Risk factors and prognosis for supraclavicular lymph node metastasis in patients with thoracic esophageal cancer. Distant or regional metastasis?

We aimed to determine the frequency and prognosis of supraclavicular (#104) lymph node (LN) metastasis compared with other LN stations in patients with advanced thoracic esophageal cancer and to identify risk factors for metastasis to delineate the indications for three-field lymphadenectomy (3FL). The study cohort of 567 eligible patients with esophageal cancer had undergone subtotal esophagectomy from 2003 to 2020. LN metastasis was defined as pathologically proven metastasis or positron emission tomography-positive LNs. The efficacy index (EI), calculated from the frequency of LN metastases and survival rates, was used as prognostic value of each LN station dissection for patient survival. Risk factors for #104 LN metastasis were determined by multivariable logistic regression. The frequency of #104 LN metastasis was 11.6% overall, 31.7% in upper and 8.3% in middle/lower third lesion. Neoadjuvant chemotherapy was administered to 71% of patients and chemo-radiation to 11%. The 5-year overall survival was 45.8%. The EI for #104 LNs (5.3) was similar to that for #101 LNs. Risk factors were age < 65 years, upper third lesion, clinical N2-3, #101/106rec LN metastasis and poorly differentiated carcinoma. The 5-year overall survival of patients with middle/lower lesions was 38% (EI 3.1), similar to that for #101 and #8/9/11 LNs. The prognosis of patients with #104 LN metastases is similar to that of patients with metastases in other regional LN stations. Therefore, we recommend 3FL exclusively for patients at a high risk of #104 LN metastasis due to the overall metastatic rate not being high.

Utility of Initial Tumor Reduction as a Prognostic Factor in Esophageal Squamous Cell Cancer Patients Undergoing Neoadjuvant Chemotherapy Followed by Surgery : A Retrospective Cohort Study.

BACKGROUND: While a neoadjuvant chemotherapy regimen using docetaxel, cisplatin, and 5-fluorouracil (NAC-DCF) is considered the standard treatment for locally advanced esophageal cancer (EC) in Japan, a reliable marker for early prediction of treatment efficacy remains unclear. We investigated the utility of the tumor response after a first course of NAC-DCF as a post-surgery survival predictor in patients with EC. METHODS: We enrolled 150 consecutive patients who underwent NAC-DCF followed by surgery for EC between September 2009 and January 2019. The initial tumor reduction (ITR), defined as the percentage decrease in the shorter diameter of the tumor after the first course of NAC-DCF, was evaluated using computed tomography. We analyzed the relationship between ITR, clinicopathological parameters, and survival. RESULTS: The median ITR was 21.07% (range -11.45 to 50.13%). The optimal cut-off value for ITR for predicting prognosis was 10% (hazard ratio [HR] 3.30, 95% confidence interval [CI] 1.98-5.51), based on univariate logistic regression analyses for recurrence-free survival (RFS). Compared with patients with ITR <10%, patients with ITR ≥10% showed a significantly higher proportion of ypM0 (80.0% vs. 92.5%) and responders in terms of overall clinical response (50.0% vs. 80.8%). Multivariate analysis for RFS revealed that ypN2-3 (HR 2.78, 95% CI 1.67-4.62), non-response in terms of overall clinical response (HR 1.87, 95% CI 1.10-3.18), and ITR <10% (HR 2.48, 95% CI 1.42-4.32) were independent prognostic factors. CONCLUSIONS: Tumor response after the first course of NAC-DCF may be a good predictor of survival in patients with EC who underwent NAC-DCF plus surgery.

Surgical tips and tricks for laparoscopic intragastric surgery for submucosal tumors relative to the esophagogastric junction.

Recent reports have described the practicality of laparoscopic intragastric surgery (l-IGS) as an alternative for resecting submucosal tumors (SMTs) near the esophagogastric junction (EGJ), where excision using an exogastric approach would be difficult. However, even using IGS to perform a full-thickness resection of SMTs that are in or extremely close to the EGJ is very difficult to do safely and avoid disrupting or causing stenosis of the EGJ, without advanced experience. This study retrospectively examined the usefulness of l-IGS for gastric SMTs located in or extremely close to the EGJ. Fourteen patients with gastric SMTs < 2 cm of the EGJ and underwent l-IGS were eligible for this study. We examined the tumor location, operative time, intraoperative hemorrhage, degree of deformation, gastroesophageal reflux disease, perioperative complications, and recurrence. Furthermore, we compared patients with tumors in the EGJ with those with tumors near the EGJ and patients in whom three-port l-IGS was performed with those who underwent single-incision laparoscopic surgery. The average tumor size, operative time, intraoperative hemorrhage, and postoperative hospitalization of the 14 patients were 30.9 ± 21.3 mm, 125.2 ± 31.1 min, 30.7 ± 103.3 mL, and 9.2 ± 3.1 d, respectively. No differences in these parameters according to the type of l-IGS or tumor location were observed. All patients underwent l-IGS without complications and were free from EGJ deformation or esophagitis. We believe that l-IGS is useful for gastric SMTs located < 2 cm of the EGJ as it can be safely performed for difficult tumor locations and does not cause deformation of the EGJ.

Efficacy of palliative surgery for gastric cancer patients with peritoneal metastasis who still have residual peritoneal dissemination after chemotherapy.

PURPOSE: Gastric cancer patients with peritoneal metastasis (PM) are generally treated with systemic chemotherapy. When PM has disappeared because of chemotherapy, radical gastrectomy (so-called conversion surgery) is usually performed. We have previously reported the efficacy of conversion surgery, but there are no reports examining the efficacy of palliative gastrectomy for patients with residual PM after chemotherapy. The purpose of this study was to investigate the efficacy of palliative surgery for gastric cancer patients with PM who still have residual peritoneal dissemination after chemotherapy. METHODS: Twenty-five gastric cancer patients with PM confirmed by laparoscopy and who had received chemotherapy but who still had residual PM were included in this study. Among the 25 patients, palliative surgery was performed in 20 patients (PS group) and chemotherapy was continued in 5 patients (CTx group), and their therapeutic outcomes were compared. RESULTS: In the PS group, total and distal gastrectomies were performed. Clavien-Dindo grade I postoperative complications occurred in two patients (10%). There were no treatment-related deaths. Postoperative chemotherapy was performed all cases. In the PS group, the median survival time (MST) reached 22.5 months, with 1- and 2-year overall survival (OS) rates of 95% and 45%, respectively, whereas in the CTx group, the MST was 15.8 months, and the 1- and 2-year OS rates were 60% and 0%, respectively. The PS group had significantly longer OS than the CTx group (P=0.044). CONCLUSIONS: Palliative surgery is safe and may prolong survival in gastric cancer patients with residual PM after chemotherapy.

Molecular diagnosis of 405 individuals with autism spectrum disorder.

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

Impact of Relative Dose Intensity of Docetaxel, Cisplatin, and 5-Fluorouracil Neoadjuvant Chemotherapy on Survival of Esophageal Squamous Cell Cancer Patients.

INTRODUCTION: This study aimed to clarify the impact of the average relative dose intensity (RDI) of neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-NAC) for resectable locally advanced esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: To identify the optimal RDI, recurrence-free survival (RFS) and cumulative incidence function (CIF) for recurrence were calculated in low and high RDI groups with any cut-off points. The optimal RDI was defined as the highest RDI administered with a significant increase in either RFS or CIF. The clinicopathological characteristics of the two groups divided by optimal RDI were investigated. The preoperative prognostic factors associated with RFS were confirmed by multivariable Cox proportional hazards model. RESULTS: Among the 150 eligible patients treated with DCF-NAC from 2010 to 2020, 3-year RFS and CIF were 56.3% and 37.8% in 90 patients in the less than 80% RDI group (<80% RDI) and 73.3% and 26.7% in 60 patients in the more than or equal to 80% RDI group (≥80% RDI), respectively. The optimal cut-off RDI was identified as 80%. The <80% RDI group included older individuals, a lower value of creatinine clearance, a higher Charlson Comorbidity Index, reduced RDI at first course, and grade 1-0 in the histopathological tumor response than the ≥80% RDI group. R0 resection and postoperative complication rates were equal in both groups. Cox proportional hazards model identified the response rate and RDI as predictors of RFS. CONCLUSION: An average RDI of more than or equal to 80% improved prognosis in patients receiving DCF-NAC for ESCC.

Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants.

BACKGROUND: Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size. METHODS: We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns). RESULTS: We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 "plausible" candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2. CONCLUSIONS: We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes.

Circular Stapler Method for Avoiding Stricture of Cervical Esophagogastric Anastomosis.

BACKGROUND: This study was performed to verify the superiority of a new "non-tensioning method" for avoiding stricture of the cervical esophagogastric anastomosis by circular stapling compared with the conventional method. METHODS: In total, 395 consecutive patients who underwent McKeown esophagectomy with gastric conduit (GC) reconstruction were reviewed. A 4 cm-wide GC was created and pulled up at the cervical site through the retrosternal route. The esophagogastrostomy site of the GC was planned as far caudally as possible on the greater curvature side. In the conventional technique, the stapler was fired while pulling the GC to avoid tissue slack. In the non-tensioning technique, the stapler was fired through the natural thickness of the stomach wall. The length of the blind end was changed from 4 to 2 cm in the non-tensioning technique. Anastomotic leakage and stricture formation were compared between the two techniques, and adjustment was performed using propensity score matching. RESULTS: The conventional group comprised 315 patients, and the non-tensioning group comprised 80 patients. Anastomotic leakage occurred in 22 (7%) and 2 (2.5%) patients, respectively (P = 0.134) [and in 9 (2.9%) and 2 (2.5%) patients, respectively, if leakage at the blind end was excluded]. Anastomotic stricture occurred in 92 (29.2%) and 3 (3.8%) patients, respectively (P < 0.001). The propensity score-matching analysis including 79 pairs of patients confirmed a lower stricture rate in the non-tensioning than conventional group (2.5% vs. 29.1%, P < 0.001). CONCLUSIONS: The non-tensioning technique significantly reduced the incidence of anastomotic stricture compared with the conventional technique.

Efficacy of conversion surgery after a single intraperitoneal administration of paclitaxel and systemic chemotherapy for gastric cancer with peritoneal metastasis.

PURPOSE: The prognosis of gastric cancer patients with peritoneal metastasis (PM) remains dismal with standard systemic chemotherapy. Intraperitoneal (i.p.) chemotherapy with paclitaxel (PTX) has local effects on intra-abdominal cancer cells. According to this phenomenon, we have developed regimens combining single i.p. PTX administration with systemic chemotherapy. This treatment strategy is very promising; however, the effect of "conversion surgery" in patients responding to this chemotherapy is unclear. Therefore, we performed a retrospective study to evaluate the safety and efficacy of conversion surgery for gastric cancer patients with PM. METHODS: We enrolled 52 gastric cancer patients with PM who were treated with single i.p. PTX plus systemic chemotherapy between 2005 and 2015. Conversion surgery was performed where PM was eliminated by combination chemotherapy. RESULTS: Among 52 gastric cancer patients, the disappearance of PM was confirmed in 33 patients (63.5%). Gastrectomy with D2 lymph node dissection was performed in all these patients. Histological response of grade ≥ 1b was achieved in 13 patients (39%). Clavien-Dindo grade II postoperative complications occurred in three patients (9%). There were no treatment-related deaths. The median survival time and 1-, 3-, and 5-year overall survival rates of the 33 patients who underwent conversion surgery were 30.7 months and 78.8%, 36.3%, and 24.2%, respectively, and those of the 19 patients who did not undergo surgery were 12.5 months and 52.6%, 5.2%, and 0%, respectively. CONCLUSION: Conversion surgery is safe and may prolong survival for gastric cancer patients with PM who have responded to single i.p. PTX plus systemic chemotherapy.

Phase II Adjuvant Cancer-specific Vaccine Therapy for Esophageal Cancer Patients Curatively Resected After Preoperative Therapy With Pathologically Positive Nodes; Possible Significance of Tumor Immune Microenvironment in its Clinical Effects.

OBJECTIVES: To elucidate the efficacy of adjuvant vaccine monotherapy using 3 Human Leukocyte Antigen (HLA)-A∗24-restricted tumor-specific peptide antigens for ESCC, upregulated lung cancer 10, cell division cycle associated 1, and KH domain-containing protein overexpressed in cancer 1. SUMMARY OF BACKGROUND DATA: ESCC patients with pathologically positive nodes (pN(+)) have a high risk for postoperative recurrence, despite curative resection after preoperative therapy. Subclinical micrometastases are an appropriate target for cancer vaccine. METHODS: This is a non-randomized prospective phase II clinical trial (UMIN000003557). ESCC patients curatively resected after preoperative therapy with pN(+) were allocated into the control and vaccine groups (CG and VG) according to the HLA-A status. One mg each of three epitope peptides was postoperatively injected 10 times weekly followed by 10 times biweekly to the VG. The primary and secondary endpoints were relapse-free survival (RFS) and esophageal cancer-specific survival (ECSS), respectively. RESULTS: Thirty were in the CG and 33 in the VG. No significant difference was observed in RFS between the CG and VG (5-year RFS: 32.5% vs 45.3%), but the recurrence rate significantly decreased with the number of peptides which induced antigen-specific cytotoxic T lymphocytes. The VG showed a significantly higher 5-year ECSS than the CG (60.0% vs 32.4%, P = 0.045) and this difference was more prominent in patients with CD8+ and programmed death-ligand 1 double negative tumor (68.0% vs 17.7%, P = 0.010). CONCLUSIONS: Our cancer peptide vaccine might improve the survival of ESCC patients, which is warranted to be verified in the phase III randomized controlled study.

[A Case of Sheath-Like Obstruction of the Entire Catheter in a Short Period of Time after Placement of an Intraperitoneal Access Port].

Intraperitoneal chemotherapy, in which an anticancer drug is administered directly into the abdominal cavity through an intraperitoneal access port(IP port), is one of the treatment options for advanced gastric cancer with peritoneal metastasis. Herein, we report a case of sheath-like obstruction of the entire catheter of the IP port due to tissue reaction within a short period of time after IP port implantation. The case was a 35-year-old woman with advanced type 4 gastric cancer with peritoneal dissemination. The IP port was placed and intravenous and intraperitoneal chemotherapy using S-1 plus paclitaxel was started. However, in the middle of the second course, the entire catheter was covered with a fibrous capsule and a sheath-like obstruction occurred, so the IP port was removed and a new IP port was reinserted. One of the IP port troubles is obstruction, but such short-term and special obstruction is rare, and the cause is considered to be a foreign body reaction of the catheter.

Comparison of Aggressive Planned Salvage Surgery Versus Neoadjuvant Chemoradiotherapy Plus Surgery for Borderline Resectable T4 Squamous Cell Carcinoma.

INTRODUCTION: We compare planned salvage surgery after definitive chemoradiotherapy (SALV) versus neoadjuvant chemoradiotherapy plus surgery (NCRS) for borderline resectable T4 esophageal squamous cell carcinoma. PATIENTS AND METHODS: A total of 37 patients underwent planned SALV, and 20 underwent NCRS from 2004 to 2017. The short-term outcome measures were the R0 resection rate, complications, and treatment-related mortality. The long-term outcome measures were the 5-year overall survival rate and causes of death. RESULTS: R0 resection rate was similar between the SALV and NCRS groups (81% versus 85%). The incidence of postoperative pneumonia (35% versus 18%) and treatment-related mortality rate (9% versus 0%) tended to be higher in the SALV. ypT grade 2-3 (65% versus 30%, p = 0.012) and Clavien-Dindo grade ≥ IIIb complications (32% versus 0%, p = 0.008) were significantly more frequent in the SALV group. The groups had similar 5-year overall survival (26% versus 27%). The causes of death in the SALV and NCRS groups were primary esophageal cancer in 35% and 55% of patients, respectively, and pulmonary-related mortality in 24% and 5%, respectively. Multivariable Cox regression analysis revealed the following significant poor prognostic factors: stable disease as the clinical response, preoperative body mass index (BMI) of < 18.5 kg/m2, ypN stage 1-3, and R1-2 resection. CONCLUSIONS: SALV was associated with a higher incidence of late pulmonary-related mortality but had a stronger antitumor effect than NCRS. Consequently, the survival rate was similar between the groups. Surgery is recommended for patients with a partial response and preoperative BMI of ≥ 18.5 kg/m2.

A comparative study of the lengths of different reconstruction routes used after thoracic esophagectomy.

BACKGROUND: A challenge in esophageal reconstruction after esophagectomy is that the distance from the neck to the abdomen must be replaced with a long segment obtained from the gastrointestinal tract. The success or failure of the reconstruction depends on the blood flow to the reconstructed organ and the tension on the anastomotic site, both of which depend on the reconstruction distance. There are three possible esophageal reconstruction routes: posterior mediastinal, retrosternal, and subcutaneous. However, there is still no consensus as to which route is the shortest. METHODS: The length of each reconstruction route was retrospectively compared using measurements obtained during surgery, where the strategy was to pull up the gastric conduit through the shortest route. The proximal reference point was defined as the left inferior border of the cricoid cartilage and the distal reference point was defined as the superior border of the duodenum arising from the head of the pancreas. RESULTS: This study involved 112 Japanese patients with esophageal cancer (102 men, 10 women). The mean distances of the posterior mediastinal, retrosternal, and subcutaneous routes were 34.7 ± 2.37 cm, 32.4 ± 2.24 cm, and 36.3 ± 2.27 cm, respectively. The retrosternal route was significantly shorter than the other two routes (both p < 0.0001) and shorter by 2.31 cm on average than the posterior mediastinal route. The retrosternal route was longer than the posterior mediastinal route in only 5 patients, with a difference of less than 1 cm. CONCLUSION: The retrosternal route was the shortest for esophageal reconstruction in living Japanese patients.

A novel method of esophagogastrostomy by overlap anastomosis with placement of the remnant stomach into the lower mediastinum after laparoscopic proximal gastrectomy.

INTRODUCTION: Control of postoperative gastroesophageal reflux (GER) is a critical consideration for patients who undergo proximal gastrectomy. This report describes a new and simple reconstruction method by esophagogastrostomy with placement of the remnant stomach into the lower mediastinum (EG-PRIME). This approach not only suppresses postoperative GER, but it can also be easily performed by total laparoscopy. Detailed herein are the methods for EG-PRIME and the results for three patients with cancer of the upper gastric body. MATERIALS AND SURGICAL TECHNIQUE: At the start of the EG-PRIME surgical procedure, a pseudo-fornix and lozenge-shaped gastric conduit were made by cutting the stomach diagonally. Next, the pseudo-fornix was inserted into the esophageal hiatus to form a new angle of His. Then overlap anastomosis was performed and the entry site was closed longitudinally. The outcomes assessed were operative time, intraoperative blood loss, postoperative complications and GER according to 24-hour pH monitoring. DISCUSSION: The operative times were 339, 288 and 236 minutes; in two patients, intraoperative blood loss was 260 and 343 mL, and in the third, blood loss was minimal. No postoperative complications were observed in any of the three patients. The degree of the GER resulting in fraction time pH<4 was 9.0%, 0.3%, and 2.9%, respectively. No esophagitis by upper gastrointestinal endoscopy was observed in any patient. This EG-PRIME method was technically feasible for reconstruction after proximal gastrectomy by total laparoscopy. This approach may be as simple and useful as esophagogastrostomy for preventing postoperative GER, but more experience with this method is required.

Controlling lymph node micrometastases by neoadjuvant chemotherapy affects the prognosis in advanced esophageal squamous cell carcinoma.

PURPOSE: The purpose of this study is to determine the clinical significance of micrometastases after neoadjuvant chemotherapy (NAC) and the difference in controlling micrometastases using different NAC regimens in resectable advanced esophageal squamous cell carcinoma (ESCC). METHODS: We analyzed patients with ESCC who underwent esophagectomy with lymph node dissection after NAC with Adriamycin + cisplatin + 5-fluorouracil (ACF) or docetaxel + cisplatin + 5-fluorouracil (DCF). Micrometastasis was defined as a single isolated cancer cell or cluster of cancer cells on the cervical, recurrent nerve, or abdominal LNs as shown by immunohistochemical staining with anti-cytokeratin antibody (AE1/AE3). The associations between micrometastases, recurrence, prognosis, and regimen differences were investigated. RESULTS: One hundred and one cases (ACF group: 51 cases; DCF group: 50 cases) were analyzed. Micrometastases occurred in 24 patients (23.8%): 17/51 (33.3%) in the ACF group and 7/50 (13.5%) in the DCF group (p = 0.0403). The 5-year recurrence-free survival (RFS) rates for patients without (n = 77) and with (n = 24) micrometastases were 62 and 32%, respectively, (hazard ratio, 2.158; 95% confidence interval, 1.170-3.980; stratified log-rank test, p = 0.0115). A multivariate analysis showed that stage pN1 or higher and micrometastases were significant risk factors affecting RFS. CONCLUSION: In resectable advanced ESCC, controlling micrometastases in the LNs after NAC varied by regimen and may be associated with preventing ESCC recurrence.

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.

Risk Factors and Prognostic Impact of Mediastinal Lymph Node Metastases in Patients with Esophagogastric Junction Cancer.

PURPOSE: We retrospectively investigated the risk factors for mediastinal lymph node (MLN) metastasis in esophagogastric junction (EGJ) cancer with an epicenter within 2 cm above and below the anatomical cardia, including both adenocarcinoma (AC) and squamous cell carcinoma (SCC). METHODS: Fifty patients who underwent initial surgery for EGJ cancer from January 2002 to December 2013 were included in this study. We defined metastatic lymph nodes as pathological metastases in resected specimens and recurrence within 2 years postoperatively. RESULTS: Thirty-four patients had AC and 16 had SCC; 24 patients underwent transhiatal resection and 26 underwent transthoracic resection. MLN metastasis was observed in 13 patients (26%) regardless of the histological type, 9 of whom had metastasis in the upper and middle mediastinum. Metastasis occurred when the esophageal invasion length (EIL) exceeded 20 mm. In addition, 10/13 patients had stage pN2-3 cancer. Multivariable analysis identified EIL ≥ 20 mm and stage pN2-3 as significant risk factors for MLN metastasis. The 5-year overall survival was 38% and 65% in the MLN-positive and -negative groups, respectively (p = 0.12). Multivariable Cox regression analysis showed that only stage pN2-3, and not the presence of MLN metastasis, was a significantly poor prognostic factor. CONCLUSION: MLN metastasis in EGJ cancer may have a close association with the EIL of the tumor, but the presence of MLN metastasis itself was not a poor prognostic factor. The significance and indications for MLN dissection should be clarified in prospective clinical trials.

A case of a gastric granular cell tumor preoperatively diagnosed and successfully treated by single-incision laparoscopic surgery.

BACKGROUND: Granular cell tumors (GCT) in the gastrointestinal tract are rare. Herein, we describe a case of a gastric GCT diagnosed preoperatively by endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) and successfully resected by single-incision laparoscopic surgery (SILS). CASE PRESENTATION: A 46-year-old Japanese woman had a tumor located in the angle of the stomach that was approximately 1.5 cm in diameter. Abdominal computed tomography (CT) revealed a submucosal tumor (SMT), which was finally diagnosed as a gastric GCT using EUS-FNAB. The tumor was not identified by CT 1 year and 4 months before diagnosis; therefore, because there was a possibility that the tumor was malignant, we performed surgical wedge resection using SILS. The patient had an uneventful recovery postoperatively and was discharged without complications 3 days after surgery. The tumor was pathologically diagnosed as a benign GCT that remained within the muscular layer. No recurrence or complications have occurred in the first 16 months since the surgery. CONCLUSION: Because gastric GCTs are generally benign and are rarely associated with lymph node metastasis, SILS seems to be a safe and feasible surgical approach for treating GCTs.

Skin and hair abnormalities of Cantu syndrome: A congenital hypertrichosis due to a genetic alteration mimicking the pharmacological effect of minoxidil.

Cantu syndrome is an autosomal dominant disorder, first described by Cantu in 1982, that is characterized by congenital hypertrichosis, characteristic facial anomalies and cardiomegaly. Recent investigations have revealed that this syndrome is caused by mutations of ABCC9, which encodes a regulatory subunit of SUR2, an adenosine triphosphate-mediated potassium channel opener, expressed not only in smooth muscle but also in hair follicles. However, the abnormalities of skin and hair in patients with Cantu syndrome have not been well explored. We herein report three Japanese patients with Cantu syndrome and describe their specific skin manifestations and alterations in the histopathology of their hair follicles and sebaceous glands. Similar alterations were shared among those three patients and may be related to the function of SUR2, namely the regulation of hair follicle growth, because SUR2 is a known pharmacological target of minoxidil.