Endocrine immune-related adverse event is a prognostic biomarker independent of lead-time bias.

OBJECTIVES: Immune-related adverse events (irAEs) are known to be associated with clinical efficacy and better prognoses in patients receiving immune checkpoint inhibitors. In particular, endocrine irAE (e-irAE) is related to better prognoses. Since the incidence of irAEs increase as treatment duration becomes longer, we should consider lead-time bias not to overvalue the result. We evaluated the impact of e-irAE on the outcome before and after 6-, 9-, and 12-week landmark analyses. MATERIALS AND METHODS: We evaluated 222 patients with advanced or recurrent non-small cell lung cancer who received anti-PD-1 antibodies such as nivolumab or pembrolizumab from January 2016 to April 2021. Treatment efficacy and outcomes of patients with or without e-irAE (e-irAE group or no e-irAE group) were retrospectively evaluated. In addition, we performed 6-, 9-, and 12-week landmark analyses to exclude the effect of lead-time bias. RESULTS: Median progression free survival (PFS) was significantly longer in the e-irAE group than in the no e-irAE group (overall: 15.3 vs 3.9 months, p < 0.0001; 6-week: 15.3 vs 4.9 months, p < 0.0002; 9-week: 19.8 vs 6.1 months, p = 0.0012, 12-week: 19.8 vs 8.4 months, p = 0.017). Overall survival (OS) was significantly longer in the e-irAE group (overall: not reached (NR) vs 15.4 months, p = 0.0003; 6-week: NR vs 19.1 months, p = 0.0049, 9-week: NR vs 22.2 months, p = 0.006; 12-week: NR vs 23.3 months, p = 0.04). We used the multivariate cox proportional hazard model to adjust for confounding factors and found that e-irAE had better impact on both PFS and OS (PFS: overall: hazard ratio 0.37 [95% confidence interval 0.23-0.56], 6-week: 0.41 [0.26-0.63], 9-week: 0.43 [0.24-0.63], 12-week: 0.52 [0.31-0.84]; OS: overall: 0.40 [0.22-0.68], 6-week: 0.46 [0.25-0.79], 9-week: 0.47 [0.24-0.84], 12-week: 0.58 [0.29-1.08]). CONCLUSION: The occurrence of endocrine irAE was associated with better efficacy and prognoses regardless of the lead-time bias.

[Retracted] Predictors of efficacy of anamorelin in patients with non­small cell lung cancer and cachexia: A retrospective study.

[This retracts the article DOI: 10.3892/ol.2023.14154.].

Role of G-protein-coupled estrogen receptor in the pathogenesis of chronic asthma.

BACKGROUND AND AIM: G protein-coupled estrogen receptor (GPER) is an estrogen receptor located on the plasma membrane. We previously reported that the administration of G-1, a GPER-specific agonist, suppressed development of acute ovalbumin (OVA)-induced asthma in a mouse model. Herein, we evaluate the involvement of GPER in a mouse model of chronic OVA asthma. METHODS: G-1 or saline was administered subcutaneously to BALB/c mice with chronic OVA asthma, and pathological and immunological evaluation was performed. In addition, Foxp3-expressing CD4-positive T-cells in the spleen and ILC2 in the lungs were measured using flow cytometry. RESULTS: We observed a significant decrease in the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) in the G-1 treated group. In the airways, inflammatory cell accumulation, Th2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and epithelial cytokine TSLP were suppressed, while in the BALF, anti-inflammatory cytokines (IL-10 and TGF-ß) were increased. Furthermore, in splenic mononuclear cells, Foxp3-expressing CD4-positive T-cells were increased in the G-1 group, whereas treatment with G-1 did not change the percentage of ILC2 in the lungs. CONCLUSION: G-1 administration suppressed allergic airway inflammation in mice with chronic OVA asthma. GPER may be a potential therapeutic target for chronic allergic asthma.

Predictors of efficacy of anamorelin in patients with non­small cell lung cancer and cachexia: A retrospective study.

Anamorelin, a ghrelin receptor agonist, is approved in Japan for the treatment of cachexia in patients with lung and gastrointestinal cancer. However, there is limited research on the usefulness of anamorelin in clinical settings, therefore, the present study evaluated its efficacy using patient characteristics. A total of 40 patients with non-small cell lung cancer and cachexia who were prescribed anamorelin in the Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine (Aomori, Japan) between July 2021 and November 2022, were retrospectively assessed. Anamorelin was prescribed at a dose of 100 mg once daily to patients who had lost >5% of their body weight within 6 months. All patients were weighed before treatment and those who continued anamorelin treatment for 12 weeks were also weighed at 12 weeks. A logistic regression analysis was used to analyze the association between background characteristics and early discontinuation of treatment with anamorelin (within 4 weeks). The median age was 67 years (range, 36-88), and 65% of the patients were male. There were 24 patients (60.0%) with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score 1, 11 patients (27.5%) with an ECOG-PS score 2 and five patients (12.5%) with an ECOG-PS score 3. The early discontinuation group included 11 patients (27.5%). An ECOG-PS score ≥2 (odds ratio, 7.85; 95% confidence interval, 1.43-43.21; P=0.018) was associated with early discontinuation. A total of 18/40 patients (45.0%) were able to continue anamorelin treatment for 12 weeks, and the mean change in body weight was +2.31 kg, which was a significant change from the weight recorded at baseline (P=0.027). The mean changes in lean body mass and soft lean mass between baseline and 12 weeks were +1.97 kg (P=0.14) and +1.26 kg (P=0.15), respectively. The results from the present study indicate that anamorelin is unlikely to be useful for patients with a poor general condition (ECOG-PS score ≥2).

A Case of Disseminated Non-tuberculous Mycobacteriosis with a Skull Lesion Controlled by Resection after Exacerbation during Antimicrobial Chemotherapy in a Patient Positive for Anti-IFN-γ-neutralizing Autoantibodies.

A 48-year-old man presented with a fever and back pain and was referred to our hospital with multiple bone destruction and abscess formation. A sputum examination revealed Mycobacterium intracellulare, and pathological findings revealed an indistinct granuloma and acid-fast bacilli, leading to a diagnosis of disseminated nontuberculous mycobacteriosis. Anti-interferon-γ-neutralizing autoantibodies were detected in the serum, and acquired immunodeficiency was suspected to be the etiology. Antimicrobial chemotherapy was initiated, and the lesions generally regressed. However, only the skull lesions worsened, requiring local resection to control the disease. Currently, the patient is continuing to receive drug therapy with good disease control after debridement.

Safety and feasibility of carboplatin and paclitaxel in combination with nintedanib for non-small cell lung cancer patients with idiopathic pulmonary fibrosis: a prospective pilot study.

Background: Idiopathic pulmonary fibrosis (IPF) is a risk factor for mortality in patients with lung cancer. Nintedanib has been known to slow down the decline of lung function and reduce IPF exacerbation. We aimed to explore the feasibility of adding nintedanib to chemotherapy for non-small cell lung cancer (NSCLC) patients with IPF. Methods: Chemotherapy-naïve stage III or IV NSCLC patients with IPF were prospectively enrolled and received carboplatin plus paclitaxel with nintedanib. Primary endpoint was incidence of treatment-related acute exacerbation of IPF within 8 weeks after the last administration of chemotherapy. We initially planned to enroll 30 patients and consider it feasible when the incident rate is less than 10%. Secondary endpoint was progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Results: After 27 patients were enrolled, trial was early terminated because 4 patients (14.8%) experienced exacerbation. Median PFS and OS were 5.4 months [95% confidence interval (CI): 4.6-9.3] and 15.8 months (95% CI: 12.2-30.1), respectively. ORR and DCR were 40.7% (95% CI: 24.5-59.2%) and 88.9% (95% CI: 71.9-96.1%), respectively. One patient discontinued trial treatment due to neuropathy. Conclusions: Although the primary endpoint was not met, there might be a survival benefit. The addition of nintedanib to chemotherapy might be useful in selected population.

Rescue computed tomography-guided drainage of a giant mediastinal mature teratoma causing airway obstruction prior to surgical resection: a case report.

BACKGROUND: Giant mediastinal mature teratomas may cause airway obstruction or decreased venous return due to the mass effect. Preoperative stabilization of the respiratory and circulatory systems is important for perioperative management to safely perform surgery, including general anesthesia. However, to the best of our knowledge, there are only a few reports regarding the preoperative computed tomography (CT)-guided drainage of mediastinal tumors. CASE PRESENTATION: A 30-year-old woman was admitted to the emergency room with sudden dyspnea. CT findings revealed a giant cystic mass in the anterior mediastinum compressing the trachea and the right main bronchus. The patient was intubated and CT-guided drainage of the fluid content of the cyst was performed to decompress the airway obstruction. Thereafter, the mediastinal tumor was resected during elective surgery and pathologically diagnosed as a mature teratoma. CONCLUSIONS: Rescue preoperative CT-guided drainage of a giant mediastinal mature teratoma allowed safe general anesthesia and surgery by releasing the airway obstruction.

Granulomatosis with Polyangiitis following COVID-19 in an Adolescent.

Granulomatosis with polyangiitis (GPA) is a systemic disease that causes vasculitis in various organs. Although the mechanism of pathogenesis remains unclear, infection has been reported to be a causative factor. We herein report a case of GPA that developed following coronavirus disease 2019 (COVID-19) in an adolescent girl. One month after contracting mild COVID-19, the patient had facial allodynia, a fever, and weight loss and was admitted for multiple nodular shadows on a chest roentgenogram. GPA was diagnosed based on pathological findings of the lung and nasal mucosal biopsies. She received methylprednisolone and rituximab, and her symptoms and radiological findings improved.

Acute Exacerbation of Interstitial Lung Disease After SARS-CoV-2 Vaccination: A Case Series.

CASE PRESENTATION: An acute exacerbation of interstitial lung disease (ILD) is an acute deterioration that can occur at any time and is associated with significant morbidity and mortality rates. We herein report three patients with ILD who experienced acute respiratory failure after SARS-CoV-2 messenger RNA vaccination. All the patients were male; the mean age was 77 years. They had a smoking history that ranged from 10 to 30 pack-years. Duration from the vaccination to the onset of respiratory failure was 1 day in two patients and 9 days in one patient. In an autopsied case, lung pathologic evidence indicated diffuse alveolar damage superimposed on usual interstitial pneumonia. In the other two cases, CT scans showed diffuse ground-glass opacities and subpleural reticulation, which suggests acute exacerbation of ILD. Two patients were treated successfully with high-dose methylprednisolone. Although benefits of vaccination outweigh the risks associated with uncommon adverse events, patients with chronic lung diseases should be observed carefully after SARS-CoV-2 vaccination.

Feasibility and safety of platinum-doublet therapy in patients with small-cell lung cancer in the third-line setting: A multi-institutional retrospective study.

Small-cell lung cancer (SCLC) is a highly malignant tumor, and no standard third-line therapy has been established. The present study retrospectively analyzed the efficacy and safety of platinum-based regimens in patients with third-line SCLC who received third-line chemotherapy. The association of regimen type with overall survival (OS) or time to treatment failure (TTF) was evaluated using the Cox hazard proportional method, including well-known covariates affecting the prognosis of SCLC. TTF and OS analyses were conducted using the Kaplan-Meier method. The data cutoff date was June 30, 2020. As a result, from January 2015 to August 2019, 111 patients were diagnosed with SCLC, and 37 received third-line chemotherapy. Subsequently, 15 patients received a platinum-doublet regimen, and 22 patients received a single-agent regimen. Only the type of regimen was significantly associated with TTF in univariate analysis (odds ratio, 0.44; 95% confidence interval, 0.20-0.95; P=0.03). There were no significant factors associated with OS. The median TTF of patients receiving a platinum-doublet regimen and those receiving a single-agent regimen were 3.9 and 2.3 months, respectively (P=0.03). The overall response rates of the platinum-doublet and single-agent regimens were 20.0 and 4.5%, respectively. Similarly, the disease control rates were 73.3 and 36.4% for platinum-doublet and single-agent regimens, respectively. There was a tendency for adverse events (AEs) with any grade to occur more often in platinum-based regimens compared with in single-agent regimens. Severe AEs of grade 3 or higher were observed more often in the platinum-based regimen, especially in myelosuppression. In conclusion, the present study demonstrated the feasibility and safety of platinum-doublet regimens in patients with SCLC in a third-line setting (Registration no. 2020-048. Date of registration, June 5, 2020).

Morphological features of bronchiectasis in patients with non-tuberculous mycobacteriosis and interstitial pneumonia.

OBJECTIVE: To compare the morphological features of bronchiectasis between patients with different underlying diseases, we performed quantitative analysis of high-resolution computed tomography (HRCT) images of 14 patients with non-tuberculous mycobacteriosis (NTM) and 13 with idiopathic pulmonary fibrosis (IPF). A 3D image of the bronchial structure was made from HRCT data. Bronchiectasis was defined as abnormal dilatation of the bronchi with the diameter greater than that of the accompanying pulmonary artery. We measured the inner and outer diameters, wall area as %total airway cross sectional area (WA%), and wall thickness to airway diameter ratio (T/D) of the 4-8th generations of bronchi. RESULTS: In patients with IPF, the inner and outer diameters linearly decreased toward the distal bronchi. In contrast, the inner and outer diameters of NTM fluctuated. The coefficient of variation of the outer diameters of the 6-7th generations of bronchi was larger in the NTM patients than in those with IPF, whereas no significant difference was observed in the coefficient of variation of the inner diameters between the groups. In IPF patients, WA% and T/D varied between the generation of bronchi, but the coefficient of variation of WA% and T/D was relatively small in those with NTM.

Diabetic ketoacidosis shortly after COVID-19 vaccination in a non-small-cell lung cancer patient receiving combination of PD-1 and CTLA-4 inhibitors: A case report.

We describe a case of diabetic ketoacidosis (DKA) shortly after the SARS-CoV-2 (COVID-19) vaccination in a 65-year-old woman with non-small-cell lung cancer under a combination treatment of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. She had no history of diabetic mellitus. A few days after the second shot of COVID-19 vaccination, she developed DKA. We speculate that the immune-related adverse event and immunogenicity of vaccination synergistically induced DKA.

The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.

Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.

Immune-mediated thrombocytopenia induced with durvalumab after chemoradiotherapy in a non-small cell lung cancer patient: A case report.

We describe a case of a 60-year-old man with a prolonged thrombocytopenia during a durvalumab maintenance therapy after chemoradiotherapy for locally advanced non-small cell lung carcinoma. Bone marrow specimen was normoplastic with the marked megakaryocyte depletion, which was assumed to be an acquired amegakaryocytic thrombocytopenic purpura. Although hematological disorders as immune-related adverse events (irAE) are rare, we should pay more attention to hematological disorders with durvalumab especially after concurrent chemoradiotherapy.

The efficacy of nintedanib in 158 patients with idiopathic pulmonary fibrosis in real-world settings: A multicenter retrospective study.

BACKGROUND: The INPULSIS trials revealed that nintedanib reduced the decline in lung function in patients with idiopathic pulmonary fibrosis. We aimed to evaluate the efficacy and safety of nintedanib in Japanese idiopathic pulmonary fibrosis patients in real-world settings. METHOD: Medical records of idiopathic pulmonary fibrosis patients, who received treatment with nintedanib in five institutions between July 2015 and June 2017, were reviewed. Patients with % forced vital capacity ⩾50% and % predicted diffusing capacity of the lung carbon monoxide ⩾30% were classified as the moderate group and those with more impaired lung functions as the severe group. RESULT: Among 158 patients analyzed, 132 (84.6%) were classified as the moderate group and 26 (15.4%) as the severe group. In the moderate group, changes in forced vital capacity in 12 months were significantly different between before and after nintedanib administration (-253 ± 163 vs -125 ± 235 mL; p = 0.0027). In contrast, changes in forced vital capacity in 12 months were not significantly changed by nintedanib treatment in the severe group (-353 ± 250 vs -112 ± 341 mL; p = 0.2374). Incidence of acute exacerbation was higher in the severe group than in the moderate group (30.8% vs 18.9%). The overall survival of the moderate and the severe groups was 17.2 and 10.1 months. CONCLUSION: In real-world practice, nintedanib showed comparable efficacy to those observed in previous trials. In the severe group, the efficacy of nintedanib might be limited.

Procalcitonin expression in patients with large cell neuroendocrine carcinoma of the lung.

OBJECTIVE: Procalcitonin (PCT) has received much attention as a serum marker for bacterial infection. Elevated serum PCT is occasionally seen in severe trauma, heatstroke, and neoplastic diseases, including lung cancer with neuroendocrine component. RESULTS: In the present study, we evaluated PCT expression in the specimen of pulmonary neuroendocrine tumors, comparing large cell neuroendocrine carcinoma (LCNEC), carcinoid, and small cell lung carcinoma (SCLC). Pathological specimens of 10 LCNEC, 4 carcinoid, and 7 SCLC cases were evaluated with immunochemical staining of PCT. Clinical characteristics and serum levels of PCT and C-reactive protein were also evaluated. We observed positive PCT expression in 5 (50%) LCNEC and 2 (50%) carcinoid specimens that were surgically resected. Whereas serum PCT levels were not elevated in patients with PCT-positive carcinoid, two out of three LCNEC patients with high PCT expression in the tumor had elevated serum PCT levels that reflected disease progression. In patients with SCLC, PCT was not detected in the tumor or serum. This is the first immunohistochemical study of the PCT expression in the lung tumor specimens. We concluded that, in patients with LCNEC, high serum PCT levels may be indicative of disease activity and serve as a biomarker.

Activity and bioavailability of tepotinib for leptomeningeal metastasis of NSCLC with MET exon 14 skipping mutation.

Tepotinib is a key drug for cancer patients with mesenchymal-epithelial transition receptor tyrosine kinase proto-oncogene (MET) exon 14 skipping mutation. However, its bioavailability in the cerebrospinal fluid (CSF) in humans has not been fully elucidated. Moreover, information about the efficacy of tepotinib in patients with leptomeningeal metastasis is limited. Here, we present the case of a 56-year-old man who was diagnosed with lung adenocarcinoma with MET exon 14 skipping mutation. He was urgently hospitalized due to leptomeningeal metastasis. We administered tepotinib 500 mg/day as the second-line therapy and observed improvement in leptomeningeal metastasis and performance status. The tepotinib concentrations reached 1,648 ng/mL in the plasma and 30.6 ng/mL in the CSF, with a penetration rate (CSF/plasma) of 1.83%. These demonstrate tepotinib could achieve a high rate of central nervous system transition and could be effective against leptomeningeal metastasis.

A Phase I/II Study of Biweekly Carboplatin and Nab-paclitaxel With Concurrent Radiotherapy for Patients With Locally Advanced Unresectable Stage III Non-small-cell Lung Cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced non-small-cell lung cell cancer (LA-NSCLC). We conducted a phase I/II study of biweekly carboplatin and nab-paclitaxel (nab-PTX) with radiotherapy (RT). MATERIALS AND METHODS: In the phase I part, patients with inoperable stage IIIA/IIIB NSCLC were treated with carboplatin (area under the time-concentration curve, 4) and nab-PTX (60-100 mg/m2) on days 1, 15, and 29. Thoracic RT was administered from day 1 to a total dose of 60 Gy in 30 fractions. In the phase II part, patients were administered carboplatin and nab-PTX on days 1, 15, and 29 at the recommended dose (RD). The primary endpoint of the phase I part was to determine the maximum tolerated dose and the RD. In the phase II part, the primary endpoint was 2-year overall survival (OS) rate, and secondary endpoints were the objective response rate, progression-free survival, OS, and safety profile. RESULTS: In the phase I part, although maximum tolerated dose was not obtained, the RD was carboplatin (area under the time-concentration curve, 4) and nab-PTX (100 mg/m2). Of the evaluable 28 patients, the rate of 2-year OS was 67.8% (95% confidence interval, 49.3%-82.1%). The objective response rate was 96.4%, and the median follow-up time was 33.2 months. The median progression-free survival was 18.2 months (95% confidence interval, 13.1 months to not reached). The most common toxicities of grade 3 or higher were neutropenia (60.5%), anemia (14.2%), thrombocytopenia (7.2%), and pneumonitis (3.6%). CONCLUSIONS: This study achieved the primary endpoint. Biweekly carboplatin and nab-PTX with concurrent RT was well-tolerated and exerted promising antitumor activity.

Destroyed lung due to sustained inflammation after chemoradiotherapy followed by durvalumab.

A 68-year-old male patient with squamous cell carcinoma (cT4N2M0) of the left upper lobe received chemoradiotherapy followed by durvalumab, an immune checkpoint inhibitor. The tumour responded well to the therapy, but an infiltrative shadow appeared in the left upper lobe, which was outside the radiation field. Despite treatment with corticosteroid and antibiotics, the development of a cavitary lesion was noted. As Aspergillus fumigatus was isolated from the bronchoscopy specimen, antifungal agents were also administered, but the cavitary lesion further developed. Because his general condition worsened and the entire left lung was destroyed, the patient underwent a left pneumonectomy and recovered without recurrence. The pathology of the removed lung revealed a scarred nodule with granulation tissue around and a cavernous lesion having a necrotic substance inside. We considered that durvalumab might further accelerate the inflammatory response, which had been introduced by fungal infection, leading to uncontrollable inflammation of the lung.

A pilot study of adjuvant chemotherapy with carboplatin and oral S-1 for patients with completely resected stage II to IIIA non-small cell lung cancer.

BACKGROUND: Adjuvant chemotherapy with platinum-based regimens for completely resected early-stage non-small cell lung cancer (NSCLC) provides overall survival benefit in several clinical trials. OBJECTIVES: We conducted this prospective study to evaluate the efficacy and safety of adjuvant chemotherapy with carboplatin and S-1 for patients with completely resected stage II to IIIA NSCLC. METHODS: Patients with completely resected stage IIA to IIIA NSCLC were treated with four cycles of carboplatin with area under the concentration time curve of 5 mg/mL/min on day 1 plus S-1 at 80-120 mg/bodyweight per day for two weeks, followed by one-week rest as adjuvant chemotherapy. The primary endpoint was the completion rate of three cycles of the treatment. The secondary endpoints were safety and two-year survival rate. RESULTS: A total of 19 patients were enrolled, until the study was terminated prematurely because of fatal pulmonary embolism in two patients. The median number of treatment cycles was three (range: 1-4). The completion rate of three cycles was 78.9% (95% confidence interval [CI]: 56.6-91.4%). Two-year disease-free survival rate was 57.8%. Grade 3 or 4 hematological toxicities included neutropenia (26.2%), anemia (5.2%), and thrombocytopenia (15.7%). Grade 3 or 4 nonhematological toxicities were anorexia (10.5%) and nausea (10.5%). Febrile neutropenia developed in 5.2%. In two patients (10.5%), grade five pulmonary embolism was observed, and the causal relationship with treatment could not be denied. CONCLUSIONS: Carboplatin and oral S-1 had modest survival benefit, but this regimen was not tolerable in an adjuvant setting because fatal pulmonary embolism occurred in two patients. KEY POINTS: Carboplatin and oral S-1 had modest survival benefit but this regimen was not tolerable. Fatal pulmonary embolism occurred in this regimen.