Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study).

BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019). CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

Systemic inflammation score as a predictor of death within one year after esophagectomy.

BACKGROUND: After radical resection for esophageal cancer, death within 1 year of surgery can occur due both to recurrence and to other diseases, even after postoperative complications have been overcome. This study identified risk factors for early death within 1 year of esophagectomy for reasons other than death in hospital in patients undergoing esophagectomy for esophageal cancer or esophagogastric junction cancer. METHODS: We reviewed 366 patients who underwent esophagectomy without adjuvant treatment between January 2009 and July 2022 for thoracic esophageal cancer or esophagogastric junction cancer. Patients who died within 1 year excluding in-hospital death were compared with those who did not. Multivariable logistic regression analysis was used to identify predictors of death within 1 year after surgery. RESULTS: Death within 1 year occurred in 32 of 366 patients, 24 from primary disease and 8 from other diseases. Deaths within 1 year were significantly older than the other cases, had significantly lower % vital capacity (%VC), and occurred significantly more often in cases in advanced stages of disease. In a multivariable analysis, a systemic inflammation score (SIS) based on serum albumin level and lymphocyte-to-monocyte ratio was identified as an independent predictor of death within 1 year. As SIS increased, %VC decreased significantly, and CRP level and neutrophil-lymphocyte ratio increased significantly. There was no relationship between SIS and pN. Death within 1 year increased as SIS increased (p = 0.001 for trend). CONCLUSION: SIS assessment undertaken before beginning esophageal cancer treatment is a useful predictor of death within 1 year of surgery.

Pseudoentropy in dS/CFT and Timelike Entanglement Entropy.

We study holographic entanglement entropy in dS/CFT and introduce timelike entanglement entropy in CFTs. Both of them take complex values in general and are related with each other via an analytical continuation. We argue that they are correctly understood as pseudoentropy. We find that the imaginary part of pseudoentropy implies an emergence of time in dS/CFT.

Holography in de Sitter Space via Chern-Simons Gauge Theory.

In this Letter, we propose a holographic duality for classical gravity on a three-dimensional de Sitter space. We first show that a pair of SU(2) Chern-Simons gauge theories reproduces the classical partition function of Einstein gravity on a Euclidean de Sitter space, namely S^{3}, when we take the limit where the level k approaches -2. This implies that the conformal field theory (CFT) dual of gravity on a de Sitter space at the leading semiclassical order is given by an SU(2) Wess-Zumino-Witten model in the large central charge limit k→-2. We give another evidence for this in the light of known holography for coset CFTs. We also present a higher spin gravity extension of our duality.

The impact of the American Society of Anesthesiology-Physical Status classification system on the treatment and prognosis of patients with esophageal cancer undergoing esophagectomy.

BACKGROUND: The American Society of Anesthesiologists-Physical Status (ASA-PS) classification system has been shown to predict morbidity and mortality after surgery. However, the impact of the ASA-PS on esophageal cancer treatment remains unclear. This study examined both the impact of the ASA-PS on treatment, including surgery and perioperative chemotherapy, and the prognostic effects of ASA-PS class in patients who had undergone esophagectomy for thoracic esophageal cancer or esophagogastric junction cancer. METHODS: ASA-PS status was collected for 301 patients who had undergone esophagectomy between January 2007 and June 2016 for thoracic esophageal cancer or esophagogastric junction cancer at a single institution. As the ASA-PS was updated in 2014, the previous classifications of all patients were reevaluated using the updated standard by a surgeon with the previous classifications masked. The dose intensity of preoperative chemotherapy was also compared across classes. Multivariate Cox regression analysis was used to analyze the association between ASA-PS class and overall survival. RESULTS: Patients whose reevaluations had placed them in a more severe ASA-PS class showed significantly poorer overall and cancer-specific survival rates. The dose intensities of cisplatin and 5-fluorouracil for preoperative chemotherapy were significantly lower in patients in the more severe ASA-PS classes. Multivariate analysis showed that ASA-PS class was an independent prognostic factor for overall survival. CONCLUSION: Preoperative ASA-PS classification may influence the intensity of perioperative treatment and may be a valuable long-term prognostic factor for patients with esophageal cancer undergoing esophagectomy.

Preoperative skeletal muscle index and visceral-to-subcutaneous fat area ratio are associated with long-term outcomes of elderly gastric cancer patients after gastrectomy.

PURPOSE: Sarcopenia is a risk factor of severe surgical complications, short-term outcomes, and long-term outcomes for patients with gastric cancer. Several computed tomography (CT) measurements have been performed to diagnose sarcopenia. However, the optimal CT measurements for determining long-term outcomes have not been revealed. METHODS: A retrospective review of gastric cancer patients with clinical stage I, II, or III who underwent gastrectomy at age 75 years or more at Shizuoka General Hospital from 2007 to 2015 was performed. Using preoperative CT, skeletal muscle index (SMI), total psoas area, intramuscular adipose tissue content in multifidus muscle, morphologic change of psoas muscle, and visceral-to-subcutaneous adipose tissue area ratio (VSR) were measured in the third lumbar section. A Cox regression analysis was used to explore prognostic factors for overall survival. RESULTS: A total of 257 patients were reviewed. There were 171, 53, and 33 patients with clinical stages I, II, and III, respectively. A multivariate analysis indicated that, in addition to age, performance status, clinical stage, and types of resection, which are known prognostic factors, SMI and VSR are prognostic factors (p = 0.016, 0.046, respectively). The prognostic score, which was the frequency of positive SMI and VSR values within the cutoff, also indicates overall survival. The five-year OS rates of patients with prognostic scores of 0, 1, and 2 were 90.9%, 62.3%, and 52%, respectively (p < 0.001). CONCLUSION: Preoperative SMI and VSR were prognostic factors for the overall survival of elderly patients with gastric cancer after gastrectomy.

Hand-assisted robotic surgery in the abdominal phase of robot-assisted oesophagectomy.

Robot-assisted minimally invasive oesophagectomy (RAMIE) has been developed to overcome the technical limitations of conventional thoracoscopic oesophagectomy. Hand-assisted laparoscopic surgery (HALS) is used as a practical and useful technique during the abdominal phase of thoracoscopic oesophagectomy. During RAMIE, a robotic vessel sealer cannot be used with HALS; another vessel sealer or ultrasonic coagulating device for laparoscopic surgery is required. We report an initial experiment using hand-assisted robotic surgery (HARS) for abdominal manipulation during RAMIE as a novel method. Under the pneumoperitoneum induced by insufflating the abdomen to 10 mmHg with carbon dioxide, the assistant surgeon lifted the stomach and greater omentum using the left hand through a 7 cm upper abdominal midline incision at approximately 2 cm below the xiphoid. Subsequently, gastric mobilisation was performed by robot-assisted surgery. Between January 2019 and February 2020, eight patients with thoracic oesophageal cancer underwent RAMIE with HARS at our hospital. The median operative time for extracorporeal manipulation and preparation for the roll-in of the robot was 39.5 min. The median console time was 47.5 min. There were no intraoperative or postoperative complications related to the use of the robot and no in-hospital mortality. In conclusion, HARS seems to be feasible and safe for abdominal manipulation during oesophageal cancer surgery.

Time-domain fluorescence lifetime imaging by nonlinear fluorescence microscopy constructed of a pump-probe setup with two-wavelength laser pulses.

We propose a time-domain approach for fluorescence lifetime measurements using nonlinear fluorescence microscopy constructed of a pump-probe setup with two-wavelength laser pulses. Nonlinear fluorescence signals generated by fluorescence reduction due to stimulated emission were detectable through a lock-in technique. Changing the time delay between the two-wavelength pulses enables acquisition of a time-resolved nonlinear fluorescence signal, which directly reflects the fluorescence lifetime of the sample and is thus applicable to fluorescence lifetime imaging. We also quantitatively demonstrate that nonlinear fluorescence microscopy possesses better optical resolution than conventional laser-scanning fluorescence microscopy. Experimental trials indicate that straightforward fluorescence lifetime imaging with high optical resolution is readily available.

Hand grip strength as a predictor of postoperative complications in esophageal cancer patients undergoing esophagectomy.

BACKGROUND: Radical esophagectomy remains the primary treatment option for resectable esophageal cancer. However, it sometimes induces postoperative complications due to its invasive nature. Recently, the impact of loss of muscle mass on postoperative complications and survival among cancer patients has been highlighted. This study aimed to identify the impact of low hand grip strength (HGS) on postoperative complications after esophagectomy. METHODS: A total of 188 patients (male: 166, female: 22) who underwent radical esophagectomy with gastric tube reconstruction between 2008 and 2014 were included. The correlation between HGS and age was analyzed using Pearson's correlation coefficient. Due to the small patient numbers, only male patients were stratified into two groups according to age (<70 years: non-elderly group, ≥70 years: elderly group). Receiver operating characteristic curve analysis was performed for each group using postoperative complication occurrence as the endpoint to determine an optimal HGS cutoff value. RESULTS: Postoperative complications occurred in 60.9% of the elderly group and 47.4% of the non-elderly group. When the cutoff values were set at 30.5 and 37 kg for the elderly and non-elderly group, respectively, low HGS was an independent predictive factor of postoperative complications on multivariate analysis only in the elderly group (p = 0.008). In the elderly group, the incidence of postoperative pneumonia was 39.5% among patients with low HGS vs. 3.8% among patients with high HGS. CONCLUSION: Preoperative HGS is an independent predictive factor of postoperative complications, especially postoperative pneumonia, for elderly male patients with esophageal cancer treated with radical esophagectomy.

[Endoscopic nasobiliary and nasopancreatic drainage contributing to healing of duodenal ulcer perforation: a case report].

A 75-year-old man with vomiting and right abdominal pain was admitted to the Department of Surgery in our hospital. With a diagnosis of perforated duodenal ulcer, he was treated conservatively. On the day 8 of hospitalization, his general condition worsened and he underwent surgery. During operation, the perforated duodenal ulcer and paraduodenal fluid collection was observed, and percutaneous drainage was accordingly established. After this procedure, renal dysfunction was exacerbated and he was transferred to our department for endoscopic treatment. On day 28 of hospitalization, nasobiliary and nasopancreatic drainage was administered. Renal dysfunction gradually improved, and healing of the perforated duodenal ulcer was recognized on day 93. On day 112, the patient was discharged.

[Virtual enteroscopy for the evaluation of stenosis in a case of chronic multiple ulcers of the small intestine].

A 39-year-old female presented to our hospital with diarrhea, vomiting, anemia, and hypoalbuminemia. Virtual enteroscopy was performed to evaluate the small bowel; we found annular stenoses at 89, 100, 116, 147, and 154 cm from the ligament of Treitz. Small bowel resection was performed, and annular ulcers were confirmed at 58, 71, 90, 130, 138, 218, and 225 cm from the ligament of Treitz. Clinical records and pathological examination failed to determine the cause of these ulcers, and we diagnosed chronic multiple ulcers of the small intestine. Thus, we believe that virtual enteroscopy can be beneficial in preoperatively diagnosing multiple ulcers and stenoses in the small bowel.

Gas Gangrene of the Spleen Caused by Clostridium perfringens After Mild Blunt Trauma.

Splenic gas gangrene caused by Clostridium perfringens is rare. A 73-year-old woman was referred to our hospital because of fatigue, dyspnea, and left hypochondrial pain. She had a history of blunt trauma to the left abdomen eight days ago. She presented with hypoxemia and a high inflammatory response on blood tests. A CT showed left pleural effusion and gas in the spleen. She was treated with antimicrobials and underwent splenectomy. C. perfringens was identified from blood and intraoperative ascites cultures. She recovered and was discharged on day 34 of hospitalization. As C. perfringens is part of the normal gut microbiota and can translocate to other parts of the body, this bacterium should be considered a splenic abscess pathogen when an intracorporeal anaerobic environment is suspected.

Risk factors for abdominal surgical infectious complications after distal gastrectomy for gastric cancer: A post-hoc analysis of a randomized controlled trial (JCOG0912).

BACKGROUND: Abdominal surgical infectious complications (ASIC) after gastrectomy for gastric cancer impair patients' survival and quality of life. JCOG0912 was conducted to compare laparoscopy-assisted distal gastrectomy with open distal gastrectomy for clinical stage IA or IB gastric cancer. The present study aimed to identify risk factors for ASIC using prospectively collected data. METHODS: We performed a post-hoc analysis of the risk factors for ASIC using the dataset from JCOG0912. All complications were evaluated according to the Clavien-Dindo classification (CD). ASIC was defined as CD grade I or higher anastomotic leakage, pancreatic fistula, abdominal abscess, and wound infection. Analyses were performed using the logistic regression model for univariable and multivariable analyses. RESULTS: A total of 910 patients were included (median age, 63 years; male sex, 61 %). Among them, ASIC occurred in 5.8 % of patients. In the univariable analysis, male sex (odds ratio [OR] 2.855, P = 0.003), diabetes (OR 2.565, P = 0.029), and Roux-en-Y (R-Y) reconstruction (vs. Billroth Ⅰ, OR 2.707, P = 0.002) were significant risk factors for ASIC. In the multivariable analysis, male sex (OR 2.364, P = 0.028) and R-Y reconstruction (vs. Billroth Ⅰ, OR 2.310, P = 0.015) were independent risk factors for ASIC. CONCLUSIONS: Male sex and R-Y reconstruction were risk factors for ASIC after distal gastrectomy. Therefore, when performing surgery on male patients or when R-Y reconstruction is selected after gastrectomy for gastric cancer, surgeons should pay special attention to prevent ASIC.

Complete Regression of an 8-cm Desmoid Fibromatosis After Treatment With Tamoxifen.

We report a case of a relatively large desmoid fibromatosis that responded completely to tamoxifen as a single drug therapy. A 47-year-old Japanese man underwent laparoscopy-assisted endoscopic submucosal dissection for a duodenal polyp. He developed postoperative generalized peritonitis and underwent an emergency laparotomy. Sixteen months after the surgery, a subcutaneous mass was found on the abdominal wall. Biopsy of the mass revealed estrogen receptor alpha-negative desmoid fibromatosis. The patient underwent total tumor resection. Two years after the initial surgery, he was found to have multiple intra-abdominal masses, with the largest mass measuring 8 cm in diameter. Biopsy revealed fibromatosis, as in the case of the subcutaneous mass. Complete resection was impossible due to the proximity of the duodenum and superior mesenteric artery. Tamoxifen was administered for three years, resulting in complete regression of the masses. No recurrence was observed for the following three years. This case indicates that relatively large desmoid fibromatosis can be successfully treated with a selective estrogen receptor modulator alone and that its effect is not dependent on the estrogen receptor alpha status of the tumor.

Skeletal Muscle Loss During Neoadjuvant Chemotherapy Predicts the Incidence of Postoperative Infectious Complications in Esophageal Cancer Patients Undergoing Esophagectomy.

BACKGROUND/AIM: Malnutrition, immune deficiency, and skeletal muscle loss are associated with a risk of postoperative complications in patients with various types of cancer. This study evaluated whether malnutrition, immunological deficiencies, and skeletal muscle loss during neoadjuvant chemotherapy (NAC) predict postoperative complications in patients with esophageal cancer. PATIENTS AND METHODS: We retrospectively reviewed 123 patients with esophageal squamous cell carcinoma treated with NAC and esophagectomy at our hospital between 2014 and 2019. Patients were divided into two groups based on the presence or absence of postoperative infectious complications, such as pneumonia, anastomotic leakage, surgical site infections, pyothorax, acalculous cholecystitis, and peripheral phlebitis. Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and Onodera prognostic nutritional index were used as indicators of systemic inflammation and nutritional status. Skeletal muscle mass was evaluated using the skeletal muscle index (SMI), calculated by evaluating the total cross-sectional area of muscle tissue at the third lumbar level in computed tomography imaging. Univariable and multivariable logistic regression analyses were used to identify predictors of postoperative infectious complications. RESULTS: Postoperative infectious complications occurred in 41 patients (33.3%). A reduction in SMI was observed in 105 patients (87.8%) during NAC. Univariable and multivariable analyses indicated that the reduction in SMI during NAC was an independent predictor of postoperative complications (odds ratio=0.89; 95% confidence interval=0.79-0.99; p=0.048). CONCLUSION: Skeletal muscle loss during NAC is a useful predictor of postoperative complications in patients with esophageal cancer undergoing esophagectomy.

Esophageal cancer presenting with brain abscess.

A 76-year-old man experienced fatigue and progressive dysphagia. He underwent endoscopy at another hospital and was diagnosed with thoracic esophageal cancer. Three days after the endoscopy, the patient was rushed to our hospital with sudden seizures of the right upper and lower extremities. Contrast-enhanced computed tomography scan revealed a ring-shaped contrast-enhanced mass formation in the left parietal lobe with edema in the surrounding brain parenchyma. Contrast-enhanced magnetic resonance imaging showed a ring-shaped lesion with a high intensity on diffusion-weighted images. He was diagnosed with a brain abscess in the left parietal lobe. For abscess drainage, a quasi-emergent small craniotomy was performed. Culture of the drainage fluid revealed Streptococcus species and Haemophilus parainfluenzae. After 6 weeks of antibiotic therapy, the patient underwent a thoracoscopic esophagectomy. After the esophagectomy, there was no recurrence of the brain abscess for more than 2 years and only symptomatic epilepsy remained. Conclusively, although brain abscesses caused by esophageal cancer are rare, the possibility of brain abscess and metastasis should be considered when patients present with convulsions or higher brain disorders.

Esophageal ulcer related to zinc deficiency following a total gastrectomy.

A 76-y-old Japanese man who had undergone gastrectomy 4.5 y earlier experienced 2 wk of sore throat, heartburn, and difficulty swallowing. Endoscopy showed deep, craterlike, longitudinal ulcers in the lower and middle esophagus. Immunohistochemistry and blood tests were negative for herpes simplex virus and cytomegalovirus infections. The patient reported no other symptoms affecting the gastrointestinal tract. Although his symptoms ameliorated after initial hospitalization and treatment, they re-emerged a few days after being discharged. Fifty-one days after being first admitted, he complained of glossalgia. The serum zinc level was found to be 38 µg/dL, which was below the reference range; the patient was diagnosed with zinc deficiency. After oral zinc administration, the patient was relieved of the symptoms, and his pain was alleviated. Upper gastrointestinal endoscopy after symptom relief showed improvement in the esophageal ulcers. He has continued taking zinc supplementations, and has not developed similar symptoms in the 5 y since being treated. To the best of our knowledge, this is the first case report of esophageal ulcers related to zinc deficiency.

Risk Factors for Candidiasis as an Intra-Abdominal Infection after Gastrectomy in Patients with Gastric Cancer.

Intra-abdominal infections (IAIs) develop in 2.4%-26.6% of patients who underwent gastrectomy for gastric cancer and are occasionally serious. However, there are few reports on the causative organisms of IAI following upper gastrointestinal tract surgery and subsequent risk factors for Candida infections. This study aimed to identify the microorganisms that cause IAIs after gastrectomy and risk factors for Candida-related IAI. The records of patients who underwent gastrectomy for gastric cancer between January 2009 and December 2019 at Shizuoka General Hospital were retrospectively collected. Patients with IAIs of grade II or higher, as measured by the Clavien-Dindo classification, were included in the analysis. The selected patients were divided into the Candida and non-Candida groups according to the presence or absence of Candida as the causative organism. Of 1,379 patients, 56 (4.1%) were diagnosed with IAIs after gastrectomy. Fifty-two patients were included in the study based on culture analyses. A total of 111 strains and 28 bacterial species were isolated during the initial culture test. Candida constituted 7.2% of all identified pathogens. Regarding the risk factors for Candida-related IAI, a history of antimicrobial use and ≥ 4 postoperative days of IAI development were independent risk factors for Candida-related IAI.

The Association Between Onset of Staphylococcal Non-menstrual Toxic Shock Syndrome With Inducibility of Toxic Shock Syndrome Toxin-1 Production.

Non-menstrual toxic shock syndrome (non-mTSS) is a life-threatening disease caused by Staphylococcus aureus strains producing superantigens, such as staphylococcal enterotoxins A, B, C, and toxic shock syndrome toxin-1 (TSST-1). However, little is known about why the TSS cases are rare, although S. aureus strains frequently carry a tst gene, which encodes TSST-1. To answer this question, the amount of TSST-1 produced by 541 clinical isolates was measured in both the presence and absence of serum supplementation to growth media. Then a set of S. aureus strains with similar genetic backgrounds isolated from patients presenting with non-mTSS and those with clinical manifestations other than non-mTSS was compared for their TSST-1 inducibility by human serum, and their whole-genome sequences were determined. Subsequently, the association of mutations identified in the tst promoter of non-mTSS strains with TSST-1 inducibility by human serum was evaluated by constructing promoter replacement mutants and green fluorescent protein (GFP) reporter recombinants. Results showed that 39 out of 541 clinical isolates (7.2%), including strains isolated from non-mTSS patients, had enhanced production of TSST-1 in the presence of serum. TSST-1 inducibility by human serum was more clearly seen in non-mTSS strains of clonal complex (CC)-5. Moreover, the whole-genome sequence analysis identified a set of sequence variations at a putative SarA-binding site of the tst promoter. This sequence variation was proven to be partially responsible for the induction of TSST-1 production by human serum. We conclude that the onset of staphylococcal toxic shock syndrome caused by TSST-1-producing CC-5 strains seem at least partially initiated by serum induction of TSST-1, which is regulated by the mutation of putative SarA-binding site at the tst promoter.

Influence of a positive proximal margin on oral intake in patients with palliative gastrectomy for far advanced gastric cancer.

BACKGROUND: Resection margin involvement is one of the most significant risk factors for local recurrence in curative gastrectomy, and local recurrence results in anastomotic stenosis. In the present study, the effects of a positive resection margin in palliative gastrectomy on the symptoms of anastomotic stenosis and the amount of oral intake were analyzed. METHODS: Between September 2002 and December 2009, 2,228 patients underwent resection for gastric cancer at Shizuoka Cancer Center, Japan, of whom 18 underwent palliative gastrectomy with a positive proximal margin because of urgent symptoms such as tumor bleeding, stenosis, or perforation. These 18 patients were analyzed retrospectively in this study. RESULTS: Twelve patients had a positive proximal margin, and six patients had both proximal and distal margin involvement. Anastomotic leakage occurred in 2 patients. The median overall survival was 7.5 months, and the median time from operation to a decrease in oral intake was 5.5 months. Anastomotic recurrence developed in 3 patients, and in all of them, anastomotic stricture was found 2-3 months after gastrectomy. One of these patients, who was in good general condition, was treated by endoscopic balloon dilatation. The other 2 patients did not undergo balloon dilatation because their general condition was poor, with peritonitis carcinomatosa. CONCLUSIONS: It does not appear necessary for palliative gastrectomy to achieve a negative proximal margin, because salvage therapies resulted in maintaining a tolerable oral intake in patients who were in good general condition.