[Effectiveness of Nivolumab in a Case of Inoperable Advanced Gastric Cancer with Lung Metastasis].

A 66-year-old man was diagnosed with inoperable advanced gastric cancer with liver and peritoneal metastases. The patient underwent SOX therapy as primary chemotherapy; subsequently, liver and peritoneal metastases disappeared. However, lung metastasis was detected later, and weekly paclitaxel(PTX)combined with ramucirumab(RAM)chemotherapy was initiated; subsequently, lung metastasis and advanced gastric cancer disappeared. During remission, lung metastasis was detected again. Although weekly PTX combined with RAM chemotherapy was reinitiated, a progressive disease status was achieved. As tertiary chemotherapy, nivolumab therapy(240 mg/body, every 2 weeks)was initiated for 20 courses over 11 months. This therapy was significantly effective, which aid the patient to achieve a complete response. The patient survived and is healthy for 5 years due to chemotherapy administration alone.

[A Case of Non-Resectable Advanced Gastric Cancer for Which Nivolumab Was Markedly Effective].

A 74-year-old man presented to our hospital because of anorexia. Upper gastrointestinal endoscopy revealed type 3 gastric cancer. Further examination disclosed metastasis to the perigastric lymph nodes and to the liver, and a diagnosis of non- resectable advanced gastric cancer(cT4N2H1P0M0)in cStage Ⅳ was made. A total of 4 courses of S-1 plus oxaliplatin therapy(80 mg/body/day and 100 mg/m2/cycle, respectively, for 2 weeks followed by a 1-week rest)were administered as the primary chemotherapy. Then, another metastasis to the abdominal lymph nodes and increased liver metastasis were found; thus, the patient's condition was rated as progressive disease(PD). Secondary chemotherapy comprising 10 courses of weekly nab-paclitaxel(nab-PTX)plus ramucirumab(RAM)therapy(100 mg/m2 on days 1, 8, and 15 and 8 mg/kg on days 1 and 15, respectively, every 4 weeks)were administered. Although temporary reductions in the perigastric lymph node metastasis and liver metastasis as compared with the baseline were observed, another metastasis to the abdominal lymph nodes occurred subsequently, resulting in PD. As tertiary chemotherapy, nivolumab therapy(240 mg/body, every 3 weeks) was repeated up to a total of 30 courses over 13 months. This therapy was markedly effective, achieving a near complete response. The patient is currently being followed up as an outpatient.

[Transverse Colon Cancer with Peritoneal Metastasis Successfully Treated with mFOLFOX6 plus Bevacizumab-A Case Report].

A male patient in his 80s, diagnosed with rectal cancer, underwent transverse colon resection(pT3, pN0, cM0, and pStage Ⅱa, RAS wild-type, BRAF-mutant). However, 19 months later, intraperitoneal metastasis was detected and the patient received 8 courses of mFOLFOX6 plus bevacizumab. Following the observation of an allergic reaction that was attributable to oxaliplatin, the regimen was changed to a total of 7 courses of sLV5FU2 plus bevacizumab. Subsequently, a marked decrease was observed in intraperitoneal metastasis. The patient completed sLV5FU2 plus bevacizumab chemotherapy. At 1 year after the marked decrease, the metastatic recurrence was not exacerbated.

[Long-Term Survival of a Patient with Inoperable Gastric Cancer with Distant Lymph Node Metastasis-A Case Report].

A 76-year-old female patient was diagnosed with inoperable gastric cancer with distant lymph node metastasis(cT3N2M1 [LYM], cStage Ⅳ), for which she received S-1 chemotherapy(orally administered on days 1-14 ofa 28-day courses). The patient received a total of4 2 treatment courses. After an initial phase of stable disease due to chemotherapy, she eventually showed progressive disease. S-1 chemotherapy was discontinued. Because ofher social background, she decided against any further chemotherapy. After 1 year, she underwent metallic stent insertion through the gastric cancer, which enabled her to consume food. She is currently alive as of 5 years and 3 months from the date of first diagnosis.

[A Case Report of Inoperable Gastric Cancer with Peritoneal Dissemination, Liver Metastasis, and Lung Metastasis Successfully Treated with Weekly Paclitaxel and Ramucirumab].

A 63-year-old man diagnosed with a perforated gastric ulcer and generalized peritonitis underwent surgical intervention. However, computed tomography(CT), esophagogastroduodenoscopy(EGD), and positron emission tomography-CT(PETCT) revealed an inoperable gastric cancer with liver and peritoneal metastases(cT4NxH1P1M0, cStage Ⅳ, for which he received S-1 and oxaliplatin chemotherapy[SOX therapy]). The patient underwent 10 SOX therapy cycles. Following the initial chemotherapy course, the peritoneal and liver metastases disappeared on radiographic images. However, lung metastasis was detected, and the patient initiated weekly paclitaxel(PTX)and ramucirumab(RAM)chemotherapy. After 4 treatment cycles, lung metastasis and gastric cancer disappeared.

[A Case Report of Sigmoid Colon Cancer with Multiple Lung Metastases Successfully Treated with S-1].

A patient in his 70s was diagnosed with sigmoid colon cancer[pT3pN1cM1(PUL1), pStage IV ]for which he underwent sigmoid colectomy and received S-1 adjuvant therapy for the lung metastases. The patient received a total of 10 courses of S- 1, administered orally on days 1-14 of a 21-day cycle. The lung metastases showed a complete response, and the patient completed the S-1 chemotherapy. No recurrence of lung metastases was detected up to 6 months later.

[A Case of Rectal Cancer with Multiple Liver, Lung, and Para-Aortic Lymph Node Metastases Successfully Treated with FOLFOX4 plus Bevacizumab].

A patient in his 70s was diagnosed with rectal cancer (pT3, pN1, cM0, and pStage IIIa) for which he underwent low anterior resection of the rectum and received adjuvant therapy with UFT/LV. Multiple liver, lung, and para-aortic lymph node metastases were detected after 6 months, and the patient then received a total of 24 courses of FOLFOX4 plus bevacizumab instead of UFT/LV. The liver and para-aortic lymph node metastases showed a complete response (CR), and the lung metastases markedly diminished. Therefore, the patient completed the FOLFOX4 plus bevacizumab chemotherapy regimen. After 2 years, a recurrence of the initial liver metastases was detected. A CR on radiological imaging does not correspond to a pathological CR. Therefore, a careful follow-upis required even when a CR on radiological imaging is achieved.

Immunophenotypic features of metastatic lymph node tumors to predict recurrence in N2 lung squamous cell carcinoma.

Patients with mediastinal lymph node metastasis (N2) in squamous cell carcinoma (SqCC) of the lung have poor prognosis after surgical resection of the primary tumor. The aim of this study was to clarify predictive factors of the recurrence of pathological lung SqCC with N2 focusing on the biological characteristics of both cancer cells and cancer-associated fibroblasts (CAFs) in primary and metastatic lymph node tumors. We selected 64 patients with pathological primary lung N2 SqCC who underwent surgical complete resection and investigated the expressions of four epithelial-mesenchymal transition-related markers (caveolin, clusterin, E-cadherin, ZEB2), three cancer stem cell-related markers (ALDH-1, CD44 variant6, podoplanin) of cancer cells, and four markers of CAFs (caveolin, CD90, clusterin, podoplanin) in both primary and matched metastatic lymph node tumors in the N2 area. In the primary tumors, the expressions of all the examined molecules were not related to recurrence. However, in the metastatic lymph node tumors, high clusterin and ZEB2 expressions in the cancer cells and high podoplanin expression in the CAFs were significantly correlated with recurrence (P = 0.03, 0.04, and 0.007, respectively). In a multivariate analysis, only podoplanin expression in the CAFs in metastatic lymph node tumors was identified as a significantly independent predictive factor of recurrence (P = 0.03). Our study indicated that the immunophenotypes of both cancer cells and CAFs in metastatic lymph node tumors, but not primary tumors, provide useful information for predicting the recurrence of pathological N2 lung SqCC.

Expression of developing neural transcription factors in lung carcinoid tumors.

In lung tumors, the association between carcinoids and high-grade neuroendocrine tumors (HGNETs) is controversial. To understand the phenotypic similarities/differences between lung carcinoids and HGNETs, we comparatively investigated the expression of three kinds of developing neural transcription factors (DNTFs: BRN2, TTF1 and ASCL1) and multiple endocrine neoplasia type 1 (MEN1) as well as RB1 and P53 using 18 carcinoids and 16 HGNETs. The DNTFs were expressed in 10 of the 18 carcinoids and in all the HGNETs, while normal neuroendocrine cells, which are considered the major cell origin of lung carcinoids and small cell carcinomas, did not express DNTFs. Both the DNTF(-) and DNTF(+) carcinoids contained typical and atypical carcinoids. All the DNTF(-) carcinoids examined were formed in the bronchial wall. All the MEN1(-) carcinoids examined were classified into the DNTF(-) carcinoids, while all the HGNETs expressed MEN1. This finding suggests that DNTF(-) MEN1(-) carcinoids are unlikely to be precursors of HGNETs. Although the status of RB1 and P53 between carcinoids and HGNETs were apparently different, the DNTF(+) carcinoids of two male patients and one female patient revealed morphologies resembling HGNET cells and relatively high Ki67 indices. Further investigation of DNTF expression in carcinoids might provide important clues to understand the association between carcinoids and HGNETs.

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer.

Thyroid transcription factor 1 (TTF1) plays crucial roles in thyroid, lung, and developing brain morphogenesis. Because TTF1-expressing neoplasms are generated from organs and tissues that normally express TTF1, such as the thyroid follicular epithelium and peripheral lung airway epithelium, TTF1 is widely used as a cell lineage-specific and diagnostic marker for thyroid carcinomas and for lung adenocarcinomas with terminal respiratory unit (TRU) differentiation. However, among lung neuroendocrine tumors, small-cell carcinomas (small-cell lung cancers (SCLCs)), most of which are generated from the central airway, also frequently express TTF1 at high levels. To clarify how SCLCs express TTF1, we investigated the molecular mechanisms of its expression using cultivated lung cancer cells and focusing upon neural cell-specific transcription factors. Both SCLC cells and lung adenocarcinoma cells predominantly expressed isoform 2 of TTF1, and TTF1 promoter assays in SCLC cells revealed that the crucial region for activation of the promoter, which is adjacent to the transcription start site of TTF1 isoform 2, has potent FOX-, LHX-, and BRN2-binding sites. Transfection experiments using expression vectors for FOXA1, FOXA2, LHX2, LHX6, and BRN2 showed that BRN2 substantially upregulated TTF1 expression, whereas FOXA1/2 weakly upregulated TTF1 expression. BRN2 and FOXA1/2 binding to the TTF1 promoter was confirmed through chromatin immunoprecipitation experiments, and TTF1 expression in SCLC cells was considerably downregulated after BRN2 knockdown. Furthermore, the TTF1 promoter in SCLC cells was scarcely methylated, and immunohistochemical examinations using a series of primary lung tumors indicated that TTF1 and BRN2 were coexpressed only in SCLC cells. These findings suggest that TTF1 expression in SCLC is a cell lineage-specific phenomenon that involves the developing neural cell-specific homeoprotein BRN2.

Prognostic factors after pulmonary metastasectomy for colorectal cancer and rationale for determining surgical indications: a retrospective analysis.

OBJECTIVE: We aimed to identify prognostic factors after pulmonary metastasectomy for colorectal cancer and propose the clinical application of them. Furthermore, we endeavored to provide a rationale for pulmonary metastasesectomy. BACKGROUND: Several prognostic factors have been proposed, but clinical application of them remains unclear. Moreover, there is no theoretical evidence that pulmonary metastasectomy is indicated for colorectal cancer. METHODS: We retrospectively analyzed 1030 patients who underwent pulmonary metastasectomy for colorectal cancer from 1990 to 2008. Prognostic factors were identified and the relationship of recurrent sites after pulmonary resection to pulmonary tumor size was assessed. RESULTS: Overall 5-year survival was 53.5%. Median survival time was 69.5 months. Univariate analysis showed tumor number (P < 0.0001), tumor size (P < 0.0001), prethoracotomy serum carcinoembryonic antigen (CEA) level (P < 0.0001), lymph node involvement (P < 0.0001), and completeness of resection (P < 0.0001) to significantly influence survival. In multivariate analysis, all remained independent predictors of outcome. In patients whose recurrent sites extended downstream from the lung via hematogenous colorectal cancer spread, pulmonary tumor size was significantly larger than in those with recurrent sites confined to the lung and regions upstream from the lung. CONCLUSIONS: We should utilize these prognostic factors to detect patients who might benefit from surgery. Therefore, we should periodically follow up advanced colorectal cancer patients by chest computed tomography to detect small pulmonary metastases before serum CEA elevation. Metastases to the lung or organs upstream from the lung are regarded as semi-local for colorectal cancer. This concept provides a rationale for validating surgical indications for pulmonary metastases from colorectal cancer.

High-resolution computed tomography findings for patients with drug-induced pulmonary toxicity, with special reference to hypersensitivity pneumonitis-like patterns in gemcitabine-induced cases.

BACKGROUND: Gemcitabine (GEM) is widely used as a chemotherapeutic agent. However, pulmonary toxicity has been rarely observed with GEM use. This article aims to determine the incidence and causes of drug-induced pulmonary toxicity, and to classify the high-resolution computed tomography (HRCT) findings for antitumor therapy-associated pulmonary toxicity based on characteristic patterns and pathological considerations, with a special focus on GEM-associated pulmonary toxicity (GAPT). METHODS: Medical records of all patients with drug-induced pulmonary toxicity seen at Kyorin University hospital between April 2006 and December 2011 were retrospectively reviewed. The study examined correlations between HRCT and the assessed pathological or clinical findings, with a specific focus on antitumor drugs. RESULTS: We identified 66 patients with drug-induced pulmonary toxicity. Among the antitumor drugs, GEM was the primary offending agent (n = 8) for pulmonary toxicity followed by docetaxel and gefitinib. HRCT patterns for the eight GAPT patients included the non-specific interstitial pneumonia (NSIP; n = 5) and the hypersensitivity pneumonitis (HP)-like pattern (n = 3). In contrast, four patients in the study were found to have the HP-like pattern, with three cases associated with GEM and one case associated with imatinib mesylate. The transbronchial lung biopsy or video-assisted thoracic surgery specimens for these patients showed granuloma or organizing tissue with a random distribution that was independent of the respiratory bronchiole. These results appeared to correspond to the HRCT-determined centrilobular nodules. CONCLUSION: GEM was the leading cause of drug-induced pulmonary toxicity in the patients examined in this study. This toxicity appears as NSIP or an HP-like pattern during HRCT examinations. This HP-like pattern may be useful for diagnosing GEM-induced pulmonary toxicity, as well as demonstrating granuloma or organizing tissue during lung pathology examinations.

Cytokine profiles, signalling pathways and effects of fluticasone propionate in respiratory syncytial virus-infected human foetal lung fibroblasts.

To examine cytokine production in response to RSV infection, we assessed the levels of 29 cytokines released from RSV-infected human foetal lung fibroblasts. We also examined the relationships between the effects of fluticasone propionate and various signalling pathways in the cells. Twenty-four hours after infection (1MOI), RSV-infected cells released cytokines, for example proinflammatory cytokines (IL-1ß, IL-6 and TNF-α), anti-inflammatory (IL-1ra), Th1 (IFN-γ, IFN-λ1a, IL-2 and IL-12), Th2 (IL-4, IL-5, IL-10 and IL-13), granulopoiesis-inducing (G-CSF and GM-CSF), eosinophil recruitment-inducing (eotaxin and RANTES) and neutrophil recruitment-inducing cytokines (IL-8, IP-10, MCP-1 and MIP-1α). Aberrant release of most was significantly suppressed by fluticasone propionate. Twelve hours after RSV infection, increased phosphorylation of Akt, p38 MAPK, ERK1/2 and IκB-α was noted. Fluticasone propionate suppressed the phosphorylation of Akt, p38 MAPK, and ERK1/2, but not IκB-α, in virus-infected cells. TLR-4 expression was unchanged in control and RSV-infected cells, and TLR-3 and RIG-I expression was not detected. The results indicate that RSV infection induces aberrant production and release of certain cytokines through these signalling pathways in human lung fibroblasts. Overproduction and imbalance of these cytokines may be associated with the pathophysiology of RSV-induced excessive and allergic inflammation.

Fluorodeoxyglucose (FDG) uptake in pulmonary rheumatoid nodules diagnosed by video-assisted thoracic surgery lung biopsy: two case reports and a review of the literature.

Two cases of rheumatoid nodules evaluated by fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and video-assisted thoracic surgery (VATS) biopsy are reported. The first case was that of a 44-year-old woman who presented with a cavitated nodule with intense standardized uptake values (SUVs) both in the early (max 3.4) and delayed (max 4.4) phases, suggesting malignancy. However, after VATS biopsy, she was diagnosed as having a rheumatoid nodule with vasculitis. The second case was that of a 74-year-old woman admitted with bilateral lung nodules, two of which showed intense early (max 2.2) and delayed (max 6.0) phase SUVs, and mild early (max 0.6) and delayed (max 0.9) phase SUVs. These two nodules were finally proven to be a lung cancer and rheumatoid nodule without vasculitis, respectively. These cases show that rheumatoid nodules with an enhanced inflammatory process, such as vasculitis, can appear false-positive for malignancy on FDG-PET/CT scan images.

[Lung cancer surgery with combined resection of the chest wall].

Lung cancer invading the chest wall is classified as T3 in the TNM classification, and surgical resection is the first choice of treatment if it is resectable. Factors affecting survival are still unclear except for the completeness of resection and degree of lymph node involvement. Recently, multidisciplinary treatments that include induction chemoradiation followed by surgery for superior sulcus non-small cell lung cancers have been reported with favorable results. Similarly, there is an ongoing phase II study of preoperative chemoradiotherapy for lung cancer with chest wall invasion, the results of which are expected soon. Based on recent evidence, platinum-based adjuvant chemotherapy after complete resection should be considered. We present strategies and techniques for radical combined resection of the chest wall, especially resection of the rib heads with chisels, and reconstruction with prostheses.

Diffusion-weighted magnetic resonance imaging in differentiating the invasiveness of small lung adenocarcinoma.

BACKGROUND: Magnetic resonance imaging (MRI) with several sequences may provide a valuable additional modality for evaluating the grade of invasiveness lesions. Diffusion-weighted magnetic resonance imaging (DWI) represents the biological characteristics of tissues. PURPOSE: To retrospectively evaluate the usefulness of DWI for evaluating the invasiveness of small lung adenocarcinomas. MATERIAL AND METHODS: From May 2005 to June 2008, 46 patients with lung adenocarcinomas measuring 2 cm or less across the greatest dimension underwent a preoperative MRI study followed by surgery at the Gunma Prefectural Cancer Center. Fourteen of the tumors were bronchioloalveolar carcinomas (so-called Noguchi's type A+B group), 26 were adenocarcinomas with mixed subtypes (type C group) and six were other histological subtypes of adenocarcinomas (type D+E+F group). The mean signal intensities of a lesion (DWI) and the spinal cord (SC) were analyzed in the region of interests (ROIs), and the mean DWI/SC ratio was then calculated with the value of DWI divided by the value of SC. RESULTS: The calculated mean DWI/SC ratio for the lesions were as follows: 0.448±0.261 (mean±standard deviation [SD]) for type A+B group, 0.963±0.465 for type C group, and 0.816±0.291 for type D+E+F group. The mean DWI/SC ratio of type A+B group was significantly lower than that for the type C (P = 0.0005) or type D+E+F groups (P = 0.0117). CONCLUSION: DWI may thus provide useful supplementary information before determining the surgical strategy, including a limited resection.

The development of new instruments (NT forceps) for video-assisted thoracoscopic surgery.

A new type of forceps (NT forceps) was developed in November 2007, designed for dividing connective tissues and for holding tissue together. These forceps measure 32 cm in length and are made of stainless steel. The insides of the forceps have atraumatic dispositions because longitudinal notches are placed on them. Therefore, they can grasp important soft organs such as the lung, azygos, and pulmonary vein. In addition, the acral forceps also possess carbide chips with cross notches. They can therefore hold vessel tape, sutures, etc. There are two types of forceps, which are curved at different angles, either a sharp angle or a slight angle. The forceps can be used for dividing and holding tissue while performing basic surgical manipulations, especially during an operation using a video-assisted procedure with a mini-thoracotomy. These forceps are useful tools for performing technical manipulations for standard operations, such as a lobectomy.

[Thymic metastasis of laryngeal cancer].

A 70-year-old man visited the Department of Head and Neck Surgery with a chief complaint of dysphagia. A tumor was observed in the epiglottis and vocal cord, and was diagnosed as squamous cell carcinoma by biopsy. Computed tomography (CT) showed a tumor mainly in the vocal cord. CT scans revealed a tumor centered on the vocal cord, with bilateral cervical lymph node metastases and a well-circumscribed 20-mm tumor in the anterior mediastinum. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed uptake in the primary lesion, left cervical lymph nodes, and anterior mediastinal tumor, which suggested a lymph node metastasis but did not exclude thymoma. The patient underwent video-assisted thoracic surgery (VATS) resection of the anterior mediastinal tumor with total laryngectomy, total thyroidectomy, and bilateral cervical lymph node dissection. The final pathological diagnosis was laryngeal cancer (glottic cancer, pT4aN2M1, pStage IVC) with thymic metastasis (presenting as an anterior mediastinal tumor). Thymic metastasis of laryngeal cancer is rare, and appears difficult to preoperatively differentiate from other mediastinal tumors.

[A case of imatinib mesylate-induced pneumonitis based on the detection of epithelioid granulomas by video-assisted thoracoscopic surgery biopsy in a patient with chronic myeloid leukemia].

A 79-year-old man with chronic myeloid leukemia was referred to our department because of dry cough and low-grade fever, 272 days after commencing imatinib mesylate (Gleevec). High resolution computed tomography (HRCT) showed tiny scattered centrilobular nodules and ground-glass opacities throughout both lung fields, suggesting drug-induced pneumonitis. A thoracic video-assisted thoracoscopic surgery (VATS) biopsy specimen from the centrilobular nodules in the right upper lobe demonstrated patchy distribution of epithelioid cell granulomas and intra-alveolar organization. Most of those lesions were predominantly located in the alveolar spaces, which implicated non-transbronchial distribution. Following drug cessation alone, the patient's general condition and radiological abnormalities improved.

[A Japanese lung cancer registry study at 2002].

OBJECTIVES: To publicize clinical results of Japanese lung cancer patients registered in 2002. Study design. In 2002, The Japanese Joint Committee for Lung Cancer Registration conducted a prospective observational study for lung cancer patients registered at starting treatments with follow-ups in 2004 and 2009. At first, 18,552 cases were registered from 358 institutes, while we analyzed 14,695 samples whose living periods could be identified. RESULTS: There were two times males as many as females with a mean age of 67.1 years. The most frequent histology was adenocarcinoma in 56.7%, following squamous cell carcinoma in 25.7% and small cell carcinoma in 9.2%. Clinical stage was IA in 29.3%, IB in 15.3%, IIA in 1.4%, IIB in 6.2%, IIIA in 11.8%, IIIB in 14.6% and IV in 21.0%. Surgery was performed in 8454 cases (57.5%). Five-year survival rate was 44.3% for all patients, 14.7% for cases of small cell carcinoma, 46.8% for non-small cell carcinoma, 59.6% for surgery cases, 8.5% for no surgery cases, 37.7% for males and 59.0% for females. The rates in clinical stage settings in cases of small cell carcinoma and non small cell carcinoma, was 52.7% and 79.4% for IA, 39.3% and 56.7% for IB, 31.7% and 49.0% for IIA, 29.9% and 42.3% for IIB, 17.2% and 30.9% for IIIA, 12.4% and 16.7% for IIIB and 3.8% and 5.8% for IV, respectively. CONCLUSION: An analysis of Japanese lung cancer patients registered in 2002 revealed that the most frequent histology type was adenocarcinoma following squamous cell carcinoma and small cell carcinoma. Prognosis in 5 years was superior in cases of female, non small cell lung cancer and surgery to those of male, small cell lung cancer and no surgery, respectively. Further investigation is needed with respect to dependences of those survival differences.