Therapeutic activity of retroviral replicating vector-mediated gene therapy in combination with anti-PD-1 antibody in a murine pancreatic cancer model.

Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. Toca 511/5-FC treatment may also induce antitumor immunity. Here, we first examined antitumor immune responses activated by Toca 511/5-FC treatment in an immunocompetent murine pancreatic cancer model. We then evaluated the therapeutic effects achieved in combination with anti-programmed cell death protein 1 antibody. In the bilateral subcutaneous tumor model, as compared with the control group, enhanced CD8+ T-cell-mediated cytotoxicity and increased T-cell infiltration in Toca 511-untransduced contralateral tumors were observed. Furthermore, the expression levels of T-cell co-inhibitory receptors on CD8+ T-cells increased during treatment. In the bilateral subcutaneous tumor model, combination therapy showed significantly stronger tumor growth inhibition than that achieved with either monotherapy. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer.

Retroviral Replicating Vector Toca 511 (Vocimagene Amiretrorepvec) for Prodrug Activator Gene Therapy of Lung Cancer.

Therapeutic efficacy of retroviral replicating vector (RRV)-mediated prodrug activator gene therapy has been demonstrated in a variety of tumor models, but clinical investigation of this approach has so far been restricted to glioma and gastrointestinal malignancies. In the present study, we evaluated replication kinetics, transduction efficiency, and therapeutic efficacy of RRV in experimental models of lung cancer. RRV delivering GFP as a reporter gene showed rapid viral replication in a panel of lung cancer cells in vitro, as well as robust intratumoral replication and high levels of tumor transduction in subcutaneous and orthotopic pleural dissemination models of lung cancer in vivo. Toca 511 (vocimagene amiretrorepvec), a clinical-stage RRV encoding optimized yeast cytosine deaminase (yCD) which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU), showed potent cytotoxicity in lung cancer cells upon exposure to 5-FC prodrug. In vivo, Toca 511 achieved significant tumor growth inhibition following 5-FC treatment in subcutaneous and orthotopic pleural dissemination models of lung cancer in both immunodeficient and immunocompetent hosts, resulting in significantly increased overall survival. This study demonstrates that RRV can serve as highly efficient vehicles for gene delivery to lung cancer, and indicates the translational potential of RRV-mediated prodrug activator gene therapy with Toca 511/5-FC as a novel therapeutic strategy for pulmonary malignancies.

The Impact of Serum Zinc Levels on Abdominal Fat Mass in Hemodialysis Patients.

BACKGROUND: Zinc deficiency is highly prevalent and is caused by inadequate dietary intake, malabsorption and removal by treatment in hemodialysis patients. This study investigated the relationship between serum zinc levels and nutritional status in hemodialysis patients. METHODS: A cross-sectional study examining 87 hemodialysis patients was performed. The serum concentrations of zinc were studied to evaluate their association with nutritional status, which was assessed by measuring abdominal muscle and fat areas with computed tomography. RESULTS: Serum zinc levels were significantly and positively correlated with subcutaneous and visceral fat areas (r = 0.299, p < 0.01, and r = 0.298, p < 0.01, respectively), but not abdominal muscle areas. Multiple regression analyses demonstrated that serum zinc levels were a significant independent predictor of visceral fat areas (p < 0.01), but not subcutaneous fat areas (p = 0.631). CONCLUSIONS: Our findings suggest that serum zinc levels could play a crucial role in determining abdominal fat mass in hemodialysis patients.

Prognosis and prognostic factors of esophageal spindle cell carcinoma treated by esophagectomy: a retrospective single-institution analysis.

BACKGROUND: Esophageal spindle cell carcinoma (ESpCC) is a malignant tumor composed of sarcomatous components. ESpCC is treated as a squamous cell carcinoma. However, because ESpCC is a rare tumor, little is known regarding its prognosis. This study aimed to analyze patients with ESpCC who were surgically treated at our hospital, determine the validity of surgery, and identify factors that indicate a prognosis. METHODS: Treatment characteristics, overall survival (OS), and recurrence-free survival (RFS) of 28 patients with ESpCC who underwent surgery at our hospital between 1990 and 2016 were assessed. Furthermore, factors associated with OS and RFS were analyzed. RESULTS: Subtotal esophagectomy with 3-field lymph node dissection and lower esophagectomy with 2-field lymph node dissection were performed in 25 and 3 patients, respectively. Chemotherapy was administered as preoperative therapy to two patients. Postoperative therapy, comprising radiotherapy and chemotherapy, was administered to three and nine patients, respectively. The 3- and 5-year RFS were 66.4% and 61.6% and the 3- and 5-year OS were 73% and 61.9%, respectively. Macroscopic type was identified as a prognostic factor. In terms of OS, prognosis was significantly worse in ulcerative-type ESpCC than in the polypoid type. CONCLUSION: The 5-year OS of ESpCC mainly treated with surgical therapy was 61.9%. However, prognosis was poor in some patients with ulcerative-type ESpCC according to macroscopic type. In the future, it will be necessary to accumulate more cases and investigate therapeutic strategies added to surgery to improve prognosis.

A Reversible Gastric Uptake of Bone Scintigraphy in a Patient with Hypercalcemia.

Hypercalcemia is a severe complication in cases of vitamin D intoxication that can result in metastatic calcification. We herein report a female case with hypercalcemia due to eldecalcitol administration associated with the increased uptake of technetium-99m hydroxymethylene diphosphonate (99mTc-HMDP) as the bone-scanning agent in the stomach. A histologic assessment using biopsy specimens identified metastatic calcification of the stomach. After the normalization of serum calcium levels, the gastric uptake of 99mTc-HMDP disappeared. This case indicates the usefulness of bone scintigraphy with 99mTc-HMDP to detect visceral metastatic calcification and to monitor its therapeutic effects in patients with hypercalcemia.

L-carnitine Improved the Cardiac Function via the Effect on Myocardial Fatty Acid Metabolism in a Hemodialysis Patient.

Patients on hemodialysis often have carnitine deficiency. We herein report a woman who experienced the dramatic improvement of cardiac dysfunction after intravenous L-carnitine administration. We also investigated the myocardial fatty acid metabolism using 123I-labeled ß-methyl-p-iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) before and after L-carnitine therapy, and the impaired metabolism was ameliorated. Taken together, these findings indicate that L-carnitine therapy improved cardiac dysfunction via the amelioration of the abnormal myocardial fatty acid metabolism, at least in part.

Effects of Lowering Dialysate Calcium Concentration on Bone Metabolic Markers in Hemodialysis Patients With Suppressed Serum Parathyroid Hormone: A Preliminary Study.

Although the Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend a dialysate calcium concentration between 2.5 and 3.0 mEq/L, its optimal concentration remains unclear. A total of 53 hemodialysis patients with intact parathyroid hormone (PTH) levels <150 pg/mL were enrolled in this prospective observational study. A dialysate calcium concentration was converted from 3.0 to 2.75 mEq/L and bone metabolic markers including bone alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase-5b (TRACP-5b) were examined. After 3 months, serum corrected calcium levels decreased (P < 0.001), while serum intact PTH, BAP and TRACP-5b levels increased (P < 0.05, P < 0.05 and P < 0.001, respectively). Multiple regression analyses showed that the amount of change in BAP was significantly associated with dialysis vintage (P < 0.01). In conclusion, the lowering of dialysate calcium concentration stimulated parathyroid gland and bone remodeling in hemodialysis patients with suppressed PTH, particularly with longer dialysis vintage.

Carbohydrate antigen 19-9 is significantly elevated in autosomal dominant polycystic kidney disease.

AIM: Liver cysts are the most common extrarenal manifestation in patients with autosomal dominant polycystic kidney disease (ADPKD). Carbohydrate antigen 19-9 (CA19-9) is generally used as a marker for biliopancreatic malignancies, although CA19-9 levels in patients with ADPKD are largely unknown. METHODS: A prospective observational study of 53 ADPKD patients and 83 non-ADPKD control subjects was performed. The serum levels of CA19-9 were studied to evaluate the association with clinical parameters and liver cysts. RESULTS: The serum CA19-9 levels were significantly higher in the ADPKD group than in the control group (32.9 U/mL vs. 9.8 U/mL, respectively, P < 0.001). The serum CA19-9 levels in the ADPKD group were positively correlated with the mean blood pressure (rho = 0.335, P < 0.05), gamma-glutamyl transferase (GTP) levels (rho = 0.541, P < 0.001), the largest cyst size (rho = 0.536, P < 0.001) and the liver cyst volume (rho = 0.682, P < 0.001). Multiple regression analyses showed that the gamma-GTP levels (P < 0.001) and the liver cyst volumes (P < 0.001) were independent predictors for serum CA19-9 levels. CONCLUSIONS: Serum CA19-9 levels are significantly elevated and appear to be dependent on the gamma-GTP levels and the volume of liver cysts in patients with ADPKD. Our findings indicate that the measurement of the baseline CA19-9 level in each patient with ADPKD may be useful for the interpretation of the value and the differential diagnosis of liver diseases, particularly the liver cyst infection.

Red Blood Cell Distribution Width Is Associated With All-Cause and Cardiovascular Mortality in Hemodialysis Patients.

Red blood cell distribution width (RDW) is an index of red blood cell variability that is usually used to differentiate the cause of anemia. However, clinical evidence for the relationship between RDW and mortality in hemodialysis patients is still lacking. We performed a single center, prospective longitudinal study. During more than 5 years of follow-up in 80 patients undergoing maintenance hemodialysis, 34 patients (42.5%) died. In the Kaplan-Meier curve analyses, higher RDW levels (≥ 14.9%) were significantly associated with all-cause and cardiovascular mortality (log-rank test, P < 0.05, each). In multivariate Cox proportional hazard models, each 1.0% increase in RDW value predicted an estimated 25% higher risk of mortality (P < 0.05) and a 40% higher risk of cardiovascular mortality (P < 0.05). In conclusion, higher RDW value was a significant predictor for all-cause and cardiovascular mortality in patients undergoing maintenance hemodialysis.

Minimally invasive surgery for esophageal cancer after esophageal perforation.

Both esophageal rupture and esophageal cancer are life-threatening diseases. We report a case of esophageal cancer that occurred after esophageal rupture was treated with thoracoscopic and laparoscopic surgery. A 76-year-old man presented with vomiting followed by epigastric pain and was diagnosed with spontaneous esophageal rupture. Laparoscopic and thoracoscopic surgery were performed. Primary closure was completed with a fundic patch, and thoracic lavage was performed. Ten months later, his condition was diagnosed as squamous cell carcinoma of the abdominal esophagus. He underwent thoracoscopic esophageal resection in the prone position, and a gastric conduit was created laparoscopically. The pathological finding was superficial esophageal carcinoma without lymph node metastasis. The patient's postoperative course was uneventful, and there was no recurrence at 21 months of follow-up.

Hypokalemia-associated paralysis and metabolic acidosis in a patient with bilateral ureterosigmoidostomy.

Ureterosigmoidostomy is a urological intervention performed to treat various conditions such as invasive bladder cancer, bladder exstrophy, vesicovaginal fistula, or urethral trauma. However, this intervention may lead to several metabolic complications. Here, we report an interesting case with quadriparesis and intestinal paralysis resulting from severe hypokalemia (the serum potassium level, 1.8 mEq/L) and hyperchloremic metabolic acidosis [pH 6.927 and the arterial bicarbonate level, 8.0 mEq/L] in a 65-year-old man who had undergone bilateral ureterosigmoidostomy for bladder cancer 16 years earlier. The abdominal computed tomography scan also showed that massive fluid consisting of the mixture of the diverted urinary stream and feces was accumulated in the dilated distal colon. The treatment with intravenous potassium and sodium bicarbonate administration combined with the drainage of the diverted urinary stream from the distal colon resulted in the restoration of hypokalemia and acidosis followed by the improvement of quadriparesis and intestinal paralysis. The underlying mechanism and the treatment of metabolic complications after ureterosigmoidostomy are briefly discussed.

Circulating 20S proteasome is independently associated with abdominal muscle mass in hemodialysis patients.

UNLABELLED: Protein-energy wasting is highly prevalent in hemodialysis patients, and it contributes to patient morbidity and mortality. The ubiquitin-proteasome system is the major pathway for intracellular protein degradation and it is involved in the regulation of basic cellular processes. However, the role of this system in the determination of nutritional status is largely unknown. To examine a relationship between protein-energy wasting and the ubiquitin-proteasome system, a cross-sectional study of 76 hemodialysis patients was performed. Plasma concentrations of 20S proteasome were studied to evaluate its association with muscle and fat mass, which were investigated by abdominal muscle and fat areas measured using computed tomography and by creatinine production estimated using the creatinine kinetic model. Plasma 20S proteasome concentrations significantly and negatively correlated with abdominal muscle areas and creatinine production (rho = -0.263, P < 0.05 and rho = -0.241, P < 0.05, respectively), but not abdominal subcutaneous and visceral fat areas. Multiple regression analyses showed that 20S proteasome was a significant independent predictor of abdominal muscle area (P < 0.05). In conclusion, plasma 20S proteasome concentrations were independently associated with abdominal muscle mass in hemodialysis patients. Our findings indicate a relationship between circulating 20S proteasomes and muscle metabolism in these patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000012341.

Plasma levels of fibroblast growth factor-23 are associated with muscle mass in haemodialysis patients.

AIM: Malnutrition is highly prevalent in haemodialysis (HD) patients, and it contributes to morbidity and mortality. Fibroblast growth factor-23 (FGF-23) and Klotho contribute to chronic kidney disease-mineral and bone disorder (CKD-MBD) in HD patients, but the role that these molecules play in determining nutritional status is currently unknown. METHODS: A cross-sectional study examining 77 HD patients was performed. The plasma concentrations of FGF-23 and soluble Klotho (s-Klotho) were studied to evaluate their association with muscle mass, which was investigated by abdominal muscle areas measured using computed tomography and by creatinine (Cr) production estimated using the Cr kinetic model. RESULTS: Plasma FGF-23 concentrations were significantly and positively correlated with abdominal muscle areas and Cr production (rho = 0.301, P < 0.01 and rho = 0.345, P < 0.01, respectively). In contrast, s-Klotho was not significantly correlated with these muscle mass indices and plasma FGF-23 concentrations. Multiple regression analyses showed that FGF-23 was a significant independent predictor of both muscle mass indices (P < 0.01 and P < 0.05, respectively). CONCLUSION: Plasma FGF-23 concentrations were associated with muscle mass indices in HD patients. Our findings suggest that FGF-23 and nutritional status are linked and this link is most likely independent of s-Klotho.

Hepatic portal venous gas caused by blunt abdominal trauma: is it a true ominous sign of bowel necrosis? Report of a case.

A case of transient portal venous gas in the liver following blunt abdominal trauma is described. Computed tomography (CT) demonstrated hepatic portal venous gas 4 h after the injury. An exploratory laparotomy revealed segmental necrosis of the small intestine with a rupture of the bladder. Pneumatosis intestinalis was evident on the resected bowel. A histopathologic study revealed congestion and bleeding in the bowel wall and a great deal of the mucosa had been lost because of necrosis. However, neither thrombus nor atherosclerotic changes were observed in the vessels. A bacteriological examination demonstrated anaerobic bacteria from the bowel mucosa, which was most likely to produce portal venous gas. Although the present case was associated with bowel necrosis, a review of literature demonstrated that portal venous gas does not necessarily indicate bowel necrosis in trauma patients. There is another possibility that the portal venous gas was caused by a sudden increase in the intra-abdominal pressure with concomitant mucosal disruption, which thus forced intraluminal gas into the portal circulation in the blunt trauma patients.