A retrospective analysis of 335 Japanese lung cancer patients who responded to initial gefitinib treatment.

BACKGROUND: Gefitinib treatment results in considerably better progression-free survival compared with that of platinum doublets in the first line treatment of nonsmall-cell lung cancer (NSCLC) carrying an activating epidermal growth factor receptor (EGFR) mutation. Some patients who respond to gefitinib have an overall survival (OS) of more than 5 years, whereas other initial responders do less well. Although there has been considerable effort made to elucidate the mechanisms of acquired resistance, there have only been a few studies that addressed the effect of clinical backgrounds and treatment histories on the survival of the patients who had responded to an EGFR-tyrosine kinase inhibitor (TKI). In this study, we especially focused on the clinical benefit of EGFR-TKI administration after progression. PATIENTS AND METHODS: We retrospectively analyzed consecutive patients with advanced NSCLC who were diagnosed before October 2010, treated with gefitinib after July 2002, and responded to it. The primary objective of this study was to evaluate how clinical backgrounds and treatment histories influence survival of the patients who respond to gefitinib. The secondary objectives were to evaluate the safety of long-term gefitinib use and to establish the optimal treatment sequence using a dynamic treatment regimen analysis (DTRA). RESULTS: A total of 335 patients were recruited. Twenty-eight (8.4%) patients survived more than 5 years. Sixty-five and 93 patients received gefitinib as rechallenge and beyond progressive disease (BPD), respectively. A statistically significant difference in OS was observed between the patients who underwent gefitinib rechallenge and those who did not rechallenge (median: 1272 days vs. 774 days; p < 0.001), a result supported by a DTRA. Patients treated with gefitinib BPD also showed a tendency of longer survival. CONCLUSIONS: Gefitinib rechallenge and BPD played a central role in long term survival of the patients who initially responded to gefitinib.

Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan Multinational Trial Organization LC00-03.

BACKGROUND: Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). METHODS: A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded. RESULTS: The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36-0.97) and 0.71 (95% CI, 0.49-1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR). CONCLUSION: Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.

Irinotecan and etoposide for previously untreated extensive-disease small cell lung cancer: a phase II trial of West Japan Thoracic Oncology Group.

Irinotecan is a topoisomerase I inhibitor that is highly active against small cell lung cancer (SCLC). Etoposide is another drug that is effective for SCLC. Since combination of these two topoisomerase inhibitors revealed a synergistic effect in vitro and showed a safety in phase I study, we conducted a phase II study in patients with previously un-treated extensive disease (ED) SCLC to evaluate the efficacy and toxicity of this combination. Fifty patients with previously untreated ED-SCLC were enrolled. Irinotecan was administered intravenously at 60mg/m(2) on days 1, 8, and 15, while etoposide was given at 80mg/m(2) on days 2-4. Treatment was repeated every 4 weeks for four cycles. The overall response rate was 66.0%, with a complete response rate of 10.0%. The median survival time was 11.5 months and the 1- and 2-year survival rates were 43.2 and 14.4%, respectively. The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (62.9%), leukopenia (28.0%), and anemia (14%). The other grade 3 toxicity was diarrhea (2%). This irinotecan and etoposide regimen is active against ED-SCLC with relatively mild toxicity.

Interobserver variability in the pathological assessment of malignant colorectal polyps.

BACKGROUND: Treatment of patients with malignant large bowel polyps is highly dependent on pathological evaluation. The aim of this study was to evaluate interobserver variability in the pathological assessment of endoscopically removed polyps. METHODS: The records of 88 patients with colorectal cancer who underwent endoscopic removal of malignant polyps were reviewed. Study investigators reviewed the initial pathology report; three experienced gastrointestinal pathologists reviewed all slides in a blinded fashion. Interobserver variability of pathological assessment of malignant polyps was analysed by kappa statistics. RESULTS: Seventy-six (86 per cent) of the 88 patients had malignant polyps and 12 (14 per cent) had carcinoma in situ. Agreement between experienced pathologists was substantial with regard to T stage (kappa = 0.725), resection margin status (kappa = 0.668) and Haggitt's classification (kappa = 0.682), but comparison of initial and experienced pathologists' assessment demonstrated only moderate agreement in these areas (kappa = 0.516, kappa = 0.555 and kappa = 0.578 respectively). Agreement between even experienced pathologists was poor with respect to histological grade of differentiated adenocarcinomas (kappa = 0.163) and angiolymphatic vessel invasion (kappa = - 0.017). CONCLUSION: Pathological assessment of malignant polyps varies between observers. Specialist pathologists appear to have a higher degree of consensus among themselves than with generalist pathologists with respect to T stage. The high interobserver variability with regard to histological grade of differentiated tumours is clinically irrelevant. However, variability in the assessment of angiolymphatic vessel invasion limits the value of this measurement for clinical decision making.

Gemcitabine and vinorelbine followed by docetaxel in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial of nonplatinum sequential triplet combination chemotherapy (JMTO LC00-02).

To evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC), we conducted the multiinstitutional phase II study. A total of 44 chemotherapy-naive patients with advanced NSCLC were treated with GEM 1000 mg m(-2) and VNR 25 mg m(-2) intravenously on days 1 and 8 every 3 weeks for three cycles. DOC 60 mg m(-2) was then administrated intravenously at 3-week intervals for three cycles. Patients were evaluated for response and toxicity with each cycle of the treatment. The major objective response rate was 47.7% (95% confidence interval (CI), 33.8-62.1%). Median survival time (MST) was 15.7 months and 1-year survival rate was 59%. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 36.3%, grade 3/4 anaemia in two patients (4.5%) and grade 3 thrombocytopenia in one patient (2.3%). Grade 3 pneumonitis occurred in two patients (4.5%) in GEM/VNR cycles. In the DOC cycles, grade 3/4 neutropenia occurred in 39.4% but no patient experienced grade 3/4 anaemia or thrombocytopenia. Of the 44 eligible patients, 33 patients completed three cycles of GEM/VNR and 22 patients completed six cycles of planned chemotherapy (three cycles of GEM/VNR followed by three cycles of DOC). The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by DOC, and was very active and well tolerated. This study forms the basis for an ongoing phase III trial that compares this nonplatinum triplet and standard platinum doublet combination (carboplatin/paclitaxel).

Identification of extracapsular invasion of the metastatic lymph nodes as a useful prognostic sign in patients with resectable colorectal cancer.

PURPOSE: The present study was undertaken to evaluate whether the microscopic patterns of distribution and extracapsular invasion of cancer cells in the regional lymph nodes were linked to the survival rates for patients with advanced colorectal cancer who undergo a curative surgical resection. METHODS: Two hundred ninety-six surgically resected metastatic lymph nodes from 84 patients with node-positive colorectal cancer were microscopically examined. The distribution of cancer cells in the lymph nodes were grouped into two types: type A (> or =50 percent cancer) and type B (<50 percent cancer). The extracapsular invasion of cancer cells in the nodes were divided into three subgroups: pattern X (no evidence of cancer cell invasion into the adjacent tissue); pattern Y (less than five cancer cells were seen in the adjacent tissue); and pattern Z (more than five cancer cells invaded the adjacent tissue). The patients, based on these microscopic manifestations of metastatic patterns in the nodes, were divided into three groups: Group 1, patients with pattern X nodal metastases only; Group 2, patients with pattern Y and pattern (X + Y) nodal metastases; and Group 3, patients with pattern Z, pattern (X + Z), pattern (Y + Z), and pattern (X + Y + Z) nodal metastases. RESULTS: The survival rates and disease-free survival rates for patients with metastatic lymph nodes showing an extracapsular invasion pattern (Groups 2 and 3) were significantly worse than those for patients with metastatic nodes showing no extracapsular invasion pattern only (Group 1; P < 0.01). There was no significant difference for the above-cited survival rates among the groups classified according to the Dukes and TNM systems. CONCLUSIONS: It is the thesis of this article that the identification of extracapsular invasion of the metastatic lymph nodes can be taken as a useful prognostic sign in patients with resectable colorectal cancer.

Human colon cancer produces a factor which induces the proliferation of venous endothelial cells.

This study was performed to investigate whether colorectal cancers produce proliferative factors for venous endothelial cells, and whether the proliferative activity is related to basic FGF and VEGF and also to the clinicopathological findings. Surgically resected specimens of 17 colorectal cancer patients were fragmented and cultured, and the supernatant was collected. A human umbilical endothelial cell line (EA-hy 926 cells) was incubated with the supernatant. The proliferative activity was examined and the levels of basic FGF and VEGF were measured. The activities were found to be significantly related to VEGF, the depth of tumor invasion and the tumor stage.

[Pulmonary granulomatous lesion with severe chest pain and hemoptysis: a case report].

We encountered a rare case of pulmonary granulomatous lesion accompanied with severe chest pain and hemoptysis. A 42-year-old man visited our hospital complaining of hemosputum. A chest radiograph showed a nodular shadow in the left lower lung field. Further examinations including fiberoptic bronchoscopy, bronchoalveolar lavage and transbronchial lung biopsy did not suggest a diagnosis. During the course of his illness, he suffered an episode of severe chest pain which could be controlled only by intravenous morphine chloride (10 mg). The chest radiograph at the time showed a broad infiltration in the left lower lung field. However, the lung perfusion scintigram taken 2 days before demonstrated decreased blood flow in the same field. We waited for the infiltration in the chest radiograph to diminish and then performed partial resection of the left lower lobe, thus terminating both hemosputum and chest pain. Histological examination showed a cavitary lesion in the periphery of the lung, surrounded by large numbers of infiltrating plasma cells and lymphocytes, among which were many hemosiderinladen macrophages. A small amount of mycelium, considered to be Nocardia or fungus, was seen in the cavity wall. These findings may indicate that an infection had contributed to the formation of a hemorrhagic granulomatous lesion, and that this lesion caused chest pain mainly because of the pleuritis and the decrease in the local pulmonary circulation.

Herniation of the small bowel through the port site following removal of drains during laparoscopic surgery.

BACKGROUND/AIMS: Generally, the port site is used as the delivery route for drainage after laparoscopic abdominal surgery. We report this case because of the rarity of the complication related to laparoscopic procedures. METHODS: A 75-year-old woman underwent a laparoscopic-assisted sigmoid colectomy for early stage cancer. RESULTS: After the operation, her postoperative course was uneventful. However, just after removing the drains, the small bowel was found to have herniated through the port site used as the insertion route for the drains. An emergency relaparotomy was done and a segment of the necrotic small bowel had to be resected. CONCLUSION: To prevent this complication, we suggest that, first of all, in elderly and thin patients smaller trocar insertion sites (<10 mm) should be utilized as insertion routes for the drains and, secondly, the fascial defect should be closed just after removing the drains whenever the defect measures 10 mm or more in size.

[Improvement in quality of life with vinorelbine as a single agent in two patients with recurrent lung cancer].

Two patients with lung cancer that recurred after surgery and chemotherapy were administered vinorelbine (20 mg/m2) as a single agent on days 1 and 8 every 4 weeks. Patient 1 had recurrences in both lung lobes and metastases in the bone and liver after surgery, while patient 2 had a recurrence in the left lung lobe and metastases in the brain and liver after prior chemotherapy. In both patients, vinorelbine treatment improved several clinical indicators of cancer symptomatology including serum LDH, levels of other clinical blood tests, as well as a subjective assessment of the quality of life (QOL). Both patients were discharged from the hospital and subsequently treated on an outpatient basis. Because recurrent lung cancer patients generally have a poor performance status, chemotherapy for these patients is thought to worsen the QOL and increase hospital stays. The present report suggests that vinorelbine, as a single agent, might improve the QOL and make it possible to treat recurrent lung cancer patients on an outpatient basis.

MRI facilitated a diagnosis of endometriosis of the rectum.

A 51-year-old pre-menopausal Japanese woman suffering from chronic lower abdominal pain was referred to our hospital. A barium enema showed a stenotic lesion in the recto-sigmoid region, and a pelvic computed axial tomography (CAT) scan revealed a thickened rectal wall. A colonoscopic examination showed the rectum to be constrictive, but the mucosa appeared to be intact. Magnetic resonance imaging (MRI) with T1 high-intensity revealed a cystic lesion in the thickened wall of the rectum, which led us to suspect possible bowel endometriosis. Part of the biopsy specimen showed endometrial epithelium within the interstitial layer of histologically normal mucosa; finally, endometriosis of the rectum was diagnosed. The patient became asymptomatic after the initiation of hormonal treatment and later experienced spontaneous menopause. MRI was effective for diagnosis and the patient did not undergo unnecessary laparotomy. Although bowel endometriosis is generally diagnosed by means of resected specimens, in our patient, diagnosis was made using MRI and biopsy, and hormonal therapy had an effective role as a bridge to menopause.

The detection of colorectal cancer at an asymptomatic stage by screening is useful.

BACKGROUND/AIMS: The validity of mass screening using fecal occult blood testing remains controversial. In addition, no controlled clinical study has yet been performed to show the usefulness of sigmoidoscopy. The purpose of the present study was to compare the surgical results achieved in asymptomatic patients with colorectal cancer detected by screening with those in symptomatic individuals. METHODOLOGY: A total of 285 patients underwent a surgical resection of colorectal cancer between 1991 and 1997 at our institution. Among them, 233 patients had complaints related to cancer at the time of diagnosis. In contrast, 52 were asymptomatic. In those 52 patients, colorectal cancer had been suspected based on routine screening including fecal occult blood testing, colonoscopy and/or elevated serum levels of carcinoembryonic antigen. RESULTS: Early stage of colorectal cancer was more frequently seen in asymptomatic patients than in symptomatic patients P < 0.01. The survival rates for asymptomatic patients was also superior to those of symptomatic patients P < 0.05. CONCLUSIONS: Screening using fecal occult blood testing, colonoscopy and tumor markers is thus considered to be beneficial for the early detection of colorectal carcinoma, which also tends to demonstrate good surgical results.

Frequency of apoptosis of tumor-infiltrating lymphocytes induced by fas counterattack in human colorectal carcinoma and its correlation with prognosis.

We investigated apoptosis in tumor-infiltrating lymphocytes (TILs) obtained from 41 colorectal carcinomas by in situ nick translation (ISNT). When the ISNT labeling index (LI) was determined as the number of positive nuclei per 1000 nuclei of TIL in tissue sections, the median LI was 12.0 (range, 2-30). The ISNT LI of colorectal carcinoma with lymph node metastasis was higher than that of colorectal carcinoma without metastasis. The cases with a high LI of 212.0 had a significantly poorer prognosis than those with a low LI. We also confirmed immunohistochemically that a part of the TILs expressed Fas using the sections adjacent to what contained abundant ISNT-positive TILs. Moreover, Fas ligand (FasL) expression was detected on the cell surface as well as the cytoplasm of colorectal cancer cells in 61% of cases. Apoptosis in TILs was consistently seen more frequently in FasL-positive cases than in FasL-negative ones. These findings indicate that the FasL expressed in colorectal carcinoma cells may kill the Fas-positive immune effective TILs by means of a Fas-FasL system termed Fas counterattack. This tumor immune evasion induced by FasL may therefore affect the malignant potential of human colorectal carcinoma.

Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity.

SETTING: Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP). OBJECTIVE: To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity. DESIGN: Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation. RESULT: Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95% CI 1.94-6.06) for intermediate-type and 28.0 (95%CI 26.0-30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types. CONCLUSION: Slow NAT2* genotype significantly affected the development of INH + RMP-induced hepatotoxicity. This suggests the possibility that NAT2* genotyping prior to medication may be useful in evaluating patients with high risk for INH + RMP-induced hepatotoxicity.

Hepatic resections for bilobar liver metastases from colorectal cancer.

The present study was performed to assess survival benefits in patients who underwent a hepatic resection for isolated bilobar liver metastases from colorectal cancer. Thirty-eight patients underwent a curative hepatic resection for isolated colorectal liver metastasis. Among them, 11 patients had bilobar liver metastases and 19 had a solitary metastasis. The remaining 8 patients had unilobar multiple lesions. We investigated survival in two groups those with bilobar and those with solitary metastatic tumors. Survival and disease-free survival were 36% and 18% at 5 years, respectively, in the patients with bilobar liver metastases, while these survivals were 43% and 34% in the patients with solitary liver metastasis. In the 38 patients, repeated hepatic resections were performed in 15 patients with recurrent liver disease. The 5-year survival and disease-free survival rates for these patients were 38% and 27%, respectively, after the second hepatic resections. Of the 11 patients with bilobar liver metastases, 5 underwent a repeated hepatic resection, and they all survived for over 42 months. Based on our observations, a hepatic resection was thus found to be effective even in selected patients with either bilobar nodules or recurrence in the remnant liver.

Detection of carcinoembryonic antigen mRNA in the mesenteric vein of patients with resectable colorectal cancer.

The detection of tumor cells in the drainage venous blood of patients with colorectal cancer was made feasible by demonstrating carcinoembryonic antigen (CEA) mRNA in the mononuclear cell component of the blood, using a nested reverse transcription-polymerase chain reaction. CEA mRNA was detected in the drainage venous blood from 11 (42%) of 26 patients, and the rate of detection increased according to the grade of vessel invasion. CEA mRNA was detected in all patients with synchronous liver metastases, even though there was no significant correlation between the presence of CEA mRNA in the drainage venous blood and the clinicopathological findings. As the presence of CEA mRNA in the drainage venous blood is an indicator of the spread of tumor cells in patients with colorectal cancer, this assay can be used to assess the possible outcome of patients with colorectal cancer, providing one more tool for the physician-oncologist to use in designing appropriate treatments.

[Metastasis of small cell lung cancer to the parotid gland as the initial clinical manifestation, followed by metastases to the pituitary gland and lumber spinal cord].

The patient was a 48-year-old woman. In January 1995, she noted swelling in the left parotid gland, and saw an otorhinolaryngologist. Needle biopsy showed small cell carcinoma, and she was subsequently admitted to our hospital. Chest radiography revealed a tumor shadow in the hilus of the right lung. Bronchial biopsy revealed small cell carcinoma of the lung (T 4 N 3 M 1, stage IV). Chemotherapy, with a CDDP-VP-16 regimen, achieved no response. She later developed bitemporal hemianopsia and abducens nerve palsy. Brain MRI revealed metastasis in the pituitary gland. Chemotherapy and radiotherapy were efficacious for only a few months. She also developed pain and numbness in the left leg, attributable to intramedullary metastasis (L 1/2, L 4/5) shown on MRI. It is extremely rare for a metastasis to the parotid gland to be the initial clinical manifestation of a small cell lung cancer which later develops widespread metastases to the pituitary gland and lumbar spinal cord.

Structural changes in blood vessels entering the growth plate during growth in rats.

We observed the structural changes in blood vessels entering the growth plates of the femur and tibia of rats during growth using scanning electron microscopy. The penetrating vessels had blind endings which were bulbous at a time when rats showed rapid skeletal development. With subsequent slowing of development, the density of the vessels decreased and the blind endings became short stumps. These changes were more prominent in the proximal femur than in the distal femur and proximal tibia. The present study indicates an intimate relation between endochondral ossification in the growth plate and the structure of the penetrating vessels.