EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery.

BACKGROUND: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. PATIENTS AND METHODS: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. RESULTS: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). CONCLUSION: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

Randomized phase II study of daily and alternate-day administration of S-1 for adjuvant chemotherapy in completely-resected stage I non-small cell lung cancer: results of the Setouchi Lung Cancer Group Study 1301.

BACKGROUND: The aim of this multicenter, randomized phase II study was to analyze the feasibility and safety of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological stage I (tumor diameter > 2 cm) non-small cell lung cancer (NSCLC). METHODS: Patients were randomly assigned to receive adjuvant chemotherapy for 1 year comprising either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Group A) or a 2-week oral administration of S-1 (80 mg/m2/day) followed by 1 week of rest (Group B). The primary endpoint was feasibility, which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: Ninety-three patients were enrolled of whom 90 patients received S-1 treatment. Median follow-up was 66.9 months. The treatment completion rate based on an RDI of 70% or more for 6 months was 84.4% (95%CI; 70.5-93.5%) in group A and 64.4% (95%CI; 48.8-78.1%) in group B. There were no grade 4 adverse events in either group. Moderate or severe adverse events (grade 2 or grade 3) were significantly more frequent in group B (67%) compared with group A (29%, P = 0.001). The 5-year relapse-free survival rate was 87.0 and 80.9% for group A and B, respectively (P = 0.451). The 5-year overall survival rate for all patients (n = 93) was 100 and 89.4% for group A and B, respectively (P = 0.136). CONCLUSION: Alternate-day oral administration of S-1 for 1 year as adjuvant chemotherapy was demonstrated to be feasible with low toxicity in completely resected stage I (tumor diameter > 2 cm) NSCLC. TRIAL REGISTRATION: Trial registration number: UMIN000011994 . Date of registration: 10/8/2013.

Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001.

BACKGROUND: This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC). METHODS: Patients received four cycles of S-1 (80 mg/m2/day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m2/day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was ≥50%. RESULTS: Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4-71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%. CONCLUSIONS: We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC. CLINICAL REGISTRATION NUMBER: UMIN000005041.

Randomized feasibility study of S-1 for adjuvant chemotherapy in completely resected Stage IA non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 0701.

OBJECTIVE: The aim of this multicenter study was to determine the appropriate administration schedule for S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological-Stage IA (tumor diameter, 2-3 cm) non-small-cell lung cancer. METHODS: Patients were randomly assigned to receive adjuvant chemotherapy consisting of either the 4-week oral administration of S-1 (80-120 mg/body/day) followed by a 2-week rest (Group A), or the 2-week oral administration of S-1 (80-120 mg/body/day) followed by a 1-week rest (Group B). The duration of adjuvant chemotherapy was 1 year in both arms. The primary endpoint was compliance, namely drug discontinuation-free survival, which was calculated using the Kaplan-Meier method with log-rank test. RESULTS: Eighty patients were enrolled in this study, and 76 patients actually received S-1 treatment. The drug discontinuation-free survival rates at 1 year were 49.1% in Group A and 52.7% in Group B (P = 0.373). The means of the relative dose intensities were 55.3% in Group A and 64.6% in Group B (P = 0.237). There were no treatment-related deaths. Patients with grade 3/4 toxicities were significantly more frequent in Group A (40.5%) than in Group B (15.4%, P = 0.021). The 2-year relapse-free survival rates were 97.5% in Group A and 92.5% in Group B, and the 2-year overall survival rates were 100% in both groups. CONCLUSIONS: The feasibility showed no significant difference between the two groups among patients with completely resected Stage IA (tumor diameter, 2-3 cm) non-small-cell lung cancer.

Randomized phase II study of daily versus alternate-day administrations of S-1 for the elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm)-IIIA of non-small cell lung cancer: Setouchi Lung Cancer Group Study 1201.

BACKGROUND: It is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC. METHODS: Elderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: We enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11). CONCLUSION: Although several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC. TRIAL REGISTRATION: Unique ID issued by UMIN: UMIN000007819 (Date of registration: Apr 25, 2012) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009128. Trial ID issued by jRCT: jRCTs061180089 (Date of registration: Mar 22, 2019, for a shift toward a "specified clinical trial" based on Clinical Trials Act in Japan) https://jrct.niph.go.jp/en-latest-detail/jRCTs061180089.

A case of esophageal rupture caused by long-term exposure to vinegar and resolved by damage control strategies.

A 75-year-old woman had the habit of drinking vinegar. She had emergent transport to our hospital because of vomiting and unconsciousness. The patient underwent emergency surgery for esophageal rupture and septic shock. Intraoperatively, a 25 mm perforated area was found, and the visible esophageal mucosa was black. Because the suture closure or anastomosis was difficult and the shock was prolonged, she was placed in the intensive care unit after undergoing resection of the thoracic esophagus and thoracic drainage. Fifteen hours after the first surgery, we performed external esophagostomy and enterostomy. The third surgery was a retrothoracic cervical esophagogastric anastomosis, and reconstructive surgery was performed 60 days after the first surgery. Prolonged exposure to vinegar may have resulted in esophageal mucosal necrosis. This is a valuable case in which the esophageal mucosa was necrotic, and we performed esophagectomy and reconstruction as a damage control strategy to save her life.

Left superior pulmonary venous thrombosis complicated with splenic infarction after video-assisted thoracoscopic left upper lobectomy.

A 72-year-old man underwent video-assisted thoracoscopic left upper lobectomy for small cell lung cancer. After 16 days, he experienced epigastric abdominal pain and vomiting, and was taken by ambulance to our hospital. Contrast-enhanced computed tomography (CT) showed a propagation of thrombus in the stump of the left superior pulmonary vein (LSPV) complicated with splenic infarction. The patient received anticoagulation therapy with heparin and warfarin, and further progression of the thrombus or any systemic embolic event was not observed during hospitalization. Here, we report a patient presenting with LSPV thrombosis complicated with splenic infarction after video-assisted thoracoscopic surgery (VATS), and describe several months follow-up CT imaging results after administration of an oral anticoagulation therapy. .

Activation of caspase-3 and cleavage of Rb are associated with p16-mediated apoptosis in human non-small cell lung cancer cells.

The p16 tumor suppressor gene is frequently inactivated in human cancer tissues and cell lines. We previously reported that wild-type p16 expression from an adenovirus vector (Adv/p16) induced p53-dependent apoptotic cell death in non-small cell lung cancer (NSCLC) cell lines. Here we show the potential mechanism of apoptosis induced by Adv/p16 infection. Infection of human NSCLC cell line A549, which carries the wild-type p53 gene, with Adv/p16 resulted in activation of caspase-3, accompanied by the cleavage of its substrate poly (ADP-ribose) polymerase (PARP), on day 3 of infection. The retinoblastoma (Rb) cell cycle regulator protein was also cleaved after activation of caspase-3; when the levels of Rb significantly diminished, apoptosis began. When A549 cells were pretreated with the caspase-inhibitory peptide N-acetyl-asp-Glu-Val-Asp-CHO (aldehyde) (Ac-DEVD-CHO), Adv/p16-mediated apoptosis and Rb cleavage were greatly inhibited. Furthermore, MDM2, a negative regulator of p53 expression was upregulated 3 days after Adv/p16 infection, and MDM2 was subsequently cleaved by caspase-3; MDM2 cleavage was inhibited by Ac-DEVD-CHO treatment. These data implied that cleavage of Rb, in addition to activation of caspase-3, represented a mechanism by which Adv/p16 induced apoptotic cell death in human NSCLC cells. Our results support the clinical relevance of Adv/p16 as a treatment for p16-null human NSCLC that express wild-type p53.

Sudden death from metastatic esophageal cancer to the ventricular septum.

A 67-year-old man was admitted to our hospital due to esophageal cancer. Cancer existed at the lower esophagus and subtotal esophagectomy and lymphadenectomy was performed. The postoperative course was uneventful. Pathological findings revealed moderately differentiated squamous cell carcinoma that metastasized to the abdominal lymph nodes which include the paraaortic lymph nodes. He complained of anorexia three months after the operation and was found to have multiple liver and mediastinal lymph node metastases. He was admitted for chemotherapy. Before starting chemotherapy, he suddenly died without any sign of hemorrhage or respiratory disorder. Autopsy showed metastatic lesions to the heart and mediastinal lymph nodes, liver, thoracic vertebrae, kidney, adrenal gland and heart. Metastatic nodules in the heart were on the ventricular septum where the conducting system exists. No direct invasion from the pericardium was observed. Blockade of the conducting system of the heart was considered to have caused the severe arrhythmia and sudden cardiac arrest.

A case of a pancreatic tumor that was diagnosed as metastasis from lung cancer by endoscopic ultrasound-guided fine needle aspiration.

Metastatic tumors are rare in the pancreas, and some cases are difficult to distinguish from pancreatic cancer. However, distinguishing between them is very important to formulate a treatment plan. A case of a rare disease, called overlap cancer, involving metastatic tumors to the pancreas and right kidney from lung cancer, and duodenal papilla cancer, is described. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is useful for diagnosing metastatic pancreatic tumors, particularly in patients with multiple cancers.

Solitary pleural metastasis from renal cell carcinoma: a case of successful resection.

While renal cell carcinoma frequently metastasizes to the lung, solitary pleural metastasis without lung involvement is extremely rare. A 69-year-old man was admitted to our hospital with a solitary pleural metastasis 6 years after surgery for renal cell carcinoma. Needle biopsy was performed, and the tumor was diagnosed as a metastasis of renal cell carcinoma. The pleural tumor was surgically resected. The patient received interferon-α as postoperative therapy. He has been alive for 9 years without recurrence. Only 11 cases of solitary pleural metastasis have been reported thus far, and of these, 7 involved a large amount of pleural effusion resulting in a poor prognosis. This is the first reported case of solitary pleural metastasis from renal cell carcinoma, which was curatively resected, as indicated by long-term survival.

[Gene therapy for lung cancer].

Surgical resection is so far the most reliable therapy for localized non-small-cell lung cancer (NSCLC). Although the combination of several modalities such as chemotherapy or radiotherapy is used to treat advanced or recurrent disease, the results have not been satisfactory. A new therapeutic strategy is thus required to improve lung cancer treatment. Gene therapy is one such new therapeutic strategy. Several clinical trials of gene therapy protocols have been conducted and patient eligibility and being efficacy are evaluated. Representative studies of gene therapy for lung cancer and an interim report on a clinical trial using adenovirus vector expressing wild-type p53 in non-small cell lung cancer in Japan are introduced in this paper. Problems encountered and future regimens are also discussed.

Effects of a novel palatinose based enteral formula (MHN-01) carbohydrate-adjusted fluid diet in improving the metabolism of carbohydrates and lipids in patients with esophageal cancer complicated by diabetes mellitus.

BACKGROUND: During perioperative management of patients with gastrointestinal cancer complicated by diabetes mellitus, adequate alimentation is required, but we often face difficulties associated with hyperglycemia and other accompanying complications. Recently, we investigated the effects of a novel palatinose based enteral formula (MHN-01) in suppressing post-prandial hyperglycemia and improving lipid metabolism in experimental animals and perioperative management of patients with esophageal cancer complicated by diabetes mellitus. MATERIALS AND METHODS: We gave normal rats and rats with type 2 diabetes mellitus a single oral dose of fluid diet, and analyzed comparatively the time course of blood glucose level in each group until 3 h after the dose. In both the normal rat group and the type 2 diabetes group, peak blood glucose level after the MHN-01 dose was significantly lower than after a dose of ordinary fluid diet and was comparable to the peak level after a dose of a fluid diet rich in MUFA (monounsaturated fatty acid). We allowed normal mice free access to fluid diet for 43 days, and measured their body fat levels. Fat accumulation was significantly lower in mice given MHN-01 than in mice given ordinary fluid diet. We also analyzed the respiratory quotient and resting energy expenditure of normal Sprague-Dawley rats fed by MHN-01 or an ordinary fluid diet. The respiratory quotient of the MHN-01 group was significantly lower than the ordinary fluid group, although the resting energy expenditure of both groups was almost the same level. The effect of MHN-01 was estimated to be based on improvement of lipid metabolism. RESULTS: Between 2003 and 2005, among 164 patients who underwent radical thoracic esophagectomy and/or reconstruction for esophageal carcinoma at Okayama University Hospital, nine patients (5.5%) were diagnosed with diabetes mellitus in pre-operative screening and were treated with MHN-01. Clinical courses of two cases with severe status of diabetes mellitus were presented as successful case reports of MHN-01. CONCLUSION: MHN-01 was very useful in perioperative management of patients complicated by diabetes mellitus, unable to ingest food p.o. such as esophageal cancer or other diseases.