Validation and comparison of prognostic scoring systems in patients with head and neck squamous cell carcinoma treated with nivolumab.

OBJECTIVE: Several scoring systems have been developed to predict prognosis in patients with refractory cancer. We aimed to validate eight scoring systems and determine the best method for predicting the prognosis of head and neck squamous cell carcinoma treated with nivolumab. METHODS: This multicentre retrospective study involved 154 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with nivolumab between 2017 and 2020. Oncological outcomes were assessed according to the scoring systems, including MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scores. Objective response, overall survival and progression-free survival were evaluated using logistic regression and Cox proportional hazards analyses. Receiver operating curve analysis was used to calculate the area under the curve and estimate the efficacy of each score. RESULTS: No significant associations were found between the responses and any score. Seven of the eight scoring systems were associated with disease control (odds ratio, 0.26-0.70). Amongst the eight scoring systems, MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio showed the highest area under the curve for predicting response and disease control. Seven scoring systems were prognostic factors for progression-free survival (hazard ratio, 1.22-1.95). All eight scoring systems were prognostic factors for overall survival (hazard ratio, 1.62-3.83). According to the time-dependent receiver operating characteristics analysis for overall survival, the Hammersmith scoring system had the best predictive ability at 3 months, and the MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio scoring system had the highest area under the curve between 6 and 24 months. CONCLUSIONS: MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scoring systems were better predictors of prognosis in patients with head and neck squamous cell carcinoma treated with nivolumab.

Simultaneous presentation and resection of esophageal cancer and metastasis to the pancreas: Α case report and literature review.

The frequency of metastasis to the pancreas is limited, and the frequency of metastasis of a squamous cell carcinoma of the esophagus is limited even further. The curative resection of this type of metastatic lesion has been reported for some patients; however, the survival benefit that can be attributed to these procedures has not yet been clearly determined. The patient examined in the present study was a 54-year-old man who was diagnosed with a lower thoracic esophageal cancer. Computed tomography revealed a 2-cm tumor at the tail of the pancreas. Since no other obvious distal metastases were observed, the patient underwent simultaneous surgical procedures, excising the esophageal squamous cell carcinoma and the pancreatic metastasis. A histopathological examination confirmed squamous cell carcinoma in both specimens. The patient has been free of disease for 9 months since the resection. A literature review of all relevant cases to date also demonstrated that the primary tumor site in all cases of patients with esophageal cancer presenting with metastasis to the pancreas was the lower thoracic esophagus. Complete simultaneous resections of esophageal squamous cell carcinoma and a solitary metastasis to the pancreas is beneficial and may produce favorable outcomes. However, due to the reduced number of corresponding reports, further studies are required for the confirmation of the benefits of surgery.

Osteopontin secreted from obese adipocytes enhances angiogenesis and promotes progression of pancreatic ductal adenocarcinoma in obesity.

PURPOSE: Obesity is a risk factor and poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms remain unclear. METHODS: PDAC cells and obese visceral adipocytes (O-Ad) derived from mice and humans were used to analyze interactions between the two cell types, and human microvascular endothelial cells were used for angiogenesis assay. A xenograft mouse model with subcutaneously injected PDAC cells was used for animal studies. The relationship between visceral fat and prognosis was analyzed using resected tissues from PDAC patients with and without obesity. RESULTS: Conditioned media (CM) from O-Ad significantly increased PDAC cell growth and migration and angiogenic capacity in both human and mice cells, and blocking osteopontin (OPN) in O-Ad canceled O-Ad-induced effects in both mouse and human cells. In addition, O-Ad directly increased the migratory and tube-forming capacities of endothelial cells, while blocking OPN canceled these effects. O-Ad increased AKT phosphorylation and VEGFA expression in both PDAC and endothelial cells, and OPN inhibition in O-Ad canceled those O-Ad-induced effects. In the xenograft model, PDAC tumor volume was significantly increased in obese mice compared with lean mice, whereas blocking OPN significantly inhibited obesity-accelerated tumor growth. OPN expression in adipose tissues adjacent to human PDAC tumor was significantly higher in obese patients than in non-obese patients. In PDAC patients with obesity, high OPN expression in adipose tissues was significantly associated with poor prognosis. CONCLUSION: Obese adipocytes trigger aggressive transformation in PDAC cells to induce PDAC progression and accelerate angiogenesis via OPN secretion.

3-Fr microcatheter-assisted endoscopic ultrasound-guided rendezvous technique with a 22-gauge needle and a 0.018-inch guidewire for difficult biliary cannulation.

Endoscopic ultrasound-guided rendezvous with a 22-gauge needle and a 0.018-inch guidewire, assisted by a 3-Fr microcatheter, effectively addresses challenges in biliary cannulation, improving guidewire manipulation and reducing risks of injury and leakage. Natsume and colleagues describe the successful extraction of common bile duct stones to demonstrate the efficacy of this technique.

Relationship between pulmonary blood flow and volume following lung resection using dynamic perfusion digital radiography.

Background: Surgical intervention for lung resection can cause ventilation-perfusion mismatches and affect gas exchange; however, minimally invasive assessment of blood flow is difficult. This study aimed to evaluate changes in pulmonary blood flow after radical lung cancer surgery using a minimally invasive dynamic digital chest radiography system. Methods: We evaluated 64 patients who underwent radical lobectomies. Postoperative changes in pulmonary blood flow, assessed using dynamic chest radiography-based blood flow ratios (BFRs), were compared with the temporal evolution of both functional lung volumes (FLVs) and estimated lung weight (ELW) derived from computed tomography (CT) volumetry. Results: FLVs on the affected side gradually recovered over time from the lowest value observed 3 months after surgery in all procedures. BFRs on the affected side also showed a gradual recovery from the lowest value 1 month after surgery, except for left upper lobectomies (LULs). In LULs, FLVs and ELWs increased proportionally up to 3 months after surgery, with lung volumes continuing to increase thereafter. The recovery of BFRs differed depending on the resected lobe. Conclusions: A relationship between pulmonary blood flow and FLV was observed in the postoperative period. Despite varying compensatory responses depending on the surgical procedure, FLV recovery coincided with increased pulmonary blood flow.

Dual role of autotaxin as novel biomarker and therapeutic target in pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target.

Histological diagnosis of polyploidy discriminates an aggressive subset of hepatocellular carcinomas with poor prognosis.

BACKGROUND: Although genome duplication, or polyploidization, is believed to drive cancer evolution and affect tumor features, its significance in hepatocellular carcinoma (HCC) is unclear. We aimed to determine the characteristics of polyploid HCCs by evaluating chromosome duplication and to discover surrogate markers to discriminate polyploid HCCs. METHODS: The ploidy in human HCC was assessed by fluorescence in situ hybridization for multiple chromosomes. Clinicopathological and expression features were compared between polyploid and near-diploid HCCs. Markers indicating polyploid HCC were explored by transcriptome analysis of cultured HCC cells. RESULTS: Polyploidy was detected in 36% (20/56) of HCCs and discriminated an aggressive subset of HCC that typically showed high serum alpha-fetoprotein, poor differentiation, and poor prognosis compared to near-diploid HCCs. Molecular subtyping revealed that polyploid HCCs highly expressed alpha-fetoprotein but did not necessarily show progenitor features. Histological examination revealed abundant polyploid giant cancer cells (PGCCs) with a distinct appearance and frequent macrotrabecular-massive architecture in polyploid HCCs. Notably, the abundance of PGCCs and overexpression of ubiquitin-conjugating enzymes 2C indicated polyploidy in HCC and efficiently predicted poor prognosis in combination. CONCLUSIONS: Histological diagnosis of polyploidy using surrogate markers discriminates an aggressive subset of HCC, apart from known HCC subgroups, and predict poor prognosis in HCC.

Theoretical step approach with 'Three-pillar' device assistance for successful endoscopic transpapillary gallbladder drainage.

BACKGROUND: Endoscopic transpapillary gallbladder drainage (ETGBD) has been reported as an alternative procedure for acute cholecystitis but remains a challenging procedure. AIMS: To elucidate the efficacy of a strategic approach for ETGBD that utilizes a four-step classification system and the optional use of 'Three-pillar' assistance with the following devices: cholangioscopy (SpyGlass DS, SG), a flex-type guidewire (Flex-GW), and a 3-Fr microcatheter (3-Fr Micro). METHODS: A total of 115 patients undergoing ETGBD were studied retrospectively. Characteristics and technical outcomes were compared between conventional ETGBD technique (Classical ETGBD, N = 50) and strategic ETGBD with optional Three-pillar assistance (Strategic ETGBD, N = 65). RESULTS: SG-assistance (15/65, 23.1%) was as an excellent troubleshooter in Category 1 (failure to identify the cystic duct [CD] orifice) and Category 2 (failure to advance the GW across the CD takeoff due to unfavorable angle). Flex-GW (19/65, 29.2%) worked for Category 3b (failure of GW access to the GB due to multiple tortuosities). 3-Fr Micro (11/65, 16.9%) was effective for Category 3a (failure of GW access to the GB due to CD obstruction) and Category 4 (failure of drainage stent insertion to the GB). The overall technical success rate was significantly higher for Strategic ETGBD (63/65, 96.9%) compared with Classical ETGBD (36/50, 72.0%) (p = 0.0001). CONCLUSIONS: Strategic ETGBD, which includes the Three-pillar assistance options of SG in the initial steps, Flex-GW for tortuous CD, and 3-Fr Micro for stenotic CD, achieved a significantly higher success rate than for Classical ETGBD.

Concomitant Pancreatic Ductal Adenocarcinoma and Type 1 Autoimmune Pancreatitis: A Potential Issue in the Diagnosis of Carcinoma by Endoscopic Ultrasound-guided Fine-needle Biopsy.

We herein report a 64-year-old man with concomitant pancreatic ductal adenocarcinoma (PDAC) and type 1 autoimmune pancreatitis (AIP). An endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) from the pancreatic head mass revealed level 2 histology of AIP and atypical glands. We diagnosed definitive focal AIP using the clinical diagnostic criteria. Computed tomography revealed that the pancreatic mass had not been reduced by steroid therapy. Surgery was performed after a histological PDAC diagnosis was made via a transpapillary biliary biopsy. The resected specimen revealed PDAC associated with AIP. It is important to consider the cooccurrence of PDAC and AIP even if the histological diagnosis via an EUS-FNB is AIP.

Long-Term Impact of Endoscopic Gallbladder Stenting for Calculous Cholecystitis in Poor Surgical Candidates: A Multi-center Comparative Study.

BACKGROUND: Although long-term stent placement using endoscopic gallbladder stenting (EGBS) reportedly reduces cholecystitis recurrence in patients unfit to undergo cholecystectomy, its efficacy and safety remain uncertain. AIMS: This study aimed to examine the long-term effect of EGBS in poor surgical candidates of cholecystectomy. METHODS: A total of 528 high-risk surgical patients with acute calculous cholecystitis met this study's eligibility criteria. The technical success and adverse events (AE) were compared between patients who underwent EGBS and those who underwent percutaneous transhepatic gallbladder drainage (PTGBD). Elective stent exchange and removal were not performed after EGBS. The external tube was removed after improvement of cholecystitis following PTGBD. RESULTS: The technical success rate was significantly lower with EGBS compared to PTGBD (75.4% versus 98.7%, P < 0.001), while the early-AE rate did not differ significantly between the two methods (7.7% versus 4.3%, P = 0.146). The 1-, 3-, and 5-year cumulative incidence rates of cholecystitis were 3.8%, 7.2%, and 7.2% with EGBS, and 11.7%, 17.6%, and 30.2% with PTGBD, respectively (P = 0.001). Conversely, those of symptomatic late-AE (except cholecystitis) were 8.2%, 22.7%, and 31.4% with EGBS, and 7.5%, 10.9%, and 13.1% with PTGBD, respectively (P = 0.035). Thus, the 1-, 3-, and 5-year cumulative incidence of overall late-AE was 12.0%, 30.4%, and 40.4% with EGBS, and 19.2%, 28.3%, and 42.5% with PTGBD, respectively (P = 0.649). CONCLUSIONS: Long-term stent placement via EGBS is useful for preventing the recurrence of cholecystitis, but the success rate is low and the frequency of other late-AE increases with the prolongation of the indwelling period.

Clinical impact of bile-derived exosomal microRNAs as novel diagnostic and prognostic biomarkers for biliary tract cancers.

Sampling of bile juice during endoscopic retrograde cholangiopancreatography (ERCP) has potential benefit of being amenable to the identification of novel biomarkers in liquid biopsy. This study reports the results of a global investigation of exosomal microRNAs (miRNAs) in bile to identify potential biomarkers for biliary tract cancers (BTCs). Eighty-eight bile samples collected during ERCP (45 BTC and 43 noncancer control samples) were enrolled in this study. Eleven BTC samples and nine control samples were assigned as the discovery set. Exosomes in bile and serum samples were collected using a glass membrane column with size-controlled macroporous glass (MPG), and exosomal miRNA expression profiles were evaluated using comprehensive miRNA microarray analysis (3D-Gene). For validation, exosomal miRNA in the bile samples of 34 BTCs and 34 controls were comprehensively evaluated using 3D-Gene. In the discovery set, eight exosomal miRNAs in bile were identified as significant aberrant expression markers, while no miRNA with aberrant expression in serum was identified. In a comparison of the discovery and validation sets, miR-451a and miR-3619-3p were identified as reproducible upregulated markers, and the combination of the two bile miRNAs showed an excellent area under the curve (0.819) value for diagnosing BTCs. In addition, high miR-3619-3p expression in bile reflects poorer prognosis of BTCs (hazard ratio = 2.89). The MPG-extracted exosomal miRNAs in bile aspirated during ERCP provide a convenient new approach for diagnosing biliary diseases. Bile-derived miRNA analysis with miR-451a and miR-3619-3p represents a potentially valuable diagnostic strategy for identifying BTCs as well as a predictive indicator of BTC prognosis.

Urolithin A targets the AKT/WNK1 axis to induce autophagy and exert anti-tumor effects in cholangiocarcinoma.

Urolithin A (UA; 3,8-dihydroxybenzo[c]chromen-6-one), a metabolite generated by intestinal bacteria during the biotransformation of ellagitannins, has gained considerable attention in treating several cancers. Cholangiocarcinoma (CCA) remains one of the most lethal cancers; it grows in a special environment constantly exposed to both blood and bile. Since UA is known to undergo enterohepatic recirculation, we hypothesized that UA might have significant antitumor effects in CCA. Here, we investigated the therapeutic potential of UA in CCA and aimed to elucidate its mechanisms, including autophagy. UA treatment inhibited cell proliferation and induced G2/M phase cell cycle arrest in CCA cells. UA also suppressed cell migration and invasion, but did not cause apoptosis. Furthermore, Western blotting and immunocytochemistry demonstrated increased LC3-II accumulation, while electron microscopy demonstrated induced autophagosomes after UA treatment, suggesting that UA upregulated autophagy in CCA cells. In xenograft mice treated with UA, tumor growth was inhibited with increased LC3-II levels. On the other hand, phospho-kinase array demonstrated downregulation of the AKT/WNK1 pathway. LC3-II expression was elevated in WNK1 knocked down cells, indicating that WNK1 is the key signal for regulating autophagy. Thus, UA exerted antitumor effects by suppressing the AKT/WNK1 signaling pathway and inducing autophagy. In conclusion, UA, a natural, well-tolerated compound, may be a promising therapeutic candidate for advanced CCA.

Use of Endoscopic Scraper and Cell Block Technique as a Replacement for Conventional Brush for Diagnosing Malignant Biliary Strictures.

Histological evidence is essential for diagnosing malignant biliary strictures. However, conventional brush cytology remains the primary method used worldwide, despite its low diagnostic sensitivity and accuracy, as it is technically easy, rapid, and cost-effective. The aim of this study was to evaluate the diagnostic performance of a recently introduced endoscopic scraper, the simplicity of which is comparable to that of a conventional brush, by comparing diagnostic yields and the number of collected cells. The sensitivity of the endoscopic scraper when using the cell block technique was significantly higher than when using brush cytology or a brush with the cell block technique (53.6% vs. 30.9%, p < 0.001; 53.6% vs. 31.6%, p = 0.024, respectively). Quantitative digital image analysis of cell block sections revealed that the median number of cells obtained with the endoscopic scraper was significantly higher than when using the brush (1917 vs. 1014 cells, p = 0.042). Furthermore, seven cases (8.3%; 7/84) were diagnosed by immunohistochemical analysis of the cell block section obtained from the endoscopic scraper. Given its simplicity and greater capacity for sample acquisition, use of the endoscopic scraper in conjunction with the cell block technique could replace brush cytology for the histological diagnosis of malignant biliary strictures.

Promoting endoscopists' health through cutting-edge motion analysis technology: Accuracy and precision of ergonomic motion tracking system for endoscopy suite (EMTES).

OBJECTIVES: Endoscopists often suffer from musculoskeletal disorders due to posture-specific workloads imposed by precise maneuvering or long procedural duration. An ergonomic motion tracking system for endoscopy suite (EMTES) was developed using Azure Kinect sensors to evaluate the occlusion, accuracy, and precision, focusing mainly on upper and lower limb movements. METHODS: Three healthy male participants pointed the prescribed points for 5 s on the designated work envelopes and their coordinates were measured. The mean occlusion rate (%) of the 32 motion tracking landmarks, standard deviation (SD) of distance and orientation, and partial regression coefficient (ß) and R2 model fit for accuracy were calculated using the time series of coordinates data of the upper/lower limb movements. RESULTS: The mean occlusion rate was 5.2 ± 10.6% and 1.6 ± 1.4% for upper and lower limb movements, respectively. Of the 32 landmarks, 28 (87.5%) had occlusion rates of 10% or less. The mean SDs of 4.2 mm for distance and 1.2° for orientation were found. Most of the R2 values were over 0.9. In the case of right upper/lower limb measurement for orientation, ß coefficients ranged from 0.82 to 1.36. CONCLUSION: EMTES is reliable in calculating occlusion, precision, and accuracy for practical motion-tracking measurements in endoscopists.