Tomoo Itoh

Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma.

The purpose of this study was to clarify the relationship between the number of tumour-infiltrating T lymphocytes and the clinicopathological features and clinical outcome in patients with non-small-cell lung cancer (NSCLC). Tissue specimens from 109 patients who underwent surgical resection for NSCLC were immunohistochemically analysed for CD4 and CD8 expression. Patients were classified into two groups according to whether their tumours exhibited a ‘high’ or ‘low’ level of CD8+ or CD4+ lymphocyte infiltration. Although the level of infiltration by CD8+ T cells alone had no prognostic significance, the survival rate for patients with both ‘high’ CD8+ and ‘high’ CD4+ T-cell infiltration was significantly higher than that for the other groups (log-rank test, P=0.006). Multivariate analysis indicated that concomitant high CD8+ and high CD4+ T-cell infiltration was an independent favourable prognostic factor (P=0.0092). In conclusion, the presence of high levels of both CD8+ T cells and CD4+ T cells is a significant indicator of a better prognosis for patients with NSCLC, and cooperation between these cell populations may allow a significantly more potent antitumour response than either population alone.

CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.

Objective Recent studies have demonstrated the importance of tumor immunity for a cancer patients prognosis. In some types of cancer, it has been shown through immunohistochemical analysis that the existence of CD8+ tumor-infiltrating lymphocytes (TILs) is a crucial factor in determining prognosis. In an experimental model, CD4+ lymphocytes together with CD8+ lymphocytes contributed significantly to tumor immunity. Methods Specimens were taken from 80 surgically resected pancreatic adenocarcinomas between 1992 and 1999. Immunohistochemical staining of CD4, CD8, and S100 protein was performed, and the levels of these proteins were determined by microscopic analysis. The percentages of patients in the CD4(+) and CD8(+) groups were 59% (47/80) and 25% (16/80), respectively. When separated into 4 groups, CD4/8(+/+), CD4/8(+/−), CD4/8(−/+) and CD4/8(−/−), the overall survival rate was significantly higher in CD4/8(+/+) patients (13 cases) compared with those in all other groups combined (67 cases; P = 0.0098). CD4/8(+/+) status was negatively correlated with tumor depth and TNM stage. Multivariate analyses showed that CD4/8(+/+) status was an independent favorable prognostic factor. The number of tumor-infiltrating S100 protein positive cells was also significantly higher in the CD4/8(+/+) group than in others (P = 0.0084). Conclusions In pancreatic adenocarcinoma, the presence of CD4+ TILs together with CD8+ TILs serves as a good indicator of the patients outcome after surgical treatment.

Impact of caveolin-1 expression on prognosis of pancreatic ductal adenocarcinoma.

Caveolin-1 is a major component of caveolae and plays a regulatory role in several signalling pathways. Caveolin-1 was recently identified as a metastasis-related gene in prostate cancer. The clinical effects of caveolin-1 expression in pancreatic carcinoma, however, remain unknown. In this study, we have investigated the relationship between caveolin-1 expression and the clinicopathologic variables and clinical outcome in 79 patients with pancreatic adenocarcinoma undergoing surgical resection. Caveolin-1 expression was determined by immunohistochemistry, using a polyclonal anti-caveolin-1 antibody. Patients were divided into two groups based on the extent of caveolin-1 expression: a negative expression group (immunoreactivity in less than 50% of cells) and a positive expression group. Positive caveolin-1 immunostaining was detected in 32 cases (40.5% of total), while non-neoplastic ductal epithelium showed little or no staining. Positive caveolin-1 expression was correlated with tumour diameter (P=0.0079), histopathologic grade (P=0.0272) and poor prognosis (P=0.0008). Upon multivariate analysis with Coxs proportional hazards model, positive caveolin-1 expression was shown to be an independent negative predictor for survival (P=0.0358). These results suggest that caveolin-1 overexpression is associated with tumour progression, thereby indicating a poor prognosis for certain patients undergoing surgical resection for pancreatic carcinoma.

Secondary tumors of the pancreas: Clinicopathological study of 103 autopsy cases of Japanese patients

To investigate the clinicopathological features of patients with secondary tumors of the pancreas, we reviewed autopsy records and pathological features of 103 cases with pancreatic secondary tumors from 690 cases of malignant tumors (excluding cases of primary pancreatic cancer) over a 10‐year period. There were 67 men and 36 women in the study, ranging in age from 2 to 94 years (mean: 61 years). The incidence of pancreatic secondary tumors was 15% in the autopsy cases of malignant tumors, and the majority of the secondary tumors were carcinomas. The stomach was the most common primary tumor site (20%), followed by the lung (18%) and extrahepatic bile duct (13%). Because the total number of each primary carcinoma differed, we paid specific attention to the incidence of pancreatic metastasis in each primary carcinoma. We found that carcinoma of the papilla of Vater showed the highest rate of incidence (75%) of pancreatic metastasis in each type of primary carcinoma. Approximately half of the metastatic lesions were solitary, but the metastatic lesions in the pancreas could not be identified macroscopically in 34 cases (33%). Histologically, the most common carcinoma was adenocarcinoma, followed by large cell carcinoma, small cell carcinoma and neuroendocrine carcinoma. The most common non‐epithelial tumor was leukemia, followed by malignant lymphoma. Undifferentiated carcinoma and neuroendocrine carcinoma were often found in cases of extrahepatic bile duct or urinary bladder carcinoma with pancreatic metastasis. As for the microscopic infiltration patterns of tumor cells, 73% of cases showed an interlobular and intralobular infiltration. Fat necrosis was most frequently seen as an associated pathological finding (19%). Our study indicates that secondary tumors of the pancreas can be found in approximately one out of six to seven autopsy cases of malignant tumors, and in Japan, the most common of these is adenocarcinoma of the stomach.

Overexpression of hypoxia-inducible-factor 1alpha(HIF-1alpha) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage.

The purpose of this study is to investigate the clinical and histopathologic significance of hypoxia-inducible-factor 1α (HIF-1α) expression in oesophageal squamous cell carcinoma. One hundred and thirty surgically resected specimens of OSCC were immunohistochemically assessed for HIF-1α expression with monoclonal antibody. High HIF-1α immunostaining was detected in 40 specimens. The percentage of high HIF-1α expression cases increased with tumour stage according to pTNM system. High HIF-1α expression correlated with pTNM stage, depth of tumour invasion, lymph node metastasis, distant metastasis, lymphatic invasion and positive surgical margin. The overall survival rate was worse in patients with high HIF-1α pattern than in patients with low-expression pattern. Univariate analyses identified high HIF-1α positivity, depth of tumour invasion, lymph node metastasis, distant metastasis, lymphatic invasion, and a positive surgical margin as risk factors. Multivariate analyses indicated that depth of tumour invasion, lymph node metastasis and positive surgical margin, but not HIF-1α, were independent prognostic factors. Survival in patients with a high HIF-1α expression was significantly worse than in those with low expression in patient treated with adjuvant therapy.

Expression of Pigment Epithelium-Derived Factor Decreases Liver Metastasis and Correlates with Favorable Prognosis for Patients with Ductal Pancreatic Adenocarcinoma

Pigment epithelium-derived factor (PEDF) is expressed in several normal organs and identified as an inhibitor of neovascularization. In the present study, we screened the expression of PEDF immunohistochemically and investigated its correlation with clinicopathological features in patients who underwent surgery for ductal pancreatic adenocarcinoma. Of the 80 patients, 22 cases (27.5%) were positive for PEDF. A significant association was found between the PEDF expression and low microvessel density (P = 0.0003). No correlation was found between PEDF expression and age, gender, depth of invasion, tumor diameter, lymphatic invasion, venous, invasion or histopathological grading. The patients in pathological stage II had a significantly higher incidence of PEDF-positive expression than those in pathological stage III or IVA (P = 0.0418). PEDF immunoreactivity was inversely associated with liver metastasis (P = 0.0422). The survival of patients that were PEDF positive was significantly longer than that of those with negative expression (P = 0.0026). Multivariate analysis using the Cox regression model indicated that PEDF-positive expression was an independent favorable prognostic factor (risk ratio, 0.394; P = 0.0016). We conclude that PEDF expression suggests a more favorable prognosis than in patients whose carcinomas lack PEDF expression.

P-ANCA-positive Wegener's granulomatosis presenting with hypertrophic pachymeningitis and multiple cranial neuropathies: case report and review of literature.

An autopsy case of hypertrophic pachymeningitis and multiple cranial neuropathies is reported. A 53‐year‐old woman with paraplegia and various neurological signs which developed over a 2 year period was diagnosed as having an epidural mass with thickened dura mater extending from the lower cervical to the thoracic spinal cord. In addition, bilateral episcleritis, blephaloptosis, and blindness of the right eye with various cranial nerve deficits were found to be caused by the mass lesions involving the paranasal sinuses, orbit, and the cavernous sinus. Perinuclear antineutrophil cytoplasmic antibody (p‐ANCA) was positive, but cytoplasmic antineutrophil cytoplasmic antibody (c‐ANCA) was negative by enzyme‐linked immunosorbent assay. The partially removed epidural mass with hypertrophied dura mater and biopsy of the paranasal lesions showed chronic granulomatous inflammation with vasculitis. The remaining lesions resolved with steroid therapy with remarkable neurological improvement. The positive p‐ANCA test, paranasal involvement, the report of a similar histopathological case and a review of the literature on granulomatous pachymeningitis suggest the presence of p‐ANCA‐positive Wegener’s granulomatosis with central nervous system involvement characterized by hypertrophic pachymeningitis and/or multiple cranial neuropathies.

A Human Anti‐CD40 Monoclonal Antibody, 4D11, for Kidney Transplantation in Cynomolgus Monkeys: Induction and Maintenance Therapy

Blockade of CD40–CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti‐CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti‐CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2‐week induction and 180‐day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T‐cell‐mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor‐specific Ab and anti‐4D11 Ab productions was obtained only with higher‐dose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B‐cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.

Clinical significance of immune cell infiltration within gallbladder cancer

To investigate the pathophysiological significance of infiltrating antitumour immune cells, we evaluated the quantity of immune cell intratumoral infiltration in 110 surgically resected gallbladder specimens by immunohistochemistry. We examined 45 cases of gallbladder cancer and 65 cases of benign gallbladder diseases for CD4+ T cells, CD8+ T cells, natural killer cells (NKCs), and dendritic cells (DCs). High levels of CD4+ T cell, CD8+ T cell, NKC, and DC infiltration were recognised in 51.1% (23 out of 45), 37.8% (17 out of 45), 33.3% (15 out of 45), and 48.9% (22 out of 45) of cancer specimens, respectively. High numbers of infiltrating CD4+ and CD8+ T cells correlated with decreasing tumour invasion, and high numbers of infiltrating DCs correlated with decreasing lymph-node tumour metastasis. Furthermore, increased infiltration of CD4+ and CD8+ T cells and DCs exhibited a significant correlation with prolonged survival. NKC infiltration, however, did not correlate with any of the clinicopathological factors examined. Additionally, high levels of infiltration were not identified in specimens from benign diseases, consistent with the cancer-specific activity of CD4+ and CD8+ T cells and DCs. In this study, we demonstrate that CD4+ and CD8+ tumour-infiltrating lymphocyte and DCs, but not NKCs, are important factors in the accurate prognosis of survival after surgical removal of gallbladder adenocarcinoma.

N stage disease in patients with non-small cell lung cancer: efficacy of quantitative and qualitative assessment with STIR turbo spin-echo imaging, diffusion-weighted MR imaging, and fluorodeoxyglucose PET/CT.

PURPOSE To prospectively compare the diagnostic capability of short inversion time inversion-recovery (STIR) turbo spin-echo (SE) imaging, diffusion-weighted (DW) magnetic resonance (MR) imaging, and fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in N stage assessment in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This prospective study was approved by the institutional review board, and written informed consent was obtained from all patients. A total of 250 consecutive patients with NSCLC (136 men; mean age, 73 years; 114 women; mean age, 72 years) prospectively underwent pretherapeutic STIR turbo SE imaging, DW MR imaging, and FDG PET/CT, as well as surgical and pathologic examinations (N0 disease, n = 157; N1 disease, n = 72; N2 disease, n = 16; N3 disease, n = 5). Lymph node-to-saline ratio (LSR), lymph node-to-muscle ratio (LMR), apparent diffusion coefficient (ADC), maximal standardized uptake value (SUV(max)), and visual scoring were assessed for 135 metastatic lymph nodes and 135 randomly selected nonmetastatic lymph nodes. Receiver operating characteristic curve analysis was used to determine feasible threshold values. Diagnostic capabilities for N stage assessment were compared with the McNemar test on a per-patient basis. RESULTS When feasible, threshold values were used for quantitative assessment; sensitivity and accuracy of LSR and LMR (sensitivity, 82.8%; accuracy, 86.8%) proved to be significantly higher than those of ADC (sensitivity: 74.2%, P = .01; accuracy: 84.4%, P = .04) and SUV(max) (sensitivity: 74.2%, P = .01). For qualitative assessment, sensitivity of STIR turbo SE imaging (77.4%) was significantly higher than that of DW MR imaging (71.0%, P = .03) and FDG PET/CT (69.9%, P = .02). CONCLUSION Quantitative and qualitative assessments of N stage disease in patients with NSCLC obtained with STIR turbo SE MR imaging are more sensitive and/or more accurate than those obtained with DW MR imaging and FDG PET/CT. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11110281/-/DC1.