Pembrolizumab-caused polyradiculoneuropathy as an immune-related adverse event.

Immune-related adverse events (irAEs) commonly involve the gastrointestinal tract, endocrine glands, skin, and liver, and rarely the nervous system. The pathomechanism of irAEs in the nervous system is unclear, and so characterizing these severe toxic effects is a priority, even if irAEs are uncommon in the nervous system. Our patient presented subacute muscle weakness and dysesthesia with colitis as irAEs caused by pembrolizumab, one of the anti-programmed death-1 (PD-1) antibodies. Electromyography revealed abundant fibrillations and fasciculations of upper and lower extremities and severe reduction in motor unit potentials; however, antineutrophil cytoplasmic antibodies, rheumatoid factor, autoantibodies against Hu and Yo, and anti-ganglioside antibodies, such as GQ1b, were undetectable in the serum. Although he was treated with high-dose glucocorticoids, antibiotics, and a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, he developed colonic perforation. The total colorectal resection was performed, and the resected colon showed mucosal defect and perforation. He died of lung aspergillosis. Postmortem examination revealed CD8-positive lymphocyte infiltration around neurons of dorsal root ganglia. The sciatic nerve displayed the widening of myelin laminae and thinning of myelinated fibers but not a decrease in the density of myelinated nerve fibers. In the sural nerve, the density of myelinated fibers slightly decreased, and some fibers showed less densely myelinated laminae. Drug safety information, including previous randomized trials of anti-PD-1 and anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies, showed that patients treated with anti-PD-1 antibodies appeared to have more frequent and severe peripheral neuropathies compared to those in patients who received anti-CTLA-4 antibodies (1.59% vs. 0.69%; Fisher exact test, P < 0.001; three severe events vs. zero severe events). The present results and drug safety information suggest that the pathomechanism of irAEs caused by anti-PD-1 antibodies is different from that by anti-CTLA-4 antibodies. The neurological irAEs might be clues to solving the pathomechanism of irAEs.

[Rapid Growing Anterior Mediastinal Leiomyosarcoma with Pericardial Infiltration:Report of a Case].

Primary mediastinal leiomyosarcoma is extremely rare, and few reports in the literature have described the clinical features of this malignancy. We report a case of a small anterior mediastinal leiomyosarcoma that showed rapid growth within a short period. An 85-year-old woman showed a small anterior mediastinal tumor on chest computed tomography (CT), three months prior to presentation. Contrast-enhanced chest CT revealed rapid tumor growth, and positron emission tomography/CT revealed significant 18-fluorodeoxyglucose uptake, suggestive of malignancy. Thoracoscopic tumor resection was performed via the left thoracic approach. In addition to the tumor and surrounding anterior mediastinal tissue, we resected an area of pericardial infiltration. The tumor was diagnosed as a primary mediastinal leiomyosarcoma based on histopathological and immunohistochemical findings.

Development of the Japanese version of an information aid to provide accurate information on prognosis to patients with advanced non-small-cell lung cancer receiving chemotherapy: a pilot study.

BACKGROUND: Without explicit prognostic information, patients may overestimate their life expectancy and make poor choices at the end of life. We sought to design the Japanese version of an information aid (IA) to provide accurate information on prognosis to patients with advanced non-small-cell lung cancer (NSCLC) and to assess the effects of the IA on hope, psychosocial status, and perception of curability. METHODS: We developed the Japanese version of an IA, which provided information on survival and cure rates as well as numerical survival estimates for patients with metastatic NSCLC receiving first-line chemotherapy. We then assessed the pre- and post-intervention effects of the IA on hope, anxiety, and perception of curability and treatment benefits. RESULTS: A total of 20 (95%) of 21 patients (65% male; median age, 72 years) completed the IA pilot test. Based on the results, scores on the Distress and Impact Thermometer screening tool for adjustment disorders and major depression tended to decrease (from 4.5 to 2.5; P = 0.204), whereas no significant changes were seen in scores for anxiety on the Japanese version of the Support Team Assessment Schedule or in scores on the Hearth Hope Index (from 41.9 to 41.5; p = 0.204). The majority of the patients (16/20, 80%) had high expectations regarding the curative effects of chemotherapy. CONCLUSION: The Japanese version of the IA appeared to help patients with NSCLC maintain hope, and did not increase their anxiety when they were given explicit prognostic information; however, the IA did not appear to help such patients understand the goal of chemotherapy. Further research is needed to test the findings in a larger sample and measure the outcomes of explicit prognostic information on hope, psychological status, and perception of curability.

[Prospective study of biotin treatment in patients with erythema due to gefitinib or erlotinib].

Gefitinib anderlotinib, which are epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs), have been usedfor the treatment of inoperable andrecurrent non-small cell lung cancer(NSCLC)patients. These drugs are known to cause a skin rash, one of the major side effects, at a high frequency. Biotin is a water-soluble vitamin, andit belongs to the vitamin B family. It is well known that biotin deficiency increases the risk of skin dermatitis. We administered biotin to four patients with skin rash, all of whom were treatedwith either gefitinib or erlotinib andwere unable to be treatedby a steroid ointment alone. In all patients, administration of biotin reduced the skin rash. Surprisingly, in 2 patients in whom EGFR-TKI therapy was discontinued because of the skin rash, the administration of biotin allowed for long-term gefitinib or erlotinib treatment. Biotin may be considereduseful for the treatment of skin rash causedby EGFR-TKIs. Further trials may be needed to confirm the value of biotin in this setting.

Methylation of breast cancer susceptibility gene 1 (BRCA1) predicts recurrence in patients with curatively resected stage I non-small cell lung cancer.

BACKGROUND: Even after early detection and curative resection of early stage non-small cell lung cancer (NSCLC), a significant fraction of patients develop recurrent disease. Molecular biomarkers that can predict the risk of recurrence thus need to be identified to improve clinical outcomes. METHODS: Using the methylation-specific polymerase chain reaction assay, promoter methylation of the breast cancer susceptibility gene 1 (BRCA1) was assessed in cancer tissues from 70 patients with curatively resected stage I NSCLC. The clinical relevance of BRCA1 methylation status was evaluated in terms of outcome of the disease. RESULTS: Methylation of the BRCA1 promoter was detected in 13 of 70 patients (18.6%). Multiple logistic regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence (P = .0197) and that patients with BRCA1 methylation demonstrated significantly poorer recurrence-free survival compared to those without (P = .0139). Cox's proportional hazard regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence-free survival (P = .0155). CONCLUSIONS: Methylated BRCA1 can be a potential biomarker that predicts the prognosis after curative resection of stage I NSCLC. Considering that BRCA1 plays a role in chemotherapy-induced apoptosis, it is plausible that identification of methylated BRCA1 could provide information that is clinically relevant to tailored adjuvant therapy.

Giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity in a patient with systemic sclerosis.

To the best of our knowledge, systemic sclerosis with overlapping characteristics of both microscopic polyangiitis and giant cell arteritis (i.e. microscopic polyangiitis involving the superficial temporal artery or giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity) has not been reported previously. An 82-year-old woman with diffuse cutaneous systemic sclerosis experienced dyspnoea on exertion and fever. No signs of infection were observed on computed tomography. Her fever persisted despite antibiotic treatment for occult bacterial infection and secondary Clostridioides difficile-associated diarrhoea. Microscopic polyangiitis was suspected because of myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity, and giant cell arteritis was suspected as a differential diagnosis due to swelling of the superficial temporal artery. Arterial biopsy revealed inflammatory cell infiltration with granuloma formation. Based on the presence of granulomatous inflammation in the superficial temporal artery, we concluded that giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity occurred as a complication. After glucocorticoid therapy, her fever and dyspnoea on exertion improved with a gradual decline in the serum myeloperoxidase anti-neutrophil cytoplasmic antibody levels. It is possible that vasculitis occurs as a complication in patients with systemic sclerosis in cases where the fever persists and cannot be explained by systemic sclerosis itself, infectious disease, or malignancy. Clinicians must be careful not to prematurely diagnose microscopic polyangiitis based on myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity or giant cell arteritis based on the swelling of the superficial temporal artery. Careful evaluation of the presence of granulomatous inflammation in an arterial biopsy specimen is essential to differentiate between microscopic polyangiitis and giant cell arteritis.

Quality of end-of-life care for patients with metastatic non-small-cell lung cancer in general wards and palliative care units in Japan.

PURPOSE: Patients with lung cancer in Japan often receive aggressive care near the end of life and die in an acute care hospital. We describe the differences in end-of-life care for metastatic non-small-cell lung cancer (NSCLC) patients between general wards and a palliative care unit (PCU). METHODS: A retrospective analysis was conducted using data from patients who received at least second-line chemotherapy between 2002 and 2007 in a single institute. Among 72 eligible patients, we categorised patients into two groups, those who died in general wards (n = 57) and those who died in the PCU (n = 15), and examined end-of-life care including chemotherapy, do-not-resuscitate (DNR) decision making and treatment in the last 48 h of life. RESULTS: Mean number of days between the last chemotherapy and death was shorter in general wards than in the PCU (P = 0.019). Furthermore, 25% of patients in general wards received chemotherapy within the last 2 weeks of life. Rates of multiple hospitalisations in the last month of life appeared higher in general wards than in the PCU. Mean number of days between documentation of DNR and death was shorter in general wards than in the PCU (P = 0.0010). Patients in general wards received a greater volume of hydration than those in the PCU (P < 0.001). CONCLUSIONS: Patients with metastatic NSCLC in general wards receive inappropriate care near the end of life. Further studies are needed to develop interventions for making decisions regarding end-of-life care.

Lymphangitis carcinomatosa from gallbladder cancer.

A 61-year-old woman was admitted to our hospital with productive cough and fever. Computed tomography images revealed ground glass opacities in both lung fields, and a space-occupying lesion in the gallbladder. Transbronchial lung biopsy revealed a poorly differentiated adenocarcinoma with invasion of the lymph ducts; accordingly, a diagnosis of lymphangitis carcinomatosa was made. We could not administer chemotherapy due to poor performance status, and the patient died of respiratory failure 30 days after admission. Owing to pathological autopsy findings of poorly differentiated adenocarcinoma in the gallbladder, we diagnosed this as a rare case of gallbladder cancer presenting with lymphangitis carcinomatosa.

Systemic Inflammatory Score Predicts Response and Prognosis in Patients With Lung Cancer Treated With Immunotherapy.

AIM: This study aimed to investigate useful prognostic factors of immunotherapy in patients with lung cancer. PATIENTS AND METHODS: We retrospectively observed 73 patients who underwent immunotherapy (nivolumab, pembrolizumab, and atezolizumab) for lung cancer. The systemic inflammatory score (SIS) was calculated as the sum of the following factors scored one point each: Hemoglobin <12.5 g/dl and serum albumin <3.6 g/dl, resulting in scores of 0-2. We examined the correlation between the SIS and initial tumor response and progression-free and overall survival with other existing markers, namely tumor programmed death-ligand 1 (PD-L1) expression level; neutrophil-to-lymphocyte ratio (NLR); modified Glasgow prognostic score; and prognostic nutritional index, etc. Results: SIS ≤1 was significantly associated with better initial tumor response. In multivariate analysis, PD-L1 expression ≥50% (p=0.010), SIS ≤1 (p=0.028) and NLR <5.6 (p=0.047) were significantly associated with longer progression-free survival, and SIS ≤1 (p=0.030) and NLR <5.6 (p=0.037) were associated with longer overall survival. CONCLUSION: SIS is a useful marker of the efficacy of immunotherapy that can be obtained via routine blood tests.

Treatment rationale and design of the PROLONG study: safety and efficacy of pembrolizumab as first-line therapy for elderly patients with non-small cell lung cancer.

BACKGROUND: Pembrolizumab is recommended as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a Programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, the safety and efficacy were not investigated among patients who were ≥75 years old. METHODS: This open-label single-arm phase II study is designed to evaluate pembrolizumab as first-line therapy for patients who are ≥75 years old with advanced NSCLC and a PD-L1 TPS of ≥50% without driver mutations. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, objective response rate, safety, and quality of life. Recruitment started in October 2017 and is expected to continue for approximately 3 years. CONCLUSIONS: Given the currently poor prognosis of elderly patients with advanced NSCLC, we hope that the findings of this study will facilitate more effective treatment in this setting.

[Clinico-pathological prognostic factors in malignant pleural mesothelioma].

The prognosis of malignant pleural mesothelioma is poor, but selected patients might benefit from multimodality treatment. To establish the means that are available to predict the variable course of the disease in malignant pleural mesothelioma patients, we retrospectively investigated the correlation of clinico-pathological features of 54 patients with survival. Twenty-three patients received treatment, while 31 were referred to supportive care only. The median survival of the entire group was 8.6 months. The 1-year survival was 33.2%. Univariate analysis of subgroups showed that age over 70 years, non-epithelial histologic type, patients treated with supportive care only, and delayed diagnosis were individually associated with lower survival. The European Organization for Research and Treatment of Cancer (EORTC) score showed a significant correlation with survival (P = 0.0146). The median survival of patients with an EORTC score of over 1.27 was 3.5 months, compared to 10.5 months for patients with an EORTC score of 1.27 or less. Tumor necrosis (TN) was a poor prognostic factor on univariate analysis (P = 0.0077). Patients with TN had a median survival of 7.0 months vs 15.5 months in negative cases. On multivariate analysis, TN was determined as an independent prognostic factor (P = 0.0349). EORTC prognostic scoring systems successfully stratify survival for a general hospital population, and TN might play an important role in poor outcome in malignant pleural mesothelioma.

The Effective Treatment of Lung Infection Due to Scedosporium prolificans with Voriconazole and Surgery.

Scedosporium prolificans is a fungus that has demonstrated resistance against most currently available antifungal agents and which causes a rapidly disseminating and potentially fatal infection. A 68-year-old woman presented with a fever and consolidation in the lung field. Her symptoms and inflammatory reaction did not improve despite treatment with tazobactam/piperacillin, meropenem, and micafungin. Scedosporium prolificans was detected from the patient's bronchial lavage fluid, and we initiated treatment with voriconazole. Voriconazole was effective in shrinking the consolidation and suppressing the inflammatory reaction. The residual lesion was surgically resected because of the risk of systemic dissemination. The patient is currently alive without relapse or dissemination.

Carboplatin plus Weekly Paclitaxel Combined with Bevacizumab as First-line Treatment for Non-small Cell Lung Cancer.

AIM: We aimed to evaluate the efficacy and safety of carboplatin plus weekly paclitaxel with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV or postoperative recurrent NSCLC (n=33) were treated with carboplatin (area under the curve of 6) on day 1; paclitaxel (80 mg/m2) on days 1, 8, and 15; and bevacizumab (15 mg/kg) on day 1 repeated every 4 weeks, for four to six cycles; followed by maintenance bevacizumab (15 mg/kg) every 3 weeks. RESULTS: The overall response rate was 76%. The median progression-free survival and overall survival were 8.4 months and 22.2 months, respectively. Grade 3-4 toxicities included neutropenia in 55% of patients, anemia in 18%, febrile neutropenia in 12%, and anorexia in 9%. No treatment-related deaths were observed. CONCLUSION: Carboplatin plus weekly paclitaxel with bevacizumab was effective and well tolerated by patients with advanced NSCLC.

[A case of bronchogenic cyst with elevated SLX levels in serum and cystic fluid].

A 27-year-old man was admitted with chest pain and cough in January 1999. Chest radiograph on admission showed a widened tracheal bifurcation. Computer tomography on admission showed a low density mass located at the tracheal bifurcation. Magnetic resonance imaging of the chest showed a well defined mass with isointensity on T1-weighted images, and high intensity on T2-weighted images. Laboratory data on admission showed mild inflammatory findings and a high level of Sialyl Lewis X-i antigen (SLX) in serum. Thoracotomy revealed a cystic mass and pathologically, the cyst wall was lined with bronchial epithelium which showed no malignancy. The level of SLX in the cystic fluid was elevated, and immunohistochemical staining of the cystic epithelium was positive for SLX. After resection of the cyst, the level of SLX in serum decreased. This represents a rare case of bronchogenic cyst with a high level of SLX in serum and cystic fluid.

A case of familial hot tub lung.

Hot tub lung is a lung disease caused by Mycobacterium avium complex. We report the first case of familial hot tub lung appearing simultaneously in a husband and wife. Our case supports the consideration that hot tub lung is a hypersensitivity pneumonitis rather than an infectious lung disease. It also suggests that the state of hot tub lung changes seasonally depending on temperature variations, in a manner similar to summer-type hypersensitivity pneumonitis. This case demonstrates similarities between hot tub lung and summer-type hypersensitivity pneumonitis in regards to familial occurrence and seasonal changes in the disease state.

Significance of pulmonary artery pressure in emphysema patients with mild-to-moderate hypoxemia.

The guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) do not recommend the measurement of pulmonary artery pressure in patients with chronic obstructive pulmonary disease (COPD). This is on the basis that the mean pulmonary artery pressure (mPAP) does not provide more clinical information than measurement of the oxygen tension in arterial blood (PaO2). The mPAP correlates well with PaO2 in emphysema patients with severe hypoxemia (PaO2 < or = 7.3 kPa (55 mmHg)). However, the occurrence and significance of mPAP is unclear in patients without severe hypoxemia (PaO2 > 7.3 kPa (55 mmHg)). In order to evaluate the usefulness of measurement of mPAP in emphysema patients without severe hypoxemia, we performed right heart catheterization and investigated the pulmonary hemodynamics of 53 patients without severe hypoxemia. In addition, we identified long-term prognostic factors with a mean follow-up term of 77 months after right heart catheterization. Seventeen of 27 patients with mild-to-moderate hypoxemia exhibited pulmonary hypertension (mPAP > or = 2.7 kPa (20 mmHg)) and the classification according to severity in GOLD exhibited a greater correlation to mPAP than PaO2. Moreover, only mPAP was found to be a significant prognostic factor according to multivariate proportional hazards analysis (P = 0.01). We conclude that mPAP is more informative about the severity of emphysema than PaO2 in patients with mild-to-moderate hypoxemia.

[Daily low-dose cisplatin plus concurrent high-dose thoracic radiotherapy in elderly patients with locally advanced unresectable non-small-cell lung cancer].

There are few prospective studies of concurrent chemoradiotherapy in elderly patients with locally advanced unresectable non-small-cell lung cancer (NSCLC), although the therapy has proved superior to radiotherapy alone for the treatment of younger patients. We conducted a pilot study to assess the tolerance and efficacy of concurrent cisplatin and thoracic radiation in elderly patients with locally advanced unresectable NSCLC. Eligible patients were more than 71 years old and had unresectable Stage I, II, or III NSCLC. Cisplatin was administered at 6 mg/m2 daily intravenously on days 1 through 5, days 8 through 12, days 29 through 33 and days 36 through 40. Beginning day on 1, thoracic radiation was delivered at 2.0 Gy daily to a total dose of 60 Gy. Twelve patients were registered and 11 were eligible. Patient characteristics were ages of 73 to 80 years, and stage III A (18%) and stage III B (73%) NSCLC. The most common grade 3 toxicities included leukopenia (20%) and thrombocytopenia (9%). Grades 3/4 elevation of serum creatinin, esophagitis and pneumonitis did not occur. The overall confirmed response rate was 82%, and median overall survival was 23 months. The 2-year survival rate was 53%. This chemoradiotherapy regimen is well tolerated with promising response and survival in elderly patients with unresectable NSCLC.

Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03.

We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naïve patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil-lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P=0.0008) and progression-free survival (P=0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm(-3) (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09-2.54). The median survival time was 19.3 months (95%CI, 16.5-21.4) for the low-neutrophil group (4500 mm(-3), n=204) and was 10.2 months (95%CI, 8.0-12.3) for the high-neutrophil group (4500 mm(-3), n=184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis.