High neutrophils and low lymphocytes percentages in bronchoalveolar lavage fluid are prognostic factors of higher in-hospital mortality in diffuse alveolar hemorrhage.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a syndrome resulting from bleeding in the microcirculation of the lung, with a poor prognosis. The study aim was to identify prognostic factors of DAH, especially bronchoalveolar lavage fluids (BALF) cell pattern. METHODS: We conducted a single-center retrospective cohort study of patients diagnosed as having DAH and hospitalized at our hospital between October 2008 and July 2020. We performed univariate logistic regressions to identify variables associated with in-hospital death. RESULTS: Sixty-eight patients were included in our analysis. In-hospital mortality was 26.5%. Variables associated with in-hospital death were neutrophils percentage in BALF ≥ 44.5% [Odds Ratio (OR) 16.0, 95% confidence interval (CI) 4.33-58.9)], lymphocytes percentage in BALF < 14% (OR 7.44, 95% CI 2.11-26.2), idiopathic DAH (OR 0.31, 95% CI 0.10-0.95), oxygen flow ≥ 4L/min (OR 3.90, 95% CI 1.20-12.6), and estimated glomerular filtration rate < 60 mL/min (OR 5.00, 95%CI 1.29-19.4). CONCLUSIONS: High neutrophils and low lymphocytes percentages in BALF were associated with poor prognosis.

Increase in echo intensity and extracellular-to-intracellular water ratio is independently associated with muscle weakness in elderly women.

PURPOSE: The changes in muscle composition and its heterogeneity during aging are associated with muscle weakness in elderly persons independent of decreases in muscle mass or muscle thickness (MT). Both the assessment of echo intensity (EI) with ultrasound imaging and the evaluation of the extracellular water/intracellular water (ECW/ICW) ratio with segmental bioelectrical impedance spectroscopy (BIS) are non-invasive and convenient methods and seem valuable for muscle quality determination. However, no previous study has evaluated both EI and the ECW/ICW ratio simultaneously to investigate their relationship to muscle strength. The purpose of the present study was to investigate whether both EI and the ECW/ICW ratio are independently associated with muscle strength in elderly women. METHODS: A total of 179 elderly women with a mean age of 74.1 ± 4.9 years, living independently in the community, were enrolled. The MT and EI of the quadriceps femoris were measured using transverse ultrasound imaging. The ECW/ICW ratio in the upper thigh was calculated from segmental BIS. The maximum knee extensor strength and the presence of knee pain were also assessed. RESULTS: Knee extensor strength showed a significant positive correlation with MT, and significant negative correlations with EI, the ECW/ICW ratio, and age. Stepwise regression analysis revealed that knee extensor strength in elderly women was predicted by MT, EI, and the ECW/ICW ratio. CONCLUSIONS: This study suggests that the simultaneous application of EI and the ECW/ICW ratio is useful in assessing muscle strength, and accurately estimates the changes in muscle quality related to muscle weakness.

Association of walking speed with sagittal spinal alignment, muscle thickness, and echo intensity of lumbar back muscles in middle-aged and elderly women.

BACKGROUND: Age-related change of spinal alignment in the standing position is known to be associated with decreases in walking speed, and alteration in muscle quantity (i.e., muscle mass) and muscle quality (i.e., increases in the amount of intramuscular non-contractile tissue) of lumbar back muscles. Additionally, the lumbar lordosis angle in the standing position is associated with walking speed, independent of lower-extremity muscle strength, in elderly individuals. However, it is unclear whether spinal alignment in the standing position is associated with walking speed in the elderly, independent of trunk muscle quantity and quality. The present study investigated the association of usual and maximum walking speed with age, sagittal spinal alignment in the standing position, muscle quantity measured as thickness, and quality measured as echo intensity of lumbar muscles in 35 middle-aged and elderly women. METHODS: Sagittal spinal alignment in the standing position (thoracic kyphosis, lumbar lordosis, and sacral anterior inclination angle) using a spinal mouse, and muscle thickness and echo intensity of the lumbar muscles (erector spinae, psoas major, and lumbar multifidus) using an ultrasound imaging device were also measured. RESULTS: Stepwise regression analysis showed that only age was a significant determinant of usual walking speed. The thickness of the lumbar erector spinae muscle was a significant, independent determinant of maximal walking speed. CONCLUSIONS: The results of this study suggest that a decrease in maximal walking speed is associated with the decrease in lumbar erector spinae muscles thickness rather than spinal alignment in the standing position in middle-aged and elderly women.

Opioids have no negative effect on the survival time of patients with advanced lung cancer in an acute care hospital.

PURPOSE: The purpose of this study is to determine whether or not opioid administration influenced the survival time of patients with advanced lung cancer in an acute care hospital setting. METHODS: This was a single institutional and retrospective study. We reviewed patients with advanced lung cancer who had died from January 2008 to December 2013 at the Osaka Police Hospital. We compared survival times, calculated from the time of the last hospitalization or the last chemotherapy, between patients who had not used any opioids, those who had used a low dose of opioids (< 60 mg/day), and those who had used a higher dose of opioids (≥ 60 mg/day). RESULTS: A total of 369 patients, of which 284 had received chemotherapy, were analyzed. Opioid users were generally younger than nonusers. There was no significant difference in survival time after the last hospitalization in terms of opioid dose at the last admission and mean daily opioid dose; there was also no significant difference in survival time after the last chemotherapy in terms of the mean daily opioid dose and the opioid dose at death. Univariate and multivariate Cox proportional hazard analysis regarding survival time after the last hospitalization or the last chemotherapy did not reveal any opioid-related variables as a significant predictive factor. CONCLUSIONS: Opioids were found to have no negative influence on survival time even in an acute care hospital.

Comparison of timing and decision-makers of do-not-resuscitate orders between thoracic cancer and non-cancer respiratory disease patients dying in a Japanese acute care hospital.

PURPOSE: The aim of the study was to compare timing and decision-makers of do-not-resuscitate (DNR) orders between patients with end-stage thoracic cancer and non-cancer respiratory diseases in a Japanese acute care hospital. METHODS: This study retrospectively reviewed the medical records of patients who died between January 2008 and March 2013 in the Department of Respiratory Medicine of Osaka Police Hospital, a teaching and acute care hospital. We compared the decision-making process, especially timing and decision-maker, of DNR orders between patients with thoracic cancer and patients with non-cancer respiratory diseases. RESULTS: There were 300 cancer patients and 147 non-cancer patients. Cancer patients were significantly younger, were hospitalized more frequently and for longer, were more likely to have a DNR order placed earlier and decided in advance of last admission, and were more likely to have normal cognitive function at the time of the DNR order than non-cancer patients. Spouses of cancer patients were more likely to participate in DNR discussion. Only approximately 6 % of patients participated in DNR discussion in both groups. Cancer patients less frequently received aggressive treatment at the end of life (EOL) and were more likely to die in general wards than in intensive care units. CONCLUSIONS: Our study found that most Japanese patients, with or without cancer, who died in an acute care respiratory department, were not included in DNR discussions and that familial surrogates usually made the DNR decision at the EOL.

Opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch for patients with stable thoracic malignancy-related pain.

BACKGROUND: The effectiveness and safety of switch from oral oxycodone to fentanyl patch is little known. Here, we investigated if early phase opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch provided any benefits for patients with thoracic malignancy and stable cancer-related pain. METHODS: This open-label two-centered prospective study enrolled patients with thoracic malignancy suffering persistent malignancy-related pain with numeric rating scale of pain intensity ≤ 3 which had been controlled by oral oxycodone ≤ 20 mg/day. Eligible patients switched from oral oxycodone to 12.5 µg/h of transdermal fentanyl matrix patch. The dose was allowed to be titrated upwards every 3 day by 25-50%, except for the first increase from 12.5 µg/hr to 25 µg/hr,until achieving adequate pain control. The data on patients' global assessment scores measured on a five-step scale, an 11-point numeric rating scale of pain intensity, the severity of adverse effects using a four-point categorical rating scale, and the Epworth sleepiness scale questionnaire were collected for 15 days. RESULTS: Forty-nine eligible patients were analyzed. Overall patients' satisfaction score significantly improved from day 1 (2.7 ± 0.9) to day 15 (2.3 ± 0.9) (p < 0.05), and 90% and 78% of patients remained to receive the minimum dose of fentanyl patch on day 8 and 15 from the opioid switch. There was a significant difference in sleepiness throughout the study period, though no difference was detected in pain intensity and other adverse effects. CONCLUSION: Transdermal fentanyl matrix patch is an alternative analgesic option for a stable cancer pain in patients with thoracic malignancies.

HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans.

HB-EGF, a member of the EGF family of growth factors, plays an important role in cardiac valve development by suppressing mesenchymal cell proliferation. Here, we show that HB-EGF must interact with heparan sulfate proteoglycans (HSPGs) to properly function in this process. In developing valves, HB-EGF is synthesized in endocardial cells but accumulates in the mesenchyme by interacting with HSPGs. Disrupting the interaction between HB-EGF and HSPGs in an ex vivo model of endocardial cushion explants resulted in increased mesenchymal cell proliferation. Moreover, homozygous knock-in mice (HB(Delta)(hb/)(Delta)(hb)) expressing a mutant HB-EGF that cannot bind to HSPGs developed enlarged cardiac valves with hyperproliferation of mesenchymal cells; this resulted in a phenotype that resembled that of Hbegf-null mice. Interestingly, although Hbegf-null mice had abnormal heart chambers and lung alveoli, HB(Delta)(hb/)(Delta)(hb) mice did not exhibit these defects. These results indicate that interactions with HSPGs are essential for the function of HB-EGF, especially in cardiac valve development, in which HB-EGF suppresses mesenchymal cell proliferation.

Emergency department visits after hours by lung cancer patients in Japan.

PURPOSE: The aims of this study were to clarify frequency with which Japanese lung cancer patients visited an emergency department (ED) after hours and their final outcome. METHODS: This is a retrospective and single institutional study. We reviewed medical records of patients who died of lung cancer from January 2008 to June 2012 at Osaka Police Hospital who had been followed up since diagnosis of lung cancer until death. We compared patients who had visited the ED after hours on weekdays, weekends, or holidays over their lives with cancer (ED visitors) and patients who had never visited the ED (non-ED visitors). RESULTS: Overall, 245 patients met the inclusion criteria for analysis. There were 149 after hours ED visits by 106 lung cancer patients. Mean number of ED visits was 0.6 for all patients. Median interval from ED visit to death was 49 days. The most common chief compliant for these patients was respiratory problems (37.6%). Most patients visited the ED during chemotherapy (32.9%) or for best supportive care (42.3%). Directly after ED visits, 56.4% of ED visitors were finally hospitalized. In a multivariate analysis, performance status (PS) (odds ratio [OR]: 11.2, 95% confidence interval [CI]: 2.1-59.0, p = 0.004) and cancer stage (OR: 0.003, 95% CI: 0.0006-0.014, p < 0.001) at diagnosis were statistically associated with ED visits after hours. CONCLUSIONS: Japanese patients with lung cancer frequently visit ED after hours. An ED visit is itself an indicator of poor prognosis.

Elevation of serum lactate dehydrogenase during methylprednisolone pulse therapy as a predictor of high mortality in acute respiratory failure: A single-center, retrospective study.

Background: Corticosteroids are common treatments in certain diseases that cause acute respiratory failure (ARF) and are sometimes administered empirically for patients with critical ARF. Associations between changes in clinical parameters following initiation of steroid pulse therapy and mortality in patients with ARF have not been previously investigated. Methods: This was a single-center and retrospective cohort study. Parameters on the day of methylprednisolone pulse therapy initiation (day 1) and the day following the end of methylprednisolone therapy (day 4) in patients who were admitted because of ARF and underwent methylprednisolone pulse therapy between October 2008 and July 2021 were reviewed. Results: A total of 98 patients were included in our analysis, and 45 (46%) died at our hospital. Change in lactate dehydrogenase (LDH) from day 1 to day 4 (ΔLDH) was significantly higher in the in-hospital death group than in the survival group (-68 IU/L in the survival group versus 46 IU/L in the in-hospital death group, p < 0.01). Multivariate logistic analyses showed that age >75 years old (odds ratio (OR), 3.88; 95% confidence interval (CI), 1.38-10.9; p < 0.01), previously diagnosed interstitial lung disease (OR, 3.43; 95% CI, 1.10-10.7; p = 0.03), ΔLDH > 0 (OR, 6.47; 95% CI, 2.30-18.2; p < 0.01), and ΔSequential Organ Failure Assessment score > 0 (OR, 3.06; 95% CI, 1.10-8.51; p = 0.03) were significantly associated with in-hospital mortality. Conclusions: This study showed that elevation of serum LDH level during methylprednisolone pulse therapy was a predictive factor for high in-hospital mortality in patients with ARF.

Long-Term Responders to Erlotinib for Pulmonary Adenocarcinoma With Wild-Type Epidermal Growth Factor Receptor: Two Case Reports and a Single-Institutional Retrospective Study.

Erlotinib is an oral and reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is now used exclusively to non-small cell lung carcinoma (NSCLC) harboring mutated EGFR. However, there was historically a transient period when erlotinib was widely used regardless of EGFR mutation status. We report two cases with adenocarcinoma and wild-type EGFR status, which responded to erlotinib for unusual long time. We also retrospectively analyzed patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital. A 60-year-old woman received the second-line and tri-weekly regimen of pemetrexed (500 mg/m2 on day 1) and intermittent erlotinib (150 mg on days 2 - 16). Pemetexed was discontinued 18 months after the initiation of this regimen, but erlotinib was continued for more than 11 years. This chemotherapy successfully reduced her brain metastasis and prevented recurrence. A 58-year-old man received erlotinib monotherapy as the third-line regimen, by which multiple brain metastases disappeared. Although we tried stopping erlotinib 9 years after the initiation of erlotinib, a solitary metastasis appeared in the brain 3 months after the discontinuation of erlotinib. Between December 2007 and October 2015, 39 patients with wild-type EGFR status initiated erlotinib-containing regimens at our hospital. The response rate, progression-free survival and overall survival were 17.9% (95% confidence interval (CI): 7.5-33.5%), 2.7 months (95% CI: 1.8 - 5.0 months) and 10.3 months (95% CI: 5.0 - 15.7 months), respectively. We reported two long-term responders and survivors to erlotinib for more than 9 years, which was much longer than patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital.

Durvalumab for Extensive-Stage of Small-Cell Lung Cancer With Lambert-Eaton Myasthenic Syndrome.

Durvalumab is an immune checkpoint inhibitor (ICI) of anti-programmed cell death protein 1 ligand antibody. ICI-combined chemotherapy has recently become a standard regimen for extensive-stage of small-cell lung cancer (ES-SCLC). SCLC is well known to be the most likely tumor associated with Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune disease of a neuromuscular junction disorder. Although LEMS has been reported to be induced by ICI as immune-mediated adverse events, it remains unknown whether ICI can deteriorate preexisting paraneoplastic syndrome (PNS) of LEMS. Our rare case was successfully treated by durvalumab plus chemotherapy without exacerbation of preexisting PNS of LEMS. We report a 62-year-old female with ES-SCLC and preexisting PNS of LEMS. She started carboplatin-etoposide in combination with durvalumab. This immunotherapy achieved nearly complete response. However, multiple brain metastases were found after two courses of maintenance durvalumab. Her symptoms and physical examinations of LEMS improved despite of no significant change in compound muscle action potential amplitude in the nerve conduction study. The titer of anti-P/Q-type voltage-gated calcium channel (VGCC) antibody decreased from 1,419.2 to 263.5 pmol/L during the immunotherapy. In conclusion, ICI in combination with platinum doublet chemotherapy is still challenging but may be a treatment option for ES-SCLC patients complicated with PNS of LEMS.

Lenvatinib-refractory thymic mucinous carcinoma with PIK3CA mutation.

Mucinous adenocarcinoma, a very rare type of thymic carcinoma, is aggressive and has a poor prognosis. The optimal treatment for advanced thymic mucinous adenocarcinoma has not yet been established because of its rarity. An oral multi-tyrosine kinase inhibitor, lenvatinib, was approved for treatment of thymic carcinoma in March 2021 in Japan. However, to the best of our knowledge, there are no published reports concerning lenvatinib for thymic mucinous adenocarcinoma. Herein, we report a 39-year-old woman who presented with a 70 mm multilocular cystic tumor in her left anterior mediastinum and a massive pericardial effusion. We diagnosed a Masaoka stage IVb thymic mucinous adenocarcinoma with multiple metastases to the liver and bones, and pericardial dissemination on the basis of the pathologic findings on examination of a video-assisted thoracoscopic tumor biopsy and radiological examinations. She received paclitaxel-carboplatin-based chemotherapy, but developed a left cerebellar metastasis. Second-line chemotherapy with lenvatinib failed to suppress the tumor. She died of cancer progression 5 months after presentation. Here, we report what we believe to be the first case of a thymic mucinous adenocarcinoma treated with lenvatinib. Our patient's thymic mucinous adenocarcinoma was refractory to both cytotoxic chemotherapy and lenvatinib. Using next-generation sequencing, we identified phosphatidylinositol 3-kinase catalytic subunit alpha mutation in the tumor. We suspected an association between this mutation and resistance to lenvatinib. We therefore recommend performing next-generation sequencing when considering introduction of lenvatinib for thymic mucinous adenocarcinoma. A surgical procedure may be necessary for accurate diagnosis and genetic analysis of this histological tumor type.

Rituximab for the Treatment of Anti-glomerular Basement Membrane Disease with Isolated Diffuse Alveolar Hemorrhage.

Anti-glomerular basement membrane (GBM) disease with isolated diffuse alveolar hemorrhage (DAH) is rare. We herein report a 91-year-old man admitted with hypoxia and diagnosed with anti-GBM disease with DAH based on positive bronchoalveolar lavage and serum antibody test results. There was no renal involvement. Although remission was achieved using glucocorticoids and plasmapheresis, the patient experienced DAH relapse one week after the last plasmapheresis. Rituximab 375 mg/m2 was administered 4 times weekly; thereafter, DAH relapse was not observed, and the glucocorticoid dosage was tapered. Rituximab was thus effective in treating anti-GBM disease with isolated DAH in an extremely elderly patient.

Sarcoid-Like Granulomatosis of the Lung Related to Durvalumab After Chemoradiation for Pulmonary Squamous Cell Carcinoma.

Sarcoid-like granulomatosis is a unique immune-related adverse event (irAE) in cancer patients treated with immune checkpoint inhibitors (ICIs). This irAE is infrequent, reported to range from 2% to 22.2% of melanoma treated with ICI. In a case of granulomatosis localized in the lung, it is difficult to differentiate granulomatosis from cancer progression or metastases. Herein, we report a case of ICI-induced sarcoid-like granulomatosis of the lung, which was confusable with localized recurrence of the primary lung cancer. A 56-year-old woman with c-stage IIIA of pulmonary squamous cell carcinoma in the right lower lobe received chemo-radiotherapy with two courses of cisplatin and vinorelbine and concurrent thoracic irradiation, followed by 1-year durvalumab consolidation therapy. The tumor in the right S6 grew and presented abnormal uptake by fluorodeoxyglucose positron emission tomography (FDG-PET), 1.5 years after durvalumab. Neither computed tomography (CT) nor FDG-PET found mediastinal and distant metastases. She underwent right lower lobe lobectomy. Histopathologically, the tumor and sampled lymph nodes contained no residue of carcinoma cells but presented diffuse epithelioid granuloma with infiltration of inflammatory cells, partial necrotic lesions and many multinucleated giant cells. In immunohistochemical stains, CD3+ and CD8+ T cells predominantly infiltrated, while there were few CD4+ T cells and a small number of CD20+ B cells. We followed her without steroid and other immunosuppressant drug. We should pay attention to the development of sarcoid-like granulomatosis as a rare irAE, which is difficult to be differentiated from cancer progression.

A Case of Radiation-Associated Vertebral Compression Fracture Mimicking Solitary Bone Metastasis of Lung Cancer.

Radiation therapy plays an important role in the treatment of lung cancer. Although adverse effects of radiation are well known, they are sometimes difficult to be diagnosed. We report a case of a radiation-associated vertebral compression fracture which mimicked bone metastasis of lung cancer. The patient was a 57-year-old man diagnosed with lung squamous cell carcinoma (cT1aN2M0, c-stage IIIA). He received concurrent chemoradiotherapy (CRT) in combination with 6 weeks of weekly carboplatin plus paclitaxel and thoracic radiation of 60 Gy/30 fractions, followed by bi-weekly durvalumab for 12 months. On the last day of the 12-month durvalumab regimen, he complained of backache. Magnetic resonance imaging showed compression fracture of the seventh thoracic vertebra with the spinal cord compressed, and fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography demonstrated weak focal uptake only at the seventh thoracic vertebra. Although the fracture had been suspected to be bone metastasis, surgical biopsy revealed no evidence of malignancy. Since the seventh thoracic vertebra was included in the irradiation area, the patient was diagnosed with a radiation-associated fracture. Dual-energy X-ray absorptiometry of the lumbar vertebrae (L2 - 4) after the surgery revealed osteopenia. In conclusion, we successfully diagnosed the radiation-associated vertebral fracture caused by radical CRT. The fracture mimicked bone metastasis in preoperative imaging tests. Thus, surgical biopsy was useful for diagnosis.

Standard versus low-dose nab-paclitaxel in previously treated patients with advanced non-small cell lung cancer: A randomized phase II trial (JMTO LC14-01).

BACKGROUND: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. CONCLUSION: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option.

Pneumonitis During Durvalumab Consolidation Therapy Affects Survival in Stage III NSCLC.

Introduction: Durvalumab consolidation therapy is the standard of care after concurrent chemoradiotherapy (CRT) for stage III NSCLC. Immune-related pneumonitis during durvalumab treatment is potentially fatal; however, information is lacking regarding the impact of pneumonitis on patient survival. This study investigates the effect of pulmonary and nonpulmonary immune-related adverse events (irAEs) on the efficacy of durvalumab treatment in patients with stage III NSCLC. Methods: We retrospectively assessed 158 patients who received durvalumab after CRT at nine Japanese institutions between July 2018 and March 2020. Survival outcomes were compared between patients who developed pneumonitis with those who developed irAEs other than pneumonitis. Patients who survived for less than 3 months were excluded to reduce immortal time bias. Results: Among 158 evaluated patients, 76 (48%) experienced grade less than or equal to one irAEs, whereas 82 (52%) experienced grade greater than or equal to two irAEs. Among the patients with grade greater than or equal to two irAEs, those with grade greater than or equal to two pneumonitis (n = 55) were compared with those with grade greater than or equal to two irAEs other than pneumonitis (n = 27). Patients with grade greater than or equal to two pneumonitis exhibited a significantly worse overall survival than those with grade greater than or equal to two irAEs that excluded pneumonitis. Multivariate analysis revealed that grade greater than or equal to two pneumonitis (hazard ratio = 3.71; 95% confidence interval, 1.85-7.45; p < 0.001) and squamous histology (hazard ratio = 2.64; 95% confidence interval, 1.29-5.42; p = 0.008) were independently associated with worse overall survival. Conclusions: After minimizing immortal time bias, pneumonitis grade two or greater and squamous histology were poor prognostic factors in patients who received consolidation durvalumab after CRT.

Combination chemotherapy with intermittent erlotinib and pemetrexed for pretreated patients with advanced non-small cell lung cancer: a phase I dose-finding study.

BACKGROUND: Erlotinib and pemetrexed have been approved for the second-line treatment of non-small cell lung cancer (NSCLC). These two agents have different mechanisms of action. Combined treatment with erlotinib and pemetrexed could potentially augment the antitumor activity of either agent alone. In the present study, we investigated the safety profile of combined administration of the two agents in pretreated NSCLC patients. METHODS: A phase I dose-finding study (Trial registration: UMIN000002900) was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m(2) of pemetrexed intravenously every 21 days and erlotinib (100 mg at Level 1 and 150 mg at Level 2) orally on days 2-16. RESULTS: Twelve patients, nine males and three females, were recruited. Patient characteristics included a median age of 66 years (range, 48-78 years), stage IV disease (nine cases), adenocarcinoma (seven cases) and activating mutation-positives in the epidermal growth factor receptor gene (two cases). Treatment was well-tolerated, and the recommended dose of erlotinib was fixed at 150 mg. Dose-limiting toxicities were experienced in three patients and included: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required reduction of the second dose of pemetrexed and grade 3 diarrhea. No patient experienced drug-induced interstitial lung disease. Three patients achieved a partial response and stable disease was maintained in five patients. CONCLUSIONS: Combination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated, with promising efficacy against pretreated advanced nonsquamous NSCLC.

Successful Dasatinib Treatment of Epidermal Growth Factor Receptor-Mutant Lung Adenocarcinoma and BCR-ABL1-Positive Chronic Myeloid Leukemia: A Case Report.

Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI), inhibits multiple kinase pathways and is a promising anti-tumor agent for various solid tumors, including lung cancer. Herein, we report a patient with coexisting epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma and BCR-ABL1-positive chronic myeloid leukemia (CML). The patient received afatinib for a postoperative intrapulmonary recurrence of lung adenocarcinoma harboring EGFR exon 19 deletion. Tumor reduction was achieved with afatinib; however, dose reduction was required because of grade 2 diarrhea and skin toxicity. The reduced dose maintained a partial response. Thirty-one months after introduction of afatinib, he was diagnosed as having BCR-ABL1-positive CML and nilotinib was added to his treatment regimen. However, the combination of nilotinib and afatinib aggravated his diarrhea, prompting discontinuation of afatinib. Because nilotinib does not have sufficient anti-tumor efficacy for CML, dasatinib was substituted for nilotinib. Thirty-five months after introduction of dasatinib, bosutinib was substituted for dasatinib because of uncontrollable pleural effusions. Dasatinib achieved 31- and 35-month progression-free survivals for CML and EGFR-mutant lung adenocarcinoma, respectively. Dasatinib is thus a therapeutic option for coexisting EGFR-mutant lung adenocarcinoma and BCR-ABL1-positive CML when TKI combination therapy is contraindicated by severe adverse events. In our patient, adding nilotinib to afatinib led to severe diarrhea. When administering TKI combination therapy, drug-drug interactions should be considered.

Cerebral Infarction Caused by Trousseau's Syndrome Associated With Lung Cancer.

Background: Lung cancer is one of the common cancers that can cause Trousseau's syndrome. However, there are few reports of cerebral infarction due to Trousseau's syndrome associated with lung cancer. The aim of this study is to investigate the clinical features of lung cancer-related cerebral infarction and effective management practice. Methods: Japanese patients diagnosed with Trousseau's syndrome-related cerebral infarction associated with lung cancer between August 2012 and November 2021 in our hospital were retrospectively enrolled. Clinical data, treatment, and outcomes of the patients were collected. Results: Ten patients were enrolled. The median age was 65 years (range: 43 - 84 years). All patients had advanced lung cancer. The histological types were adenocarcinoma (n = 8), pleomorphic carcinoma (n = 1), and small cell lung cancer (n = 1). Recurrent cerebral infarction occurred in six patients. Among four patients who had continued heparin since the initial infarction, recurrence occurred in one. D-dimer was high in all 10 patients at the initial cerebral infarction. D-dimer level at the time of recurrent cerebral infarctions was higher than that at the first cerebral infarctions. Since performance status declined in nine patients, one patient continued anticancer drugs after cerebral infarction. Four patients died within 100 days of the onset of cerebral infarction. Conclusions: Cerebral infarction of lung cancer-related Trousseau's syndrome has poor prognosis. Heparin may be effective in controlling the condition. In addition, D-dimer may serve as a marker of cancer-related thrombosis.