytoscopic and pathologic diagnosis for surveillance colonoscopy interval recommendation (SCIR) and performed a validation study to verify the agreement rates.For 748 lesions in 573 cases diagnosed as colorectal adenoma using endocytoscopy, the results were as follows: sensitivity of the NP sign for low-grade adenoma, 85.0%; specificity, 90.7%; positive predictive value, 96.6%; negative predictive value, 66.1%; accuracy, 86.4%; and positive likelihood ratio, 9.2 (P .001). The agreement rate between endocytoscopic and pathologic diagnosis for SCIR was 94.4% (95% confidence interval [CI], 92.2%-96.1%; P .001) under United States guidelines and 96.3% (95% CI, 94.5%-97.7%; P .001) under European Union guidelines. All inter- and intraobserver agreement rates for expert and nonexpert endoscopists had κ values ≥0.8 except one nonexpert pair.Endocytoscopy is an effective modality in determining the differential diagnosis of colorectal low-grade adenoma. (University Hospital Medical Information Network Clinical Trials database registration number: UMIN000018623.).

【Background】 Weight loss in patients with cancer is caused by cancer cachexia and chemotherapy-induced nausea and vomiting (CINV). Recent developments in antiemetic drugs have substantially improved CINV, but nutritional intervention did not improve body weight. This study aimed to investigate the effects of nutrition intervention with appropriate antiemetic treatment in patients with non-small-cell lung cancer during chemotherapy. 【Methods】 Patients received individualized nutrition counseling by a registered dietitian and were provided with oral supplements for 90 days. Body weight and other parameters were measured at baseline and after 90-day intervention. To evaluate this nutrition intervention, patients were also retrospectively set as control, and then body weight change was compared with inverse probability of treatment weights (IPTW) analysis. 【Results】 Ten patients received individualized nutrition counseling and were provided with oral supplements for 90 days. Of them, 7 patients consumed nutritional supplements, and the mean intake was 130 kcal/day. After 90-day intervention, the patients did not show significant weight and BMI loss during the course of cytotoxic chemotherapy. A total of 38 patients were retrospectively enrolled as controls. The number of the patients who gain the body weight after 90 days in the study cohort was significantly larger than that in the retrospective controls with the IPTW analysis (Odds Ratio (OR) = 8.4; 95% Confidence Interval (CI): 1.6-42; P = 0.01). 【Conclusion】 Early intensive nutrition intervention with appropriate antiemetic treatment prevents weight loss. Nutrition interventions might be also beneficial for quality of life, treatment response and survival.

BACKGROUND AND AIM Application of artificial intelligence in medicine is now attracting substantial attention. In the field of gastrointestinal endoscopy, computer-aided diagnosis (CAD) for colonoscopy is the most investigated area, although it is still in the preclinical phase. Because colonoscopy is carried out by humans, it is inherently an imperfect procedure. CAD assistance is expected to improve its quality regarding automated polyp detection and characterization (i.e. predicting the polyp's pathology). It could help prevent endoscopists from missing polyps as well as provide a precise optical diagnosis for those detected. Ultimately, these functions that CAD provides could produce a higher adenoma detection rate and reduce the cost of polypectomy for hyperplastic polyps. METHODS AND RESULTS Currently, research on automated polyp detection has been limited to experimental assessments using an algorithm based on ex vivo videos or static images. Performance for clinical use was reported to have >90% sensitivity with acceptable specificity. In contrast, research on automated polyp characterization seems to surpass that for polyp detection. Prospective studies of in vivo use of artificial intelligence technologies have been reported by several groups, some of which showed a >90% negative predictive value for differentiating diminutive (≤5 mm) rectosigmoid adenomas, which exceeded the threshold for optical biopsy. CONCLUSION We introduce the potential of using CAD for colonoscopy and describe the most recent conditions for regulatory approval for artificial intelligence-assisted medical devices.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010.The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents.Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S.aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S.pneumoniae were 1.1% and 0.0%, respectively. Among H.influenzae, 17.6% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be β-lactamase-non-producing ABPC-resistant and 11.0% to be β-lactamase-producing ABPC-resistant strains. Extended spectrum β-lactamase-producing K.pneumoniae and multi-drug resistant P.aeruginosa with metallo β-lactamase were 2.9% and 0.6%, respectively.Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis., Journal of Infection and Chemotherapy, 21(6), pp.410-420; 2015

Objectives Zoledronate (ZOL) is usually used for prevention of skeletal-related events in cancer patients with bone metastases. The first administration of ZOL is occasionally associated with development of acute-phase reaction (APR), which is due to activation of γδ T cells. ZOL-related APR was associated with better overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in our previous retrospective study. However, it remains to be clarified whether γδ T cells are more activated in patients who experienced ZOL-related APR, and whether γδ T cell activation is involved in prolongation of OS. Materials and Methods Twenty-three patients with advanced NSCLC were recruited between 2012 and 2014 in this study. We administered ZOL to participants with standard care. The patient characteristics, change in γδ T cell counts and cytokines, OS, and skeletal-related event-free survival were compared between patients with APR (APR group) and those without APR (non-APR group). Results Ten patients (43.5%) experienced a ZOL-related APR. The number of γδ T cells at baseline in the APR group was significantly higher than that in the non-APR group. Serum interleukin-6 and tumor necrosis factor-α in the APR group were significantly increased, but no change in the number of γδ T cells was observed after the first administration of ZOL in both groups. OS in the APR group was significantly longer than that in the non-APR group (median survival time: 23.1 vs. 14.5 months, p Conclusion We showed that APR is related to higher numbers of γδ T cells at baseline and increased cytokines after the first ZOL administration, but not to proliferative responses of γδ T cells. In addition, better OS was observed in the APR group. Therefore, the number of γδ T cells might be a prognostic marker in patients with NSCLC.

Epidermal growth factor receptor (EGFR) gene mutation testing is essential for choosing appropriate treatment options in patients with advanced non-small cell lung cancer (NSCLC). However, a time delay occurs between histological diagnosis and molecular diagnosis in clinical situations. To minimize this delay, we developed a novel point-of-care test for EGFR mutations, based on a high-speed real-time polymerase chain reaction (PCR) system designated here as ultrarapid PCR combined with highly accurate bronchoscopic sampling. We investigated whether our system for detecting EGFR mutations was valid by comparing test results with those obtained using a commercialized EGFR mutation test. We obtained small amounts of bronchial lavage fluids after transbronchial biopsies (TBBs) were performed on enrolled patients (n=168) who underwent endobronchial ultrasonography using a guide sheath (EBUS-GS). EGFR mutation analysis was performed by ultrarapid PCR immediately after EBUS-GS-TBBs were obtained (on the same day). After pathological diagnoses of NSCLC, EGFR mutation status in formalin-fixed, paraffin- embedded samples was confirmed by the PCR-invader method, and the concordance rates between the PCR methods were compared. The total diagnostic yield of EBUS-GS-TBB was 91.0%. The positive concordance rates for detecting 19del and L858R with the ultrarapid PCR and PCR-invader methods were both 100%. Negative concordance rates were 97.2 and 98.1%, respectively. We also demonstrated a dramatic effect of early erlotinib administration, based on ultrarapid PCR results, for a 52-year-old woman suffering from respiratory failure due to severe intrapulmonary metastases with poor performance status. In conclusion, ultrarapid PCR combined with EBUS-GS-TBB enabled rapid and reliable point-of-care testing for EGFR mutations.

Chest computed tomography (CT) is not performed routinely or worldwide as the initial diagnostic procedure for patients with head and neck cancer (HNC). The significance of the chest CT scan for HNC diagnosis has not been thoroughly defined. The present study reports findings in an effort to broaden the acceptance and application of CT for HNC.Using medical records, we assessed initial chest CT scans of the patients with new-onset HNC between April 2004 and March 2010. The results were classified into three groups: nodules ≥ 1 cm, small nodules (1 cm) that were indeterminate and normal lungs without nodules. Lung nodules that increased in size and/or number at follow-up were regarded as malignant. First, the sensitivity of X-ray and CT for detection of lung nodules in patients with HNC was compared. Second, the nodules were estimated to be malignant or not malignant by follow-up chest CT. Third, statistical analyses were performed to determine the association between variables and distant lung metastases in patients with head and neck squamous cell carcinoma.In total, 332 patients underwent a chest CT scan as part of the initial examination. Lung nodules were detected on the initial chest CT in 77 patients: in contrast, lung nodules were detected on the initial chest X-ray in only five patients. On initial chest CT scans, lung nodules ≥ 1 cm were observed in 10 patients, small solitary lung nodules were observed in 67 patients, and lungs without nodules were observed in 255 patients. Lung nodules were detected in 77 (23.2%) patients, 25 (32.5%) of whom had malignant lung nodules. Moreover, in 18/67 patients (26.9%), small lung nodules initially classified as indeterminate were determined as malignant at follow-up. However, 30/255 patients (11.8%) without nodules at initial diagnosis developed lung nodules at follow-up. T3 or T4 disease (P = 0.006), N2 or N3 disease (P0.001) and stage 3 or 4 disease (P = 0.001) individually and significantly correlated with the development of lung metastases. In addition, lung nodules in initial CT scans (P = 0.004) and other distant metastases (P0.001) were significant predictors for the development of lung metastases at follow-up.Initial chest CT scan is recommended for patients with advanced HNC. Further, patients with advanced HNC with or without lung nodules, as detected on initial chest CT scans, should be followed up with additional scanning.

Previously we showed that Akt-suppressing agents, combined with amrubicin, synergistically inhibited the growth of small cell lung cancer cells. The combined effects of chemotherapeutic agents and Akt-suppressing agents, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, were evaluated in A549 lung adenocarcinoma cells harboring K-ras mutation and wild-type EGFR. Only amrubicin and not other chemotherapeutics (cisplatin, pemetrexed and paclitaxel) synergistically inhibited cell growth when combined with an Akt inhibitor, LY294002. The combination of amrubicin and LY294002 enhanced Annexin V binding to cells. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin. Two EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, suppressed Akt activity at clinically achievable concentrations and demonstrated synergism when combined with amrubicin. The suppression of K-ras expression by siRNA interfered with this synergism and inhibited both EGFR and Akt activity in A549 cells. In Ma10 cells, which harbor wild-type EGFR and K-ras, EGFR-TKIs neither suppressed Akt activity nor exhibited such synergism when combined with amrubicin. We concluded that the synergism by the combination of EGFR-TKI and amrubicin is attributable, at least partially, to K-ras mutation in A549 cells. The combination of EGFR-TKI and amrubicin may be a promising treatment for lung cancer with wild-type EGFR and K-ras mutation.

Background and Aim Endocytoscopy (EC) at ultra-high magnification enables in vivo visualization of cellular atypia of gastrointestinal mucosae. Clear images are essential for precise diagnosis by EC. The aim of the present study was to evaluate the optimal staining method for EC in the colon. Methods Thirty prospectively enrolled patients were allocated 1:1:1 to three distinct staining methods: 0.05% crystal violet (CV) alone, 1% methylene blue (MB) alone, or CV + MB (CM double). Normal rectal mucosae were stained with each dye and videos of EC images were recorded. Visibility of nuclei and gland formation after staining were evaluated as ‘recognizable’ or ‘not recognizable’. Time for each parameter to become ‘recognizable’ was measured, and the average times for the three staining regimens were compared. Results MB alone and CM double staining resulted in ‘recognizable’ (102 ± 27 vs 89 ± 22 s, P = 0.263) nuclei within comparable periods of time, whereas CV alone was unable to identify nuclei. Gland formation became ‘recognizable’ sooner after CM double staining than after MB alone (61 ± 16 vs 108 ± 24 s, P

Kenichi Takeda,1 Yuji Kawasaki,2 Kazumasa Yoshida,3 Yoji Nishida,3 Tomoya Harada,1 Kosuke Yamaguchi,2 Shizuka Ito,1 Kiyoshi Hashimoto,1 Shingo Matsumoto,1 Akira Yamasaki,1 Tadashi Igishi,1 Eiji Shimizu1 1Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Japan; 2Department of Regional Medicine, Faculty of Medicine, Tottori University, Yonago, Japan; 3Department of Rehabilitation Medicine, Yoka Hospital, Yabu, Japan Background: Upper-extremity exercise is for pulmonary rehabilitation. The 6-minute pegboard and ring test (6PBRT) was developed to evaluate arm exercise capacity in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to characterize the 6PBRT and evaluate its relationship with upper-extremity activities of daily living (ADLs) in COPD patients. Methods: Twenty outpatients with mild to very severe COPD underwent the 6PBRT and spirometry, and their maximal inspiratory and expiratory pressures and grip strength were measured. For the 6PBRT, subjects were asked to move as many rings as possible in 6 minutes, and the score was the number of moved rings during the 6-minute period. Upper-extremity ADLs were evaluated with the upper extremity activities subdomain of the modified Pulmonary Functional Status and Dyspnea Questionnaire. Upper-extremity ADLs were also measured objectively by using a wrist accelerometer every day for 1 week. Results: There was a positive correlation between 6PBRT score and inspiratory capacity (r = 0.71, P < 0.001), inspiratory capacity/total lung capacity predicted (r = 0.68, P < 0.01), and forced vial capacity (r = 0.57, P < 0.01). There was also a positive correlation between 6PBRT score and accelerometer count (r = 0.54, P < 0.05) and a negative correlation between 6PBRT score and arm activity score (ρ = -0.49, P < 0.05). Conclusion: The 6PBRT may be a predictive test to maintain and improve upper-extremity ADL during pulmonary rehabilitation in patients with COPD. Keywords: pulmonary rehabilitation, inspiratory capacity, COPD, wrist accelerometer, modified Pulmonary Functional Status and Dyspnea Questionnaire

SMARCA4-deficient thoracic sarcoma is a recently proposed new entity of soft tissue sarcomas with an undifferentiated round cell morphology that is diagnostically challenging. Here we report a case of this tumor where the diagnosis was established using limited samples and resources. A woman in her early 30s developed two intrathoracic masses. Biopsies for these lesions showed sheets of undifferentiated round/rhabdoid cells that retained SMARCB1 expression. Further analysis revealed a reduced SMARCA4 expression and a complete loss of SMARCA2 expression in tumor cells. Subsequent Sanger sequencing identified a nonsense c.1546A>T (p.516Lys>Ter) mutation in SMARCA4 and confirmed the diagnosis. Our case highlighted clinicopathological correlation and rational use of tissue sections for immunohistochemistry may enable to diagnose this tumor even when only limited samples are available. Recognition of this new entity is important for further understanding of the disease and the future development of specific therapies.

Background and aim: Permeation of a vein or lymphatic vessel by a tumor is a key risk factor for lymph node metastasis. We examined the features of colorectal tumor vessel permeation using endocytoscopy, an ultra-high magnifying endoscopic system combined with a narrow-band imaging capability (EC-NBI). Patients and methods: We examined 188 colorectal lesions using EC-NBI before treatment was started. We measured the diameters of tumor vessels on EC-NBI images. We used the tumor vessel diameter (the mean diameter of four tumor-associated vessels) and the variation in tumor vessel caliber (the difference between the maximum and minimum diameters of the vessels expressed as a proportion) to judge changes in vessel formation. We examined the relationship between these variables and the extent of venous or lymphatic vessel permeation (vessel invasion) established by immunohistochemical examination of the resected specimen using monoclonal antibodies against the CD34 and D2 – 40 antigens. We also analyzed the relationships between tumor vessel diameter, tumor vessel caliber variation, and depth of tumor invasion. Results: There were significant differences in tumor vessel diameter and caliber variation between tumors in situ and T1 – T3 carcinomas. In T1 carcinomas, larger tumor vessel diameter and greater tumor vessel caliber variation were significantly associated with venous permeation. In T2 and T3 carcinomas, greater tumor vessel caliber variation was significantly associated with venous permeation. Conclusions: The vessel diameter and caliber variation of colorectal tumor microvasculature are associated with depth of invasion and venous permeation, especially in T1 carcinomas.

A 60-year-old man was diagnosed as multiple hepatic abscesses. Failure in the first empiric therapy led to extension into the pericardium, causing acute cardiac tamponade. Actinomyces species were not cultured from the pericardial effusion. The definitive diagnosis was acquired by ultrasound guided needle biopsy.

Objective : Health-care associated pneumonia (HCAP) is a new category of pneumonia. We investigated differences of epidemiology, pathogens, and outcomes be- tween HCAP patients in large hospitals and those in small hospitals. Methods : This was a retrospective observational study of patients hospitalized with HCAP from December 2009 to March 2010. HCAP was defined according to ATS/IDSA criteria. A large hospital was defined as 200 beds and a small hospital was 200 beds. Results : Of 117 patients, 61 patients were admitted to large hospitals and 56 patients were admitted to small hospitals. There was a significant difference of HCAP diagnostic criteria between the two groups. The A-DROP severity class was worse in the large hospital group than the small hospital group (P 0.05). Respiratory failure and disturbance of consciousness were more frequent in the large hospital group (P 0.05). The mortality rate was 8.2% n the large hospital group versus 1.8% in the small hospital group. Patients in the very severe A-DROP class had a high mortality rate of 33% in both groups. Conclusion : Patients with severe HCAP were more likely to be admitted to large hospitals. Patients in the very severe A-DROP class should receive intensive antibiotic therapy, but not all patients need broad-spectrum therapy. J. Med. Invest. 58 : 67-74, February, 2011

A 69-year-old woman with a history of cervical cancer was admitted to our hospital for further investigation of abnormal shadows on her chest roentgenogram. Histologic examination of transbronchial lung biopsy specimens revealed epithelioid cell granuloma, and Mycobacterium intracellulare was detected in the bronchial lavage fluid. The plasma level of (1→3)-beta-d-glucan was very high, and this elevated level was attributed to administration of sizofiran for treatment of cervical cancer 18 years previously. Therefore, in patients with cervical cancer, it is important to confirm whether or not sizofiran has been administered before measuring (1→3)-beta-d-glucan levels.

Background Computer-aided diagnosis (CAD) for colonoscopy may help endoscopists distinguish neoplastic polyps (adenomas) requiring resection from nonneoplastic polyps not requiring resection, potentially reducing cost. Objective To evaluate the performance of real-time CAD with endocytoscopes (×520 ultramagnifying colonoscopes providing microvascular and cellular visualization of colorectal polyps after application of the narrow-band imaging [NBI] and methylene blue staining modes, respectively). Design Single-group, open-label, prospective study. (UMIN [University hospital Medical Information Network] Clinical Trial Registry: UMIN000027360). Setting University hospital. Participants 791 consecutive patients undergoing colonoscopy and 23 endoscopists. Intervention Real-time use of CAD during colonoscopy. Measurements CAD-predicted pathology (neoplastic or nonneoplastic) of detected diminutive polyps (≤5 mm) on the basis of real-time outputs compared with pathologic diagnosis of the resected specimen (gold standard). The primary end point was whether CAD with the stained mode produced a negative predictive value (NPV) of 90% or greater for identifying diminutive rectosigmoid adenomas, the threshold required to "diagnose-and-leave" nonneoplastic polyps. Best- and worst-case scenarios assumed that polyps lacking either CAD diagnosis or pathology were true- or false-positive or true- or false-negative, respectively. Results Overall, 466 diminutive (including 250 rectosigmoid) polyps from 325 patients were assessed by CAD, with a pathologic prediction rate of 98.1% (457 of 466). The NPVs of CAD for diminutive rectosigmoid adenomas were 96.4% (95% CI, 91.8% to 98.8%) (best-case scenario) and 93.7% (CI, 88.3% to 97.1%) (worst-case scenario) with stained mode and 96.5% (CI, 92.1% to 98.9%) (best-case scenario) and 95.2% (CI, 90.3% to 98.0%) (worst-case scenario) with NBI. Limitation Two thirds of the colonoscopies were conducted by experts who had each experienced more than 200 endocytoscopies; 186 polyps not assessed by CAD were excluded. Conclusion Real-time CAD can achieve the performance level required for a diagnose-and-leave strategy for diminutive, nonneoplastic rectosigmoid polyps. Primary funding source Japan Society for the Promotion of Science.

In July 2009, a 69-year-old man was admitted to our hospital because an abnormal chest shadow had been noted on medical examination. Chest radiography and computed tomography showed mediastinal and bilateral hilar lymphadenopathy. Bronchoalveolar lavage fluid (BALF) from the right B(5) revealed an increased CD4/CD8 ratio. Histological examination of the biopsy specimens obtained from the tumor in the left upper bronchus revealed small cell lung cancer, whereas examination of the specimens obtained from the left B(3) revealed noncaseating epithelioid cell granulomas containing giant cells, confirming the diagnosis of sarcoidosis. The patient underwent chemotherapy with carboplatin and etoposide without any steroids. After 4 courses of chemotherapy, bronchoscopic examination revealed that the tumor had shrunk, and the BALF CD4/CD8 ratio had decreased; further, no histological evidence of sarcoidosis was seen in specimens obtained from the left B(3). Concomitant small cell lung cancer and sarcoidosis is rare. Interestingly, cancer chemotherapy might improve pulmonary sarcoidosis.