Effects of Interleukin-12 on the Induction of Cytotoxic T Lymphocytes from the Regional Lymph Node Lymphocytes of Patients with Lung Adenocarcinoma

Lung cancer-specific cytotoxic T lymphocytes (CTL) were induced by repeated stimulations of regional lymph node lymphocytes (RLNL) in lung cancer patients with either autologous or HLA-A-locus-matched tumor cells. To investigate the effect of interleukin-12 (IL-12), IL-12 was added during the stimulation of RLNL from HLA A24 / adenocarcinoma patients with either autologous tumor cells or HLA A24-positive adenocarcinoma cells (PC-9) in combination with, or instead of interleukin-2 (IL-2), and then the cytotoxic activity, cytokine production and populations of the lymphocyte subsets were examined. The addition of IL-12, or the substitution of IL-2 by IL-12 was found to enhance the cytotoxic activity and the cytokine production (IFN-γ, GM-CSF) of the CTL as compared with IL-2 alone. The cytotoxic activity and cytokine production were both partially inhibited by anti-MHC-class I monoclonal antibody. The CTL thus induced by IL-12 had a higher proportion of CD3⁺/CD56⁺ cells than the CTL induced with IL-2 alone. The positively selected CD8⁺/CD56^– lymphocytes showed PC-9-specific cytotoxic activity, because the population did not show any cytotoxicity to K562 or A549 (HLA-A26/A30). However, the CD3⁺/CD56⁺ lymphocytes were cytotoxic to both PC-9 and K562. In conclusion, IL-12 is considered to be a useful cytokine for both the induction of lung-cancer specific CTL and the augmentation of non-MHC-restricted cytotoxicity against tumor cells, and may be applicable for adoptive immunotherapy using CTL.     

Protein and energy depletion in chronic hemodialysis patients: clinical applicability of diagnostic tools.

Protein and energy depletion states are common and associated with increased morbidity and mortality in chronic hemodialysis (CHD) patients. Therefore, proper use of diagnostic tools to assess depleted states in CHD patients is critical. Assessment of protein and energy status can be done by an array of methodologies that include simple estimates of the visceral and somatic pools of protein to more refined techniques to measure protein and energy balance. The nutritional and metabolic derangements in the CHD population are highly complex and can be confounded by multiple comorbidities and fluid shifts between body compartments. Therefore, assessment of protein and energy status in CHD patients requires a wide range of methodologies that not only identify depleted states but also monitor nutrition therapy and predict clinical outcome. Most important, these methods require cautious and individualized interpretation in order to minimize the interference of comorbid conditions frequently observed in the CHD population. Currently, there is not a single method that can be considered the gold standard for assessment of protein and energy status in CHD patients. Therefore, a combination of methods is recommended. In this review, we describe available methods to assess protein and energy status, with special considerations pertaining to CHD patients.     

A case of metachronous adenocarcinoma of the urinary bladder and the right upper urinary tract

Bilateral hydronephrosis identified by a local physician brought a 65-year-old man to our hospital. Emergency percutaneous nephrostomy was bilaterally established for obstructive renal failure. After recovering renal function, the patient underwent radical cystectomy under the diagnosis of invasive bladder cancer and the construction of an ileal conduit. The pathology reported well differentiated adenocarcinoma (pT2, pL1, pV1). Five years after the surgery, gross hematuria developed. A computed tomographic scan revealed right hydronephrosis with a solid mass in the upper calyx. The urinary cytology was negative. The patient underwent right nephrectomy in May, 1999. The pathology then revealed well differentiated adenocarcinoma in the renal pelvis and ureter (pT3, pL0, pV0 and pT1, pL0, pV0, respectively). He is alive with mild chronic renal insufficiency with evidence of tumor at ten months after surgery. To our knowledge, this is the first case of metachronous adenocarcinoma of the urinary bladder and the upper urinary tract reported in the Japanese literature.     

Weekly paclitaxel administration and intraabdominal CBDCA injection possibly beneficial treatment for recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation--a case report

A 46-year-old woman who had received mastectomy for breast cancer 6 years earlier complained of abdominal distension. Computed tomography and ultrasonography revealed massive ascites and ovarian swelling of both sides. She was diagnosed as having primary ovarian cancer and peritoneal dissemination, and underwent a total hysterectomy as well as ovarectomy on both sides. After surgery, she received a sequential chemotherapy, ie, intraabdominal injection of carboplatin (CBDCA 300 mg/m2) and div administration of paclitaxel (PTX 180 mg/m2) as a standard regimen for advanced ovarian cancer. However, detailed histological examinations showed that the ovarian cancer had metastasized from her breast cancer. It is well-known that breast cancer easily metastasizes to the bone, liver, pleura and lymph node, but rarely to the ovarium or peritoneum when chemotherapy is conducted. Therefore, no standard therapy has been established for breast cancer metastasizing to the ovarium. Our patient received 4 cycles of weekly administration of PTX (PTX 80 mg/m2, 3 consecutive weeks, 1-week break), followed by oral administration of doxifluridine+anastrozole on an outpatient basis. No evidence of recurrence of breast cancer has been noted 1 year after surgery. This result suggests that weekly administration of PTX and intraabdominal injection of CBDCA might be beneficial in the treatment of recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation.     

Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma.

PURPOSE: Nitroglycerin may improve the response to chemotherapy in advanced non-small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported. EXPERIMENTAL DESIGN: Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1, and p53 proteins in their resected tumor by semiquantitative immunohistochemical analyses. Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not. Furthermore, to study the relationship between changes in plasma VEGF levels by nitroglycerin treatment and response to DCb, 29 patients with advanced lung adenocarcinoma were treated with nitroglycerin for 3 days before chemotherapy using DCb. RESULTS: The rates of immunoreactive cells for HIF-1alpha, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin, but those for p53 were not different between those treated with and without nitroglycerin. Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1alpha in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma. CONCLUSIONS: Nitroglycerin treatment may improve response to DCb in patients with lung adenocarcinoma, partly through decreasing VEGF and P-gp production via reduction of HIF-1alpha.     

CD10 down expression in follicular lymphoma correlates with gastrointestinal lesion involving the stomach and large intestine

Follicular lymphoma (FL) shows co‐expression of B‐cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa‐associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10^down) GI‐FL. The diagnosis of CD10^down FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10^down GI‐FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI‐FL and nodal FL when the analysis was confined to primary GI‐FL (55.2% vs 3.5%, P < 0.001). Compared to CD10⁺ GI‐FL, CD10^down GI‐FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10^down group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa‐associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10^down GI‐FL, and an identical clone was found between CD10^down follicles and CD10⁺BCL2⁺ neoplastic follicles. In the diagnosis of cases with CD10^down BCL2⁺ follicles, careful examination with molecular studies should be carried out.     

A phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable biliary tract cancer

Background

Many clinical trials have been conducted with gemcitabine- or 5-fluorouracil-based regimens as treatment for unresectable biliary tract cancer; however, the results remain unsatisfactory. Because further therapeutic improvements are required, we conducted a phase I study of arterial infusion chemotherapy using a combination of gemcitabine and 5-fluorouracil.

Methods

In the first 3 cohorts, patients were to receive an arterial infusion of gemcitabine 600, 800 or 1000?mg/m², respectively, over 30?min on days 1 and 15, plus a continuous arterial infusion of 5-fluorouracil 300?mg/m²/day on days 1–5 and 15–19. In the final cohort, patients were to receive an arterial infusion of gemcitabine 1000?mg/m² over 30?min on days 1 and 15, plus 5-fluorouracil 400?mg/m²/day on days 1–5 and 15–19.

Results

Eighteen patients were enrolled. In the final cohort, three of six patients experienced grade 3 non-hematological toxicities (cholecystitis, cellulitis and pneumonia). Thus, we determined the maximum tolerated doses of gemcitabine and 5-fluorouracil in arterial infusion chemotherapy to be 1000 and 400?mg/m², respectively.

Conclusion

This regimen of gemcitabine and 5-fluorouracil is tolerable and warrants further investigation in biliary tract cancer.     

Branched Chain Amino Acids Promote ATP Production Via Translocation of Glucose Transporters

PurposeWe have previously shown that maintenance of ATP levels is a promising strategy for preventing neuronal cell death, and that branched chain amino acids (BCAAs) enhanced cellular ATP levels in cultured cells and antagonized cell death. BCAAs attenuated photoreceptor degeneration and retinal ganglion cell death in rodent models of retinal degeneration or glaucoma. This study aimed to elucidate the mechanisms through which BCAAs enhance ATP production.MethodsIntracellular ATP concentration was measured in HeLa cells under glycolysis and citric acid cycle inhibited conditions. Next, glucose uptake was quantified in HeLa cells and in 661W retinal photoreceptor-derived cells under glycolysis inhibition, endoplasmic reticulum stress, and glucose transporters (GLUTs) inhibited conditions, by measuring the fluorescence of fluorescently labeled deoxy-glucose analog using flow cytometry. Then, the intracellular behavior of GLUT1 and GLUT3 were observed in HeLa or 661W cells transfected with enhanced green fluorescent protein-GLUTs.ResultsBCAAs recovered intracellular ATP levels during glycolysis inhibition and during citric acid cycle inhibition. BCAAs significantly increased glucose uptake and recovered decreased glucose uptake induced by endoplasmic reticulum stress or glycolysis inhibition. However, BCAAs were unable to increase intracellular ATP levels or glucose uptake when GLUTs were inhibited. Fluorescence microscopy revealed that supplementation of BCAAs enhanced the translocation of GLUTs proteins to the plasma membrane over time.ConclusionsBCAAs increase ATP production by promoting glucose uptake through promotion of glucose transporters translocation to the plasma membrane. These results may help expand the clinical application of BCAAs in retinal neurodegenerative diseases, such as glaucoma and retinal degeneration.     

Abdominal aortic calcification is associated with Fibrosis‐4 index and low body mass index in type 2 diabetes patients: A retrospective cross‐sectional study

Aims/IntroductionThis study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus.Materials and MethodsThis retrospective cross‐sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models.ResultsThe AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis‐4 (Fib‐4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography‐diagnosed fatty liver. There was a significant interaction between BMI and Fib‐4 index; lower BMI and Fib‐4 index >2.67 showed a synergistic association with high AAC grade.ConclusionsAAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib‐4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus.