Phase I study of weekly nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8-100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2-21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

[Successful treatment of HHV8-negative effusion-based lymphoma with drainage of pleural effusion].

Two cases of human herpesvirus 8 (HHV8)-negative effusion-based lymphoma (EBL) involving unilateral pleural effusion that regressed only after drainage are reported. Cases 1 and 2 were 91- and 81-year-old men with right and left pleural effusion, respectively. No chemotherapy was administered to either patient because of their advanced age and the presence of cardiac comorbidities. They completely recovered after effusion drainage alone without relapse till the last observation. Thus, this study suggests that some patients with HHV8-negative EBL can be safely managed with effusion drainage alone.

Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer and a poor performance status.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC) in patients who have good performance status (PS). However, the efficacy and safety of osimertinib for patients with poor PS is unknown. METHODS: We retrospectively evaluated the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2-4 and who were administered 80 mg of osimertinib once daily between March 2016 and February 2017. RESULTS: Thirty patients (8 men and 22 women) with EGFR T790M mutation-positive NSCLC were evaluated; their median age was 66 years (range: 39-89 years). Twenty-four and six patients had PS scores of 2 and 3, respectively; none had a PS score of 4. All patients had previously been treated with first- or second-generation EGFR-TKIs. T790M was detected in the tumor samples of 23 patients, the blood samples of two patients, and both the tumor and blood samples of five patients. The overall response rate was 53% (95% confidence interval: 36-70%), and the PS score improvement rate was 63%. The median progression-free survival was 8.2 months (95% confidence interval: 4.3-13.2 months), while the median overall survival time was not reached. No patient required treatment cessation owing to adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Osimertinib therapy demonstrates promising efficacy and acceptable safety in patients with EGFR T790M mutation-positive NSCLC who have poor PS.

Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer.

PURPOSE: Cancer cachexia (CC) is commonly seen in advanced lung cancer patients and associated with poor prognosis. However, little is known about CC that develops during chemotherapy. We evaluated the prognostic impact of CC and skeletal muscle wasting that develops during the course of chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. METHODS: The clinical data of 134 newly diagnosed NSCLC patients were retrospectively reviewed. CC was defined as a body weight loss >5 or >2 % in patients with a body mass index of <20 kg/m(2). CC was assessed at baseline (T1) and 3 months (T2), 6 months (T3), and 12 months (T4) after chemotherapy initiation. Skeletal muscle mass was assessed using the lumber skeletal muscle index (LSMI). RESULTS: The proportion of patients with CC at T1, T2, T3, and T4 was 45.6, 46.1, 25.5, and 26.0 %, respectively. The frequency of grade 3 chemotherapy-induced anorexia was higher in patients with CC than those without CC at T2 (15.4 vs. 0.0 %, P = 0.0044). At all time points, patients with CC had shorter survival times than those without CC. Patients with low LSMIs (men, <41 cm(2)/m(2); women, <38 cm(2)/m(2)) tended to have poor prognosis. Adjusted Cox proportional hazard ratios and corresponding confidence intervals for CC at T1, T2, T3, and T4 were 2.53 (1.33-4.88), 1.97 (1.27-3.06), 3.86 (2.14-6.81), and 1.62 (0.80-3.16), respectively. CONCLUSION: CC presence and decreased skeletal muscle mass are associated with poor prognosis in advanced NSCLC patients receiving chemotherapy.

The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harboring mutations of the epidermal growth factor receptor.

BACKGROUND: It is unclear whether there is a difference in the effect of gefitinib treatment between patients with postoperative recurrent non-small cell lung cancer (NSCLC) and those with stage IV NSCLC harboring mutations in the epidermal growth factor receptor (EGFR). METHODS: We retrospectively reviewed the medical records of consecutive patients with postoperative recurrent NSCLC (postoperative group) or stage IV NSCLC (stage IV group) harboring EGFR mutations who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012 to compare the effect of gefitinib on survival from treatment initiation. RESULTS: A total of 168 patients were treated with gefitinib (postoperative group, 49 patients; stage IV group, 119 patients). The response rate of gefitinib treatment in the postoperative group was similar to that in the stage IV group (58 vs. 61 %, p = 0.613). In contrast, median progression-free survival (PFS; 15.8 vs. 9.8 months, p < 0.001) and median overall survival (OS; 51.1 vs. 22.2 months, p < 0.001) were significantly longer in the postoperative group. In addition, postoperative recurrent disease, performance status (0-1), and a single metastatic organ were independent favorable prognostic factors in the multivariate analysis of survival. CONCLUSIONS: PFS and OS were superior in patients with postoperative recurrent NSCLC harboring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest that postoperative recurrent disease may be considered a stratification factor in clinical trials for NSCLC with EGFR mutations.

Phase II study of IRInotecan treatment after COmbined chemo-immunotherapy for extensive-stage small cell lung cancer: Protocol of IRICO study.

INTRODUCTION: Combined treatment using anti-programmed death-ligand 1 antibody (anti-PD-L1) and platinum-etoposide is the current standard first-line treatment for patients with extensive-stage (ES) small cell lung cancer (SCLC). However, the best treatment for relapsed ES-SCLC after the first-line treatment remains unclear. There are some approved chemotherapeutic agents that can be used against ES-SCLC, and treatment with irinotecan is well established as both a monotherapy and a combined therapy, in combination with platinum. Therefore, we conduct a phase II study with irinotecan in the second- or later-line setting for patients with ES-SCLC who have been previously treated with combined treatment. METHODS: Our study will enroll total 30 patients who are diagnosed with ES-SCLC and have experienced disease progression after the combined treatment. Patients will receive irinotecan on days 1, 8, and 15, which will be repeated every 4 weeks. Doses of irinotecan (100/80/60 mg/m2 ) will be determined according to the type of UGT1A1 gene polymorphism, and the treatment will be discontinued following disease progression, intolerance, withdrawal of patient consent, and based on the investigator's decision. The primary endpoint of the study is the response rate, and the secondary endpoints are overall survival, progression-free survival, and safety. DISCUSSION: Since the present first-line treatment has been changed to the combined treatment, the second- or later-line treatment should be re-evaluated for patients with relapsed SCLC. Irinotecan is a major chemotherapeutic agent used for SCLC. This study demonstrates and re-evaluates the clinical benefits of irinotecan after combined treatment with anti-PD-L1 and platinum-etoposide for patients with ES-SCLC. REGISTRATION DETAILS: This study was registered in the Japan Registry of Clinical Trials (no. jRCT s071210090) on November 4, 2021.

Febrile Neutropenia in a Patient with Non-Small Cell Lung Cancer Treated with the Immune-Checkpoint Inhibitor Nivolumab.

BACKGROUND Nivolumab is a human IgG4 monoclonal antibody against human programmed cell death 1 (PD-1). It has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). Treatment with nivolumab is sometimes associated with immune-related adverse events (ir AEs) in patients. These specific ir AEs include pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy. However, hematological toxicity is rare. CASE REPORT A 57-year-old man with lung adenocarcinoma, with brain and adrenal gland metastases, was therefore started on nivolumab therapy as third-line treatment. After administration of the second dose with nivolumab, grade 3 febrile neutropenia (FN) and grade 2 liver dysfunction developed in the patient. The patient was started to on intravenous antibiotics, granulocyte colony-stimulating factor (G-CSF), and corticosteroids. Neutrophil counts and liver function gradually improved, and corticosteroids were tapered over 6 weeks. However, the patient was re-treated with G-CSF because the neutrophil counts decreased again. CONCLUSIONS Care needs to be taken with such patients because neutropenia due to treatment with nivolumab can recur, as well as other ir AEs.

[Case of toxocariasis showing migratory nodular shadows with halos].

A 30-year-old man, who had kept a dog for nine years and often ate raw beef liver, visited a hospital because of a chest nodular shadow in the left lung field found on a checkup examination. Chest computed tomography obtained 8 days after the checkup showed no abnormal shadow in the left lung but two nodular shadows with halos in the right upper and lower lobes. Peripheral blood eosinophil counts and serum IgE values were elevated. Immunological examination including microplate ELISA showed a high titer of specific antibody against Toxocara canis in the serum. He was successfully treated with albentazole. Parasitic disease, especially toxocariasis, is an important consideration in the differential diagnosis of migratory nodular shadow with a halo on chest computed tomography, and serology is useful in diagnosis screening.

Diffusion-weighted imaging is a feasible method for screening colorectal cancer: report of a case.

The liver is one of the most common sites for metastatic disease. It is sometimes difficult to detect the primary site. We describe herein the feasibility of diffusion-weighted imaging (DWI) for searching primary site of liver metastases. A 93-year-old male patient presented to us with the chief complaints of hematochezia. Ultrasonography (US) and computed tomography (CT) showed multiple masses in the liver. However, these examinations revealed no primary tumor. DWI showed bright signal mass in the rectum. Furthermore, the apparent diffusion coefficient (ADC) map in that area was depicted as a low ADC value. A histopathological analysis demonstrated the tumor to be moderately differentiated adenocarcinoma. We consider that DWI is a feasible method for screening colorectal cancer, especially for unknown primary site cancers.

Plasma epidermal growth factor receptor mutation testing with a chip-based digital PCR system in patients with advanced non-small cell lung cancer.

OBJECTIVES: Epidermal growth factor receptor (EGFR) mutation testing is a companion diagnostic to determine eligibility for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). Recently, plasma-based EGFR testing by digital polymerase chain reaction (dPCR), which enables accurate quantification of target DNA, has shown promise as a minimally invasive diagnostic. Here, we aimed to evaluate the accuracy of a plasma-based EGFR mutation test developed using chip-based dPCR-based detection of 3 EGFR mutations (exon 19 deletions, L858R in exon 21, and T790M in exon 20). MATERIALS AND METHODS: Forty-nine patients with NSCLC harboring EGFR-activating mutations were enrolled, and circulating free DNAs (cfDNAs) were extracted from the plasma of 21 and 28 patients before treatment and after progression following EGFR-TKI treatment, respectively. RESULTS: Using reference genomic DNA containing each mutation, the detection limit of each assay was determined to be 0.1%. The sensitivity and specificity of detecting exon 19 deletions and L858R mutations, calculated by comparing the mutation status in the corresponding tumors, were 70.6% and 93.3%, and 66.7% and 100%, respectively, showing similar results compared with previous studies. T790M was detected in 43% of 28 cfDNAs after progression with EGFR-TKI treatment, but in no cfDNAs before the start of the treatment. CONCLUSION: This chip-based dPCR assay can facilitate detection of EGFR mutations in cfDNA as a minimally invasive method in clinical settings.

A multicenter phase II trial of S-1 combined with bevacizumab after platinum-based chemotherapy in patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: This phase II trial investigated the efficacy and safety of S-1 plus bevacizumab (SB) after failure of platinum-based chemotherapy in patients with non-squamous non-small cell lung cancer (non-sq NSCLC). METHODS: Patients with non-sq NSCLC who had undergone prior platinum-based chemotherapy, regardless of the use of bevacizumab, were eligible. S-1 (80 mg/m(2)) was administered orally twice daily for 14 days, and bevacizumab (15 mg/kg) on day 1 every 3 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty-eight patients (14 males and 14 females; median age 62 years; performance status 0/1/2: 21/7/0) were accrued from 4 centers. Almost half (n = 15, 53.6 %) of these had received prior bevacizumab therapy. The median PFS and overall survival were 3.2 months [95 % confidence interval (CI) 2.2-4.0 months] and 11.4 months (95 % CI 8.9-13.9 months), respectively. Prior exposure to bevacizumab did not affect the PFS. An objective response was observed in 4 patients, the response rate and disease control rate being 14.3 and 85.7 %, respectively. The treatment was well tolerated, the most common treatment-related side effects being anorexia (75 %) and fatigue (68 %). CONCLUSION: Although SB was well tolerated, this combination did not provide any additional benefit in terms of PFS for patients with non-sq NSCLC after failure of platinum-based chemotherapy. It will be important to clarify the most suitable agent for use with bevacizumab, and the optimal timing of bevacizumab therapy for lung cancer.

Assessment of ascending aorta using epiaortic ultrasonography during off-pump coronary artery bypass grafting.

BACKGROUND: Use of an aortic partial clamp for proximal anastomosis during off-pump coronary artery bypass is known to increase the risk of fatal complications. The purpose of this study was to assess the management of the ascending aorta evaluated with epiaortic ultrasonography during off-pump coronary artery bypass. METHODS: Intraoperative ultrasonography of the ascending aorta with a 10-MHz probe was performed consecutively in 155 patients undergoing off-pump coronary artery bypass between August 1999 and July 2001. The findings from ultrasonography, surgical modifications, and operative results were analyzed. RESULTS: In 54 patients (34.8%), epiaortic ultrasonography showed atherosclerotic findings in the anterior side of the ascending aorta (group A). The remaining 101 patients had either normal findings or atherosclerotic findings in only the posterior side (group NA). A proximal anastomosis to the aorta was preoperatively planned in 117 patients (group A, 42; group NA, 75). In group A, a graft modification without clamping was implemented in 29 patients (24.8% of 117 patients), whereas the clamp site was modified to a different segment in 13 patients (11.1% of 117 patients). In all 75 patients in group NA, partial clamping was used in the standard fashion. There were no cerebral infarctions or operative deaths related to partial clamping. However, aortic dissection occurred in 1 patient in group NA. CONCLUSIONS: In 35% of patients undergoing off-pump coronary artery bypass, epiaortic ultrasonography identified atherosclerotic findings in the anterior wall of the ascending aorta. This study suggests that revascularization without aortic manipulation during off-pump coronary artery bypass is indicated in as many as 25% of patients.

Surgical treatment of primary pulmonary artery tumor: two cases of malignant fibrous histiocytoma and leiomyosarcoma.

We report two cases of rare primary pulmonary artery (PA) tumor. Case 1 was a 65-year-old man with malignant fibrous histiocytoma which caused severe stenosis over the main PA and right PA. Case 2 was a 49-year-old woman with leiomyosarcoma which caused severe stenosis from the right ventricular outflow tract (RVOT) to the main PA. Both cases underwent endarterectomy, tumor resection, and PA reconstruction under cardiopulmonary bypass. The symptoms of right heart failure improved postoperatively. Tumor recurrences were however recognized in both cases in the early postoperative period, and both patients died of the disease 12 (case 1) and 21 (case 2) months after operation respectively. Tumor resection by endarterectomy techniques may be incomplete because of frequent local recurrence. Postoperative adjuvant therapy in addition to radical resection and reconstruction of the PA and tumor might increase the length of survival.

Off-pump coronary artery bypass grafting in octogenarians.

OBJECTIVES: Off-pump coronary artery bypass grafting (CABG) has become accepted for myocardial revascularization because it reduces perioperative morbidity. We assessed the safety and efficacy of bypass surgery on the beating heart in elderly patients. METHODS: Off-pump CABG was done in 25 patients aged 80 years or older between February 1996 and February 2001. We retrospectively compared clinical results for these patients to those of 18 consecutive age-matched patients undergoing on-pump CABG during the same period. RESULTS: Mean patient age in both groups was similar--82.2 +/- 2.3 years in the off-pump group vs 81.9 +/- 2.0 years in the on-pump group (p = 0.66). Preoperative risk was similar in both groups, but significantly more patients in the on-pump group had triple-vessel disease. Distal anastomoses were significantly fewer in the off-pump group than in the on-pump group at 2.0 +/- 1.0 vs 2.8 +/- 0.5 (p < 0.01). The off-pump group had a shorter postoperative ventilation--13.4 +/- 17.2 hours vs 45.2 +/- 52.8 hours (p < 0.05)--, and less blood transfused--16% vs 89% (p < 0.01)--than the on-pump group. Mean postoperative hospitalization and intensive care unit stay were 18.6 days and 3.2 days in the off-pump group, versus 37.1 days and 9.4 days in the on-pump group (p < 0.05). No difference was seen in the incidence of major postoperative complications between groups. No hospital deaths occurred in the off-pump group. CONCLUSION: Off-pump CABG is thus a safe and effective for myocardial revascularization in the elderly.

Differences in the efficacy of S-1 monotherapy according to histological type in pretreated patients with advanced non-small cell lung cancer.

BACKGROUND: S-1 is a novel antimetabolic agent that inhibits thymidylate synthase. The expression of thymidylate synthase is higher in squamous (Sq) non-small cell lung cancer (NSCLC) than in non-Sq NSCLC. The aim of this retrospective study was to assess the efficacy of S-1 monotherapy for advanced NSCLC according to the histological subtype. METHODS: We reviewed the clinical records of patients with advanced NSCLC treated with S-1 monotherapy as second- or third-line therapy between May 2005 and July 2012 at the Shizuoka Cancer Center. RESULTS: A total of 71 patients were included in this retrospective study. Patient characteristics were similar in the Sq NSCLC (n = 15) and non-Sq NSCLC (n = 56) groups, except with regard to gender and smoking status. The overall response rates were 0% (95% confidence interval [CI] 0-17%) for Sq NSCLC and 11% (95% CI 3-19%) for non-Sq NSCLC (P = 0.33). For Sq NSCLC and non-Sq NSCLC, the median progression-free survival times were 2.1 and 2.8 months (P = 0.02), respectively, and the median overall survival times were 6.1 and 10.1 months (P = 0.01), respectively. CONCLUSION: S-1 monotherapy may be more effective in patients with non-Sq NSCLC than in those with Sq NSCLC.