Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data.

BACKGROUND: Management of cancer-associated venous thromboembolism (VTE) is essential in cancer treatment selection and prognosis. However, currently, no method exists for assessing VTE risk associated with advanced lung cancer. Therefore, we assessed VTE risk, including driver gene mutation, in advanced lung cancer and performed a Khorana score validation. METHODS: The Rising-VTE/NEJ037 study was a multicenter prospective observational study that included patients with advanced lung cancer. In the Rising-VTE/NEJ037 study, the Khorana score was calculated for enrolled patients with available data on all Khorana score components. The modified Khorana score was based on the body mass index of ≥ 25 kg/m2, according to the Japanese obesity standard. A multivariate logistic regression analysis, including patient background characteristics, was performed to evaluate the presence of VTE 2 years after the lung cancer diagnosis. RESULTS: This study included 1008 patients with lung cancer, of whom 100 (9.9%) developed VTE. From the receiver operating characteristic curve analysis, VTE risk could not be determined because both the Khorana score (0.518) and modified Khorana score (0.516) showed very low areas under the curve. The risk factors for VTE in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2 and diastolic blood pressure. CONCLUSION: The Khorana score, which is widely used in cancer-VTE risk assessment, was less useful for Japanese patients with advanced lung cancer. Prothrombin fragment 1 + 2, a serum marker involved in coagulation, was more suitable for risk identification. CLINICAL TRIAL INFORMATION: jRCTs061180025.

A randomized trial of sodium alginate prevention of esophagitis in LA-NSCLC receiving chemoradiotherapy: OLCSG1401.

BACKGROUND: Radiation esophagitis is a critical adverse event that needs to be appropriately managed while administering thoracic irradiation. This trial aimed to investigate whether sodium alginate has preventative effects on esophagitis in patients with non-small-cell lung cancer (NSCLC) receiving concurrent chemoradiotherapy (CRT). METHODS: Patients with untreated stage III NSCLC who were eligible for concurrent CRT were randomly assigned at a 1:1:1 ratio to receive one of the following treatments: initial or late use of oral sodium alginate (arms A and B) or water as control (arm C). The primary endpoint was the proportion of patients developing G3 or worse esophagitis. RESULTS: Overall, 94 patients were randomly assigned between February 2014 and September 2018. The study was prematurely terminated because of slow accrual. The proportions of patients with G3 or worse esophagitis were 12.5%, 9.8%, and 19.4% in arms A, B, and C, respectively. Patients receiving sodium alginate had fewer onsets of G3 esophagitis; however, differences compared with arm C were not significant (A vs. C: p = 0.46; B vs. C: p = 0.28). The rates of grade 3 or worse non-hematologic toxicities besides esophagitis were 29%, 26%, and 43% in arms A, B, and C, respectively. Interestingly, compared with arm C, a low rate of febrile neutropenia was observed in arm A (3.1% vs. 19.4%: p = 0.04). CONCLUSIONS: Sodium alginate did not show significant preventative effects on radiation-induced esophagitis in patients with NSCLC. The frequency of CRT-induced febrile neutropenia was lower in the early use sodium alginate arm. TRIAL REGISTRATION: ClinicalTrials.gov Identifier Registry number: UMIN000013133.

A case of immunoglobulin G4-Related disease with pleural effusion, requiring exclusion of tuberculous pleurisy.

Immunoglobulin G4 (IgG4)-related pleurisy is a rare type of IgG4-related disease. We present the case of a 69-year-old woman with left pleural effusion and elevated adenosine deaminase levels. Initially, tuberculous pleuritis was suspected; however, the bacterial cultures and polymerase chain reaction test results for tuberculosis were negative. Thoracoscopic pleural biopsy revealed dense lymphocytic infiltrates with large numbers of IgG4-positive plasma cells. The ratio of IgG4-positive to IgG-positive plasma cells exceeded 40%. The patient was diagnosed with IgG4-related disease.

Incidence of venous thromboembolism in advanced lung cancer and efficacy and safety of direct oral anticoagulants: a multicenter, prospective, observational study (Rising-VTE/NEJ037 study).

Background: Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors. Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation. Results: Data were available for 1008 patients. The median age was 70 years (range: 30-94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group. Conclusions: VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate. Trial registration: jRCTs061180025.

A new risk-assessment tool for venous thromboembolism in advanced lung cancer: a prospective, observational study.

Management of cancer-associated venous thromboembolism (VTE) is essential in treatment selection and cancer prognosis. However, to date, there is no method to assess the risk of VTE specifically associated with advanced lung cancer. Our aim was to create a new risk assessment scoring system that can predict the concomitant or incidence of VTE in advanced lung cancer. We used the dataset of 1008 patients with lung cancer in the Rising-VTE/NEJ037 study, of which 100 (9.9%) developed VTE. The items extracted in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2, and diastolic blood pressure. This model had a maximum score of 8 points, with ≥ 5 points indicating a high risk of VTE. This simple risk-assessment model for VTE complications with advanced lung cancer could help identify cases that required monitoring for VTE.

Effect of Prophylactic Anti-emetics on Opioid-induced Nausea and Vomiting: A Retrospective Observational Cohort Study.

BACKGROUND: The guidelines on pharmacotherapy for cancer-related pain advocate active measures against the adverse effects of opioids to increase adherence to medication. However, preventative therapy for the management of nausea and vomiting has not been specified. This study aimed to verify the effects of prophylactic anti-emetics in preventing opioid-induced nausea and vomiting. PATIENTS AND METHODS: We conducted a retrospective analysis of cases at our hospital in which oral opioids or patches were initiated for the management of pain due to malignant tumours from January 2017 to September 2019. RESULTS: Strong opioids were initiated for 349 patients; of these, data for 298 patients were analysed. A total of 193 patients were on anti-emetic prophylaxis. We found that the group that did not receive anti-emetic prophylaxis was significantly more likely to be prescribed an additional anti-emetic. CONCLUSION: Prophylactic administration of anti-emetics at the time of initiating opioid analgesics may reduce gastrointestinal toxicity.

Successful Treatment with Lorlatinib after the Development of Alectinib-Induced Liver Damage in ALK-Positive Non-Small-Cell Lung Cancer: A Case Report.

Alectinib is a key drug for treating anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). Alectinib-induced hepatotoxicity is less common than that through other ALK inhibitors, such as crizotinib or ceritinib. Herein, we describe a case of ALK-positive adenocarcinoma successfully treated with lorlatinib after developing alectinib-induced hepatotoxicity. A 57-year-old Japanese man received alectinib as first-line therapy for ALK-positive NSCLC. After 79 days, alectinib was discontinued because of hepatotoxicity and later restarted at 150 mg/day, inducing hepatotoxicity again after 64 days. Switching to lorlatinib treatment (continued for >4 months) caused no severe adverse effects. Hence, lorlatinib may be useful for patients experiencing alectinib-induced hepatotoxicity.

Limited effect of afatinib in a non-small cell lung cancer patient harboring an epidermal growth factor receptor K860I missense mutation: A case report.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are key drugs in the treatment of non-small cell lung cancer (NSCLC) patients with EGFR mutations; however, first-generation EGFR-TKIs, such as gefitinib and erlotinib, are not effective in patients with uncommon EGFR mutations. In contrast, efficacy of afatinib has been reported in some types of uncommon EGFR mutation such as G710X, L861Q. The effect of afatinib in NSCLC patients with the EGFR K860I mutation has been shown in vitro, but its clinical efficacy has not been demonstrated. Here, we report the experience of afatinib administration in an NSCLC patient with an EGFR K860I mutation. A 69-year-old woman presented with right hemiplegia and dysarthria. Multiple brain and lung tumors were observed. She underwent craniotomy and was diagnosed with lung adenocarcinoma. After stereotactic brain radiation therapy, cisplatin, pemetrexed, and bevacizumab combination therapy was initiated. Unfortunately, she was unable to continue chemotherapy as she had an intestinal perforation after two cycles. After five months, recurrence of multiple brain metastases and an increase in primary lung cancer were confirmed. Next-generation sequencing (NGS) was performed in a clinical trial, and an EGFR K860I mutation was detected in her tumor. Afatinib was administered and the primary lung tumor shrank, but multiple brain metastases were exacerbated. After irradiation of the brain, afatinib administration was continued. In conclusion, afatinib may show an effect in NSCLC patients with the EGFR K860I mutation, but its efficacy is limited.

Retrobulbar Optic Neuritis Induced by Pembrolizumab in a Patient with Lung Adenocarcinoma.

Pembrolizumab is a monoclonal antibody with anti-tumor effects. Only a few reports have previously described retrobulbar optic neuritis induced by pembrolizumab. We herein report the case of a 63-year-old man with advanced lung adenocarcinoma who received cisplatin, pemetrexed, and pembrolizumab combination therapy for six months. Following treatment, a visual field test showed a left central scotoma. Imaging studies showed left optic neuritis without brain metastasis. Blood tests showed an elevated serum creatinine level. He was diagnosed with retrobulbar optic neuritis and pembrolizumab-induced renal failure. After receiving corticosteroid treatment, his renal function rapidly improved. The optic neuritis improved somewhat, but it was not adequately resolved.

Successful transcatheter arterial embolization of asymptomatic aneurysm associated with left inferior phrenic artery-to-left pulmonary artery fistula: A case report.

Cases of inferior phrenic artery-to-pulmonary artery fistulas and those complicated by massive hemoptysis have been rarely reported. A 38-year-old man presented to our hospital with a chief complaint of coughing. Computed tomography (CT) revealed a nodule in the left lower lobe, and contrast-enhanced CT showed inflow of contrast medium into the nodule. CT angiography detected an aneurysm associated with a left inferior phrenic artery-to-left pulmonary artery fistula. Transcatheter arterial embolization (TAE) was performed to prevent hemoptysis. Hemoptysis did not occur during the 2-year follow-up. We report a rare case of asymptomatic aneurysm associated with a left inferior phrenic artery-to-left pulmonary artery fistula, which was successfully treated using TAE to prevent hemoptysis.

Successful corticosteroid treatment of necrotizing sarcoid granulomatosis associated with tracheal lesion recurred after a surgical lung biopsy.

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that presents with nodular lung lesions and necrosis. The pathology is consistent with sarcoidosis, but the necrosis can lead to a diagnosis of tuberculosis. Herein, we report a rare case of NSG that recurred four years after the initial diagnosis was made by surgical lung biopsy. A 51-year-old woman was initially referred to our hospital for the evaluation of multiple lung nodules. The pathological evaluation of a lung biopsy showed granulomas with necrosis and the infiltration of lymphocytes; thus, she was diagnosed with NSG. The lung nodules gradually improved after the diagnosis and we continued to follow her even though she did not require treatment. Four years after her initial diagnosis, she complained of back pain. Upon evaluation, we found that multiple lung nodules had recurred. Bronchoscopy also revealed a tracheal polypoid lesion, which showed granulomas with necrosis pathologically. Therefore, we diagnosed her with the recurrence of NSG. After the corticosteroid therapy, multiple lung nodules drastically improved. NSG patients should be carefully followed-up over several years, even if they do not require treatment.

Carboplatin, pemetrexed, and pembrolizumab was effective for primary salivary gland-type lung adenocarcinoma diagnosed due to esophageal stricture: A case report.

Primary salivary gland-type tumors of the lung are rare, accounting for <1% of all lung tumors. There are few reports on chemotherapy for the treatment of primary salivary gland-type tumors of the lung. The patient in this report was a 71-year-old woman who presented with a chief complaint of dysphagia. Upper gastrointestinal endoscopy revealed an esophageal stricture, but biopsy showed no malignancy. Chest computed tomography (CT) showed carcinomatous lymphangiomatosis and a nodule in the right lung. Bronchoscopy showed a rough mucous membrane of the central bronchi, while biopsy showed adenocarcinoma. The patient was diagnosed with bronchogenic adenocarcinoma and received carboplatin, pemetrexed, and pembrolizumab, which alleviated the esophageal stricture and cancerous lymphangiopathy. However, the adenocarcinoma progressed, and she subsequently received several rounds of chemotherapy. One year after diagnosis, the patient died, and pathological autopsy revealed primary salivary gland-type tumors of the lung.

Heerfordt's Syndrome Associated with Trigeminal Nerve Palsy and Reversed Halo Sign.

Heerfordt's syndrome is a rare subtype of sarcoidosis and features a combination of facial palsy, parotid swelling, and uveitis, associated with a low-grade fever. Cases with two of three symptoms are called "incomplete Heerfordt's syndrome." Heerfordt's syndrome involving other cranial nerve symptoms is relatively rare. We herein report a case of incomplete Heerfordt's syndrome presenting with trigeminal nerve palsy and a reversed halo sign, a rare manifestation of pulmonary sarcoidosis. The histological diagnosis following a biopsy of the parotid gland and endobronchial ultrasound-guided trans-bronchial needle aspiration of the mediastinal lymph nodes was sarcoidosis. The symptoms and lung lesions improved after corticosteroid therapy.

Randomized study comparing mannitol with furosemide for the prevention of cisplatin-induced renal toxicity in non-small cell lung cancer: The OLCSG1406 trial.

AIM: Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. METHODS: Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. RESULTS: The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. CONCLUSION: The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.

A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202.

INTRODUCTION: S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown. METHODS: The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40mg/m2, twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40mg/m2, twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated. RESULTS: Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134days (95% CI: 79-173) and 479days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P<0.01). CONCLUSION: This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option.