Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas.

The purpose of the present study was to establish accurate prognostic markers to predict the post-operative recurrence of stage I lung adenocarcinomas (ADC). One-hundred and ninety cases of stage I ADC were examined for KRAS mutations and Ki-67 expression, and their associations with disease recurrence were analyzed. KRAS-mutated cases showed a significantly higher risk of recurrence than cases without mutations (5-year disease-free survival (DFS) 61.0% vs. 85.8%, P=0.017: adjusted Hazard ratio (HR) 4.55, 95% Confidence Interval (CI) 1.61-12.82, P=0.004). Ki-67 high-expressers (labeling index >10%) also showed a higher risk of recurrence than low-expressers (5-year DFS 68.7% vs. 93.2%, P<0.001: adjusted HR 3.84, 95% CI 1.18-12.45, P=0.025). Ki-67 high-expressers with KRAS mutations showed an additional higher risk of recurrence compared to low-expressers without mutations (5-year DFS 37.5% vs. 93.3%, P<0.001: adjusted HR 16.82, 95% CI 3.77-74.98, P<0.001) and their 5-year DFS was nearly equivalent to that of stage II non-small cell lung cancer (NSCLC) in our facility (37.5% vs. 37.2% for stage II NSCLC, p=0.577). The combined use of KRAS status and Ki-67 expression level could be an excellent prognostic marker to predict the post-operative recurrence of stage I ADC.

Strangulation necrosis of the intestine in a patient with giant polycystic kidney disease: a rare cause of acute abdomen.

We recently treated a patient with strangulating intestinal necrosis caused by the enlarged abdominal cysts characteristic of autosomal dominant polycystic kidney disease (ADPKD). A 75-year-old Japanese woman with a 30-year history of ADPKD underwent surgery to treat a diagnosis of acute abdomen. Surgery confirmed that the mesenterium was stretched caudally over the huge cysts that occupied the entire abdominal cavity, and the intestines were necrotic from the jejunum to the transverse colon. Veins from the necrotic intestine were dilated, and an arterial pulse could be felt. These findings resulted in a diagnosis of strangulation necrosis of the intestine caused by occlusion of the mesenteric vein by the enlarged cysts. The necrotic intestine was excised, and a proximal jejuno-transverse colostomy was performed. Pathological examination revealed hemorrhagic necrosis and marked congestion of the resected intestine. This case describes a rare, but clinically important, variation of ADPKD.

Long-term outcome after hernia repair with the prolene hernia system.

PURPOSE: We evaluated the long-term outcome and symptoms after inguinal hernia repair using the Prolene Hernia System (PHS). METHODS: We reviewed the medical records of all patients who underwent PHS surgery at our hospital to assess the postoperative complications and recurrence rates. Late symptoms were evaluated by a standardized interview using a questionnaire. RESULTS: A total of 395 hernias in 367 patients were studied. Postoperative complications developed after 20 repairs (5.1%), including a severe mesh infection in one patient. Seven (1.8%) patients suffered recurrence. Of 395 cases, 363 (91.9%) responded to the interview. After a median follow-up interval of 19.3 months (range 1.0-55.8), moderate pain and moderate discomfort were reported by only 1.9% and 0.8% of patients, respectively. CONCLUSIONS: Prolene Hernia System surgery is a safe and feasible procedure with low rates of complication, recurrence, and late symptoms.

Growth index, assessed with Ki-67 and ssDNA labeling; a significant prognosticator for patients undergoing curative resection for hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: The aggressiveness and greater malignant potential of cancers are characterized by several biological phenomena such as accelerated growth invasiveness, and the ability to form distant metastasis. Thus, knowledge of such biological difference may be a more accurate prognosticator for cancer patients. Tumor growth depends on the degree of imbalance between cell production and loss. This study aimed to clarify a possible role for the modified prognosticator, growth index (GI); defined as the difference between Ki-67 (%) and single-stranded DNA (ssDNA) (%) labeling indices, in patients undergoing curative resection for hepatocellular carcinoma (HCC). METHODS: Tissue specimens were obtained from 40 HCC patients who underwent curative surgery. Immunohistochemical staining was performed using the avidin-biotin-peroxidase-complex method. RESULTS: The GI in HCC ranged from -1.90% to 28.65%, median 3.73. GI was related to histologic grade, intrahepatic metastasis, and pathologic T stage. Cumulative survival was poorer in patients with higher GI (> or = median value). Multivariate analysis demonstrated that GI is an independent prognosticator along with vascular invasion and intrahepatic metastasis. CONCLUSIONS: The higher GI values were significantly associated with histologic aggressive features of HCCs, and GI was a significant independent prognosticator in HCC patients after curative resection.

[Two cases of advanced gastric cancer, successfully treated with TS-1/CDDP combination chemotherapy--case report].

We reported 2 cases with advanced gastric cancer, successfully treated with TS-1 and CDDP. Case 1 had Type 3 gastric cancer with left supra-clavicular (Virchow) and para-aortic lymph node metastases. Those distant node metastases completely disappeared after two courses of neoadjuvant chemotherapy (NAC) consisting of TS-1/ CDDP, and radical surgery for cure was conducted. The second case had Type 3 carcinoma with peritoneal dissemination. The primary lesion significantly decreased after four courses of the combination chemotherapy. The patient has been alive for 1 year and a half after 14 courses of TS-1/CDDP with stable disease. Significance of TS-1/CDDP in far advanced gastric cancer was discussed.

Expression of survivin mRNA associates with apoptosis, proliferation and histologically aggressive features in hepatocellular carcinoma.

The clinical impact of survivin on human cancer pathogenesis and prognosis has been investigated. To clarify the clinical effect of survivin on tumor behavior and prognosis of patients with hepatocellular carcinoma (HCC), the expression of survivin mRNA in 40 samples of HCC tissue and matched-adjacent liver tissue, as well as 7 healthy hepatic tissue samples were measured by a real-time reverse transcription polymerase chain reaction. The expressed level of survivin mRNA (log copies/microg total RNA) in healthy liver tissue was 1.95+/-0.44, in morbid liver tissue adjacent to the tumors was 4.79+/-0.96, and in HCC tissue was 5.87+/-0.73 (values are mean +/- SD and P<0.001). The amount of survivin mRNA in HCC tissues correlated negatively with the apoptotic indices (r=-0.573 and P<0.001) and correlated positively with the proliferation indices (r=0.433 and P=0.005). Expression of survivin was significantly related with histologic grade (P=0.011) and pathological tumor stage (P=0.017). Patients with HCC tumors that had a large amount of survivin mRNA (> or = mean) had lower survival rate (P=0.030), but multivariate analysis showed only Ki-67 labeling index, histologic grade, and pathologic T stage to be the independent prognosticators. These findings indicate that survivin is associated with reduced tumor cell apoptosis, increased tumor cell proliferation, and histologically aggressive tumor features, and may play an important role in tumor progression of HCC. However, further examination is needed to clarify its predictive significance for HCC patients.

Is bursectomy necessary for patients with gastric cancer invading the serosa?

BACKGROUND/AIMS: To confirm the impact of bursectomy on survival, we reviewed the clinical records of patients who underwent radical total gastrectomy with bursectomy for gastric cancer invading the serosa, with special reference to the location of tumor invasion. METHODOLOGY: From the records, patients were selected for this retrospective cohort study according to the following criteria: (a) Invasion beyond the serosal surface, (b) No metastases to liver, peritoneum, or distant organs, (c) Negative for peritoneal lavage cytology, and (d) Patients underwent curative D2 total gastrectomy with complete omental bursectomy. A total of 134 patients were eligible. These patients were divided into a group I which included patients with tumors that invaded only the posterior wall and a group II which included those with others. Survival was examined by uni- and multivariate analyses. RESULTS: Survival rates at 3 and 5 years were 67.3% and 53.0% for group I and 68.8% and 53.8% for group II. There was no significant difference in the survival between the two groups (p=0.969), even if survival was stratified by various clinicopathological factors. Multivariate analyses demonstrated that the significant independent factors for the survival were macroscopic type and lymph node metastasis. Location of the invasion was not a significant factor. CONCLUSIONS: These results suggested that bursectomy did not inhibit the spreading of tumor cells into the retro-stomach space. There might be no survival benefit of bursectomy in patients with gastric cancer.

Effects of TS-1 on peritoneal dissemination of gastric cancer in nude mice.

BACKGROUND/AIMS: We investigated the effects of TS-1 on the survival of nude mice developing peritoneal dissemination of gastric cancer. METHODOLOGY: MKN-45 cells were injected into the peritoneal cavity of nude mice and a model of peritoneal dissemination was developed. TS-1 was administered orally every day from day 1 to day 10 or day 10 to day 19. RESULTS: Survival time of these treatment groups was significantly longer than untreated controls. In a pharmacokinetic study, TS-1 was administered on day 10 and the 5-fluorouracil levels were retained and maintained for a longer time, in the ascites and tumor than in plasma. The area under the concentration curve for 5-FU in the tumor was higher, than in plasma or ascites. CONCLUSIONS: TS-1 could be effective in treating peritoneal dissemination of gastric cancer, due to the supply of 5-fluorouracil in the tumor by systemic and intraperitoneal circulation.

Can surgical diagnosis of "early" gastric cancer and lymph node metastasis be accurate?

BACKGROUND: The objective of this study was to evaluate the accuracy of the intraoperative assessment of early gastric cancer (EGC) and lymph node status. METHODS: A total of 280 patients underwent gastrectomy for primary gastric cancer at the Department of Surgery, Yokohama City Kowan Hospital, from 1994 to 2002. Of these 280 patients, 140 were diagnosed as having EGC during surgery (sT1), while the rest were diagnosed with advanced disease (sT2-T4). Of the former 140 patients, 136 patients, who underwent curative resection with D1 or D2 lymphadenectomy, were further investigated for the assessment of lymph node status. RESULTS: The sensitivity, specificity, and accuracy of the surgical diagnosis of EGC were 96.4% (135 of 140), 90.0% (126 of 140), and 93.2% (261 of 280), respectively, while these values for the assessment of lymph node metastases were 55.6% (5 of 9), 94.5% (120 of 127), and 91.9% (125 of 136), respectively. In a further analysis in which patients with tumors of macroscopically depressed type and undifferentiated histology were excluded, all patients staged as sT1sN0 had no lymph node metastases pathologically. CONCLUSION: Although the depth of tumor invasion can be correctly assessed intraoperatively, it is difficult to be precise regarding the presence of nodal metastases. One practical solution to this problem might be to employ limited surgery for those patients with macroscopically elevated and histologically differentiated tumors.

[A case of small cell carcinoma of the stomach].

We report a case of small cell carcinoma of the stomach in a 60-year-old man. The patient was found to have a gastric tumor by routine upper gastrointestinal endoscopy for chronic gastrititis, and was admitted to the hospital. The patient underwent a curative distal gastrectomy with D2 lymph node dissection following a diagnosis of early gastric cancer at the posterior wall of the antrum, in June 2001. Surgical findings were T1, N1, P0, H0, M0, stage I b. The final pathological diagnosis was small cell carcinoma of the stomach with severe lymphatic and vascular invasion (INF alpha, sm, ly3 v2, n1 (+)). In a review of 47 cases seen in the Japanese literature, only 5 patients had early gastric cancer. Lymph node metastasis was observed in 95.0% of all cases, and liver metastasis in 41.0%. Four of the 5 patients with early gastric cancer (80.0%) had lymph node metastases. The prognosis was reported to be extremely poor because small cell carcinoma frequently metastasizes to lymph nodes and/or the liver even in an early stage. The chemotherapy selected by many hospitals is mainly CDDP, but the use of chemotherapeutic drugs varied from hospital to hospital and no effective chemotherapy for the disease has been established as yet.

Clinical usefulness of intraoperative sentinel-node biopsy in gastric cancer.

BACKGROUND/AIMS: Minimally invasive surgery has been used to improve the quality of life after operation in patients with gastric cancer. Sentinel-lymphnode biopsy can help to limit the extent of lymph node dissection, but the diagnostic and therapeutic usefulness of this technique has not been accurately evaluated in gastric cancer. This study was designed to clarify the role of intraoperative sentinel-node biopsy in patients with gastric cancer. METHODOLOGY: We were conducted to evaluate 1) mapping sentinel nodes according to tumor location 2) comparison sentinel node metastases as assessed by frozen section, permanent section (HE stain) and immunohistochemical diagnoses, and 3) comparison non-sentinel node metastases as assessed by permanent section (HE stain) and immunohistochemical diagnosis. RESULTS: All sentinel nodes were identified in the regional perigastric lymph node group close to the tumor. Four of the 43 sentinel lymph nodes were positive for metastasis. Similar diagnostic results were obtained by the 3 different procedures. Lymph node metastasis was found in 10 (4 sentinel nodes and 6 non-sentinel nodes) of 779 lymph nodes (1.28%) on HE staining. Immunohistochemical studies revealed a similar number of positive sentinel nodes as that obtained on HE staining, but identified metastases in 15 in non-sentinel nodes in 2 patients, as compared with only 6 nodes on HE staining. In one patient, sentinel nodes at No. 1 and No. 3 were negative for metastasis, whereas non-sentinel lymph nodes at NO. 3 were positive for metastasis. The other patient had negative sentinel nodes at No. 3 and No. 4d, but positive non-sentinel nodes at No. 4d. CONCLUSIONS: The results of this small study do not yet provide a firm basis for recommending that sentinel-node biopsy is used to reduce the extent of lymph node dissection.

Correlation between lymph node micrometastasis and histologic classification of small lung adenocarcinomas, in considering the indication of limited surgery.

The validity of limited surgery for lung carcinomas have not been clearly established. Several reports suggest that not only tumor size but also the histological findings may be of importance in this role. By conducting immunohistochemical examinations of lymph node micrometastases from small lung adenocarcinomas, we considered the suitability of limited surgery for especially localized bronchioloalveolar carcinoma (LBAC) without active fibroblastic proliferation (Noguchi's histologic classification types A and B). In this study, we enrolled 54 patients with lung adenocarcinoma smaller than 2 cm in diameter. Lymph node involvement was demonstrated in 11 (20.4%) patients. Lymph node micrometastasis was present in 11 (25.6%) of the 43 patients at pN0 disease. However, 13 patients with LBAC without active fibroblastic proliferation (types A and B) had neither lymph node involvement nor micrometastasis. Our results indicate that limited pulmonary resection may be acceptable procedure for LBAC without active fibroblastic proliferation.

[Recurrence of right breast cancer at the thoracic wall successfully treated with intra-arterial infusion of doxorubicin hydrochloride--a case report].

We report a recurrent case of breast cancer successfully treated with intra-arterial infusion of doxorubicin hydrochloride (ADM) combined with systemic CAF therapy. The patient, a 37-year-old woman, was diagnosed with a recurrence at the thoracic wall 55 months after curative resection for right breast cancer. She was treated with intra-arterial infusion chemotherapy of ADM, 30 mg, combined with systemic CAF therapy of cyclophosphamide, 100 mg from days 1 to 14, ADM, 30 mg on days 1 and 8, and 5-fluorouracil, 500 mg on days 1 and 8, as one course. Two courses of the treatment resulted in a complete response of the tumor. This result suggests that local and systemic chemotherapy could be effective for the treatment of local recurrence of breast cancer.

Osteoclast-like giant cell tumor of the pancreas.

A rare case of osteoclast-like giant cell tumor of the pancreas is reported. A 45-year-old woman presented with upper abdominal pain and weight loss. Examination revealed a tumor in the tail of pancreas, and distal pancreatectomy with splenectomy was performed. Pathological findings showed the tumor was composed of two cell types: atypical mononuclear round cells and abundant osteoclast-like multinucleated giant cells with central nucleoli. Immunohistochemical study showed that the atypical cells were strongly reactive for vimentin and negative for CD68, while the giant cells were immunoreactive for CD68, but negative for vimentin. The tumor was diagnosed as osteoclast-like giant cell tumor of the pancreas. We report this case and review 31 cases previously described in the literature.

Prediction of postoperative pulmonary function using perfusion magnetic resonance imaging of the lung.

PURPOSE: To assess semiquantitatively the regional distribution of lung perfusion using magnetic resonance (MR) perfusion imaging. MATERIALS AND METHODS: Subjects were 20 consecutive patients with bronchogenic carcinoma, who underwent MR imaging (MRI) and radionuclide (RN) perfusion scans for preoperative evaluation. Three-dimensional (3D) images of whole lungs were obtained before and 7 seconds after bolus injection of contrast material (5 ml of Gd-DTPA). Subtraction images were constructed from these dynamic images. Lung areas enhanced with the contrast material were measured and multiplied by changes in signal intensity, summed for the whole lung, and the right-to-left lung ratios were calculated. The predicted postoperative forced expiratory volume in 1 second (FEV1) was estimated using MR and RN perfusion ratios. RESULTS: The correlation between perfusion ratios derived from the MR and RN studies was excellent (r = 0.92). Sixteen of 20 patients underwent surgery, and 12 patients had postoperative pulmonary function tests. The predicted FEV1 derived from the MR perfusion ratio correlated well with the postoperative FEV1 in the 12 patients (r = 0.68). CONCLUSION: Perfusion MRI is suitable for semiquantitative evaluation of regional pulmonary perfusion.

Aberrant nuclear localization and gene mutation of beta-catenin in low-grade adenocarcinoma of fetal lung type: up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors that form morules.

The salient histopathologic features of low-grade adenocarcinoma of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA. These observations lead us to hypothesize that up-regulation of the Wnt signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma of the fetal lung type (H-FLAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for beta-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the beta-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the beta-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of beta-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of beta-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA. The present study together with other available data also suggests that abnormal up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites.