Tumor Lysis Syndrome in a Patient with BRAFV600E Mutated Colon Cancer Treated with Cetuximab and Encorafenib.

Tumor lysis syndrome (TLS) is a fatal complication associated with chemotherapy. We herein report a case of TLS in a 73-year-old woman with metastatic BRAFV600E mutated colon cancer after she received combined treatment with cetuximab and encorafenib. The serum uric acid, urea nitrogen, and creatinine levels were elevated on day four of the first cycle. The fibrin degradation product (FDP) and D-dimer levels were also high. Diuresis and rasburicase were initiated for TLS, and the laboratory data all normalized on day 8. Thus, the possibility of TLS being induced by targeted drugs in patients with solid tumors, including colorectal cancer, must not be overlooked.

Exploratory analysis of immunochemotherapy compared to chemotherapy after EGFR-TKI in non-small cell lung cancer patients with EGFR mutation: A multicenter retrospective study.

BACKGROUND: Patients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer have received immunochemotherapy as one of the treatment options after tyrosine kinase inhibitor (TKI) failure. METHODS: We retrospectively examined EGFR-mutant patients treated with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) therapy or platinum-based chemotherapy (Chemo) after EGFR-TKI therapy at five institutions in Japan. RESULTS: A total of 57 patients with EGFR mutation were analyzed. The median progression-free survival (PFS) and overall survival (OS) in the ABCP (n = 20) and Chemo (n = 37) were 5.6 and 20.9 months, 5.4 and 22.1 months, respectively (PFS, p = 0.39; OS, p = 0.61). In programmed death-ligand 1 (PD-L1)-positive patients, median PFS in the ABCP group was longer than in the Chemo group (6.9 vs. 4.7 months, p = 0.89). In PD-L1-negative patients, median PFS in the ABCP group was significantly shorter than in the Chemo group (4.6 vs. 8.7 months, p = 0.04). There was no difference in median PFS between the ABCP and Chemo groups in the subgroups of brain metastases, EGFR mutation status, or chemotherapy regimens, respectively. CONCLUSION: The effect of ABCP therapy and chemotherapy was comparable in EGFR-mutant patients in a real-world setting. The indication for immunochemotherapy should be carefully considered, especially in PD-L1-negative patients.

Efficacy and safety of immuno-chemotherapy in patients with advanced non-small-cell lung cancer harboring oncogenic mutations: a multicenter retrospective study.

PURPOSE: The effect of immuno-chemotherapy on patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic mutations remains poorly understood. This study aimed to characterize the efficacy of immuno-chemotherapy and determine the optimal treatment strategy for such patients. METHODS: We conducted this retrospective cohort study on patients with NSCLC harboring oncogenic driver alterations and treated with an immune checkpoint inhibitor combined with chemotherapy at five institutions. The clinical characteristics and outcomes of immuno-chemotherapy for NSCLC with oncogenic mutations in a real-world setting were analyzed. RESULTS: Among 846 patients diagnosed with advanced or recurrent NSCLC between April 2017 and April 2021, 43 patients with oncogenic mutations were treated with immuno-chemotherapy. The median age of patients was 68 (range 44-78) years; 42% of patients never smoked, and adenocarcinoma was the most common histology (95%). In patients with KRAS mutations (n = 10) or PD-L1 expression of 50% or greater (n = 10), the disease control rate was 100%. The median progression-free survival (PFS) was 5.4, 6.3, and 8.9 months in patients harboring mutations in EGFR, KRAS, and other genes, respectively (P = 0.22). Patients with PD-L1 expression of 50% or greater had significantly longer median PFS than patients with PD-L1 expression of less than 50% (16.4 vs. 5.1 months; P = 0.001). Two patients experienced grade 3 immuno-related adverse events. CONCLUSION: Immuno-chemotherapy has a clinical benefit and is safe for patients with oncogenic mutations. Notably, patients with PD-L1 expression of 50% or more experience greater benefit from immuno-chemotherapy than those with PD-L1 expression of less than 50%.

Wild-type Transthyretin Amyloidosis with Diffuse Alveolar-septal Amyloidosis Diagnosed by a Transbronchial Lung Biopsy.

A 69-year-old man visited our pulmonary medicine department for dyspnea. Chest computed tomography (CT) revealed ground-glass opacity bilaterally in the lungs. Upon performing a transbronchial lung biopsy (TBLB), organizing pneumonia was diagnosed. His electrocardiogram revealed low voltage, and the cardiac ultrasound revealed hypertrophy of the interventricular septum. The patient had bilateral carpal tunnel syndrome, and amyloidosis was suspected. Congo red stain was added to the lung biopsy specimen. Amyloid deposition of transthyretin (ATTR) was positive, mutations with amino acid changes were not observed in the TTR gene. Wild-type ATTR Amyloidosis (ATTRwt amyloidosis) was diagnosed using a TBLB. Chest CT after treatment with steroids revealed diffuse alveolar-septal amyloidosis.

Abdominal pain as an initial symptom of isolated ACTH deficiency induced by nivolumab in a patient with malignant mesothelioma.

Used for a wide range of cancers, nivolumab has been reported to cause immune-related adverse events, including isolated adrenocorticotropic hormone deficiency (IAD). We report an 81-year-old woman with malignant mesothelioma who presented with abdominal pain after eight courses of nivolumab therapy, leading to the diagnosis of nivolumab-induced IAD. We should consider adrenal insufficiency (AI) when a patient on nivolumab complains of abdominal pain and has no other explanatory findings. Infusion-resistant hypotension and hyponatraemia can further suggest AI.

Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9-17.5), and the median OS was 22.0 months (95% CI: 16.0 months-not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3-4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were ≥75 years old.

Management and Outcomes of Newly Diagnosed Non-Small Cell Lung Cancer Patients with Brain Metastases: A Real-World Study in Japan.

BACKGROUND: Brain metastases (BM) are one of the strongest negative prognostic factors in patients with non-small cell lung cancer (NSCLC). Molecularly targeted agents are standard of care for NSCLC patients with a driver mutation; however, their efficacy in patients with BM is not fully understood because patients with BM are usually excluded from clinical studies. This study investigated the current management and outcomes of newly diagnosed NSCLC patients with BM in Japanese clinical practice, focusing on their driver mutation status. PATIENTS AND METHODS: We enrolled newly diagnosed, treatment-naïve NSCLC patients with BM between January 2012 and December 2015 from 4 institutions in Japan. The medical records of each patient were retrospectively reviewed, and the treatment details and outcomes were evaluated. RESULTS: In total, 203 patients with BM were enrolled in this study and 73 (36%) were neurologically symptomatic. Regarding initial treatment, 110 patients (54%) received local therapy, including radiotherapy and surgery, whereas 77 (38%) received systemic therapy. The median overall survival (OS) was 14.3 months for all patients, and it was significantly longer among patients with a driver mutation (28.9 months; 95% confidence interval [CI], 20.9-41.0) than among patients without a driver mutation (9.9 months; 95% CI, 7.0-13.4) (hazard ratio [HR] 0.39; 95% CI, 0.27-0.57; p < 0.001). Multivariate analysis identified performance status (HR 1.78; 95% CI, 1.16-2.72; p = 0.009) and driver mutation status (HR 0.27; 95% CI, 0.17-0.44; p < 0.001) as significant prognostic factors. No significant difference in OS was noted according to the type of initial treatment, i.e., local versus systemic. CONCLUSION: The median OS of patients with a driver mutation was longer than 2 years, even of patients with BM, and it was significantly longer than that of patients without a driver mutation. Driver mutation status, in addition to performance status, was a significant prognostic factor in NSCLC patients with BM.

A Phase II Study of Cisplatin Plus Gemcitabine followed by Maintenance Gemcitabine for Advanced Squamous Non-Small-Cell Lung Cancer: Kyoto Thoracic Oncology Research Group 1302.

BACKGROUND: There has been no study so far on gemcitabine continuous maintenance therapy targeting only squamous non-small-cell lung cancer (NSCLC) patients. This study aimed to assess the efficacy and safety of cisplatin plus gemcitabine followed by maintenance gemcitabine for chemotherapy- naïve Japanese patients with advanced squamous NSCLC. METHODS: The patients received 4 cycles of gemcitabine (1,000 mg/m2, days 1 and 8) and cisplatin (80 mg/m2, day 1) every 3 weeks, followed by gemcitabine alone as maintenance therapy every 3 weeks until disease progression or unacceptable toxicity. The primary end point of the study was progression-free survival (PFS) from the date of registration. RESULTS: From May 2013 to October 2018, 26 patients were enrolled, and 25 patients received ≥1 cycle of planned treatment. Eighteen patients (69.2%) received 4 cycles of cisplatin plus gemcitabine, and 16 patients (61.5%) received ≥1 cycle of maintenance gemcitabine. The median PFS from the date of registration was 5.3 months (95% CI 2.9-7.3 months). In 16 patients who received ≥1 cycle of maintenance gemcitabine, the median PFS from the date of maintenance gemcitabine initiation was 3.8 months (95% CI 2.3-5.2 months). Their median overall survival from the date of registration was 11.9 months (95% CI 7.5-26.5 months). During the maintenance therapy, adverse events (AEs) were mostly Common Terminology Criteria for AE grade 1. CONCLUSIONS: While this trial did not meet the primary endpoint, the sufficient efficacy and feasibility of gemcitabine maintenance therapy were suggested.

Osimertinib in Elderly Patients with Epidermal Growth Factor Receptor T790M-Positive Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment: A Phase II Trial.

LESSONS LEARNED: Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients.In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population.Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. BACKGROUND: Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. RESULTS: A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%-72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1-82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. CONCLUSION: Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.

Effects of Nodal inhibition on development of temnopleurid sea urchins.

Adult rudiment formation in some temnopleurids begins with the formation of a cell mass that is pinched off the left ectoderm in early larval development. The cell mass forms the adult rudiment with the left coelomic pouch of the mesodermal region. However, details of the mechanisms to establish position of the cell mass are still unknown. We analyzed the inhibiting effect of Nodal, a factor for morphogenesis of the oral region and right side, for location of the cell mass, in four temnopleurids. Pulse inhibition, at least 5 min inhibition, during coelomic pouch formation allowed a cell mass to form on both sides, whereas treatments after that period did not. These results indicate that Nodal signaling controls the oral-aboral axis before gastrulation and then affects the position of the cell mass and adult rudiment up to coelomic pouch formation. They also indicate that the position of the adult rudiment under Nodal signaling pathways is conserved in temnopleurids, as adult rudiment formation is dependent on the cell mass.

Pulmonary Tumor Thrombotic Microangiopathy Caused by a Parotid Tumor: Early Antemortem Diagnosis and Long-term Survival.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a high-mortality disease that is difficult to diagnose clinically. Our patient was an 80-year-old woman who came to us due to symptoms of increasing dyspnea. A clinical evaluation showed that she had hypoxemia and pulmonary arterial hypertension without any abnormalities in the major pulmonary arteries, bronchi, or alveoli. A lung perfusion scan showed multiple wedge-shaped perfusion defects. Further examination revealed adenocarcinoma in her right parotid gland with metastasis to the submandibular lymph nodes. We diagnosed her to have PTTM caused by a parotid tumor. The patient survived for 11 months with chemotherapy. An early antemortem diagnosis by minimally invasive examinations will help PTTM patients to survive longer.

Comparison of vinorelbine plus cisplatin and S-1 plus cisplatin in concurrent chemoradiotherapeutic regimens for unresectable stage III non-small cell lung cancer.

BACKGROUND: Based on the results of phase I/II studies, S-1 plus cisplatin (CDDP) and vinorelbine (VNR) plus CDDP are commonly used chemoradiotherapeutic regimens for the treatment of non-small cell lung cancer(NSCCLC) in Japan. However, there have been no studies that have compared S-1 and CDDP combined with thoracic radiotherapy (TRT) with VNR and CDDP combined with TRT. PATIENTS AND METHODS: A total of 39 and 50 patients with stage III non-small cell lung cancer (NSCLC) were treated with S-1 and CDDP plus concurrent TRT, or with VNR and CDDP plus concurrent TRT, respectively, between 2002 and 2010. RESULTS: In the S-1 plus CDDP plus TRT group, the median progression-free survival (PFS) and the median overall survival (OS) were 327 days and 1012 days, respectively. In the VNR plus CDDP plus TRT group, the median PFS and the median OS were 328 days and 905 days, respectively. The differences in the PFS and OS were not statistically significant. Grade 3 or more leukopenia and neutropenia were significantly more common in the VNR plus CDDP plus TRT group. Grade 3 or more thrombocytopenia, esophagitis and eruption tended to be more common in the S-1 plus CDDP plus TRT group. CONCLUSION: Due to the difference in the toxicity profiles of the two combinations, S-1 plus CDDP plus TRT or VNR plus CDDP plus TRT should be selected depending on each patient's baseline characteristics.

Detection and prevalence of chronic obstructive pulmonary disease in a cardiovascular clinic: evaluation using a hand held FEV1/FEV6 meter and questionnaire.

BACKGROUND AND OBJECTIVE: COPD is one of the leading causes of morbidity and mortality worldwide, and its prevalence continues to increase. Although spirometry is indispensable for the diagnosis of COPD, other simple and reliable tools are necessary for screening of COPD because spirometry is not widely available. This study investigated the usefulness of a combination of an electronic FEV1/FEV6 meter (PiKo-6) with a COPD questionnaire as a screening method in patients with cardiovascular diseases. METHODS: The PiKo-6 and the COPD questionnaire of the International Primary Care Airways Group were used to screen patients attending a cardiovascular outpatient clinic. Patients with FEV1/FEV6 < 70% were defined as having airflow limitation. Patients diagnosed with airflow limitation underwent spirometry. Using data from the PiKo-6 and the COPD questionnaire, patients were assigned to a COPD group or a non-COPD group. The relationship between PiKo-6 measurements and spirometry was also evaluated. RESULTS: Among 753 patients, 82 (10.9%) showed airflow limitation when assessed with the PiKo-6. Of these patients, 79 (10.5%) were assigned to the COPD group. FEV1, FEV6 and FEV1/FEV6, as measured with the PiKo-6, correlated significantly with FEV1, FVC and FEV1/FVC, respectively, as measured by spirometry (r = 0.865, 0.751 and 0.57). Among the cardiovascular comorbidities, heart failure and ischaemic heart disease showed slightly stronger associations with airflow limitation (13.8% and 12.5%, respectively). CONCLUSIONS: Combination of the PiKo-6 with a COPD questionnaire may be a useful and feasible method of identifying undiagnosed COPD patients attending a cardiovascular outpatient clinic.

[Qualitative analysis of interns' decision-making process of selecting respiratory medicine as their specialty].

BACKGROUND: Because there is a shortage of pulmonologists in Japan, it is crucial to understand interns' decision-making process of selecting respiratory medicine as their specialty. OBJECTIVE: The objectives of the study were to illustrate the process in which residents pursue the specialty of respiratory medicine and to establish a strategic springboard that may encourage more residents to select respiratory medicine as their specialty. METHODS: A qualitative study using semi-structured interviews was performed. Eleven doctors who had selected respiratory medicine were recruited. We measured categories which constitute the process of career choice. RESULTS: The present analysis of 11 interviews produced three main categories that influenced residents' career decision. Those were "ambiguous preference for respiratory medicine", "triggers for interests on respiratory medicine", and "comparisons and contemplations among specialties". "Triggers for interests" were as follows: experiencing effectual mentorship in respiratory medicine, being impressed with pulmonologists' daily practice, taking an interest in anatomy and physiology, and exposing themselves to clinical practice repeatedly. Through "comparisons and contemplations among specialties", the interviewees recognized respiratory medicine as attractive, because of its close association with other internal medicine disciplines, the comprehensive diagnostic process, and the diversity of respiratory diseases. CONCLUSION: Experiencing enthusiastic mentorship, being impressed with pulmonologists' daily practice, and realizing profoundness of respiratory medicine influenced the decision-making process.

Budd-Chiari syndrome: a case with a combination of hepatic vein and superior vena cava occlusion.

We here report a recent, rare case of Budd-Chiari syndrome, associated with a combination of hepatic vein and superior vena cava occlusion. A young female, who had been in good health, was admitted to our hospital because of massive ascites. The patient had used no oral contraceptives. Tests for coagulation disorders, hematological disorders, and antiphospholipid syndrome were all negative. Budd-Chiari syndrome was diagnosed by radiographic examination. The patient was suffering from a combination of hepatic vein and superior vena cava occlusion. In particular, the venous flow returned from the liver mainly through a right accessory hepatic vein, and stenosis was recognized at the orifice of this collateral vein into the vena cava. Subsequently, the patient underwent percutaneous balloon dilatation therapy for this stenosis. After this treatment, the massive ascites was gradually reduced, and she was discharged from our hospital. It has now been one year since discharge, and the patient has been doing well. If deteriorating liver function or intractable ascites occur again, a liver transplantation may be anticipated. This is the first case report of Budd-Chiari syndrome associated with a superior vena cava occlusion.