Ramucirumab Plus Docetaxel for Patients with Non-small cell Lung Cancer with Brain Metastases: A Multicenter, Open-Label Single-Arm Phase II Trial.

BACKGROUND: Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. METHODS: Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. RESULTS: Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. CONCLUSION: No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).

Cytokine Release Syndrome with Relative Adrenal Insufficiency Induced by Ipilimumab and Nivolumab Combination Therapy for Clear Cell Renal Cell Carcinoma.

Combination therapy with ipilimumab and nivolumab is indicated for many types of cancers; however, several patients experience immune-related adverse events (irAEs). We herein report a case of cytokine release syndrome (CRS) in a 63-year-old woman with stage IV left clear cell renal cell carcinoma. Our patient developed CRS while taking prednisolone, 43 days after the start of ipilimumab and nivolumab administration. The patient was treated with steroid pulse therapy, which improved the symptoms of shock and respiratory failure. Increased vascular permeability and relative adrenal insufficiency are considered to be the main pathogeneses. The early administration of high-dose steroids is crucial as a replacement for corticosteroids.

Prophylactic treatment of dacomitinib-induced skin toxicities in epidermal growth factor receptor-mutated non-small-cell lung cancer: A multicenter, Phase II trial.

BACKGROUND: Dacomitinib significantly improves progression-free survival and overall survival (OS) compared with gefitinib in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. However, dacomitinib often causes skin toxicities, resulting in treatment discontinuation. We aimed to evaluate a prophylactic strategy for skin toxicity induced by dacomitinib. METHODS: We performed a single-arm, prospective, open-label, multi-institutional phase II trial for comprehensive skin toxicity prophylaxis. Patients with NSCLC harboring EGFR-activating mutations were enrolled and received dacomitinib with comprehensive prophylaxis. The primary endpoint was the incidence of skin toxicity (Grade ≥2) in the initial 8 weeks. RESULTS: In total, 41 Japanese patients participated between May 2019 and April 2021 from 14 institutions (median age 70 years; range: 32-83 years), 20 were male, and 36 had a performance status of 0-1. Nineteen patients had exon 19 deletions and L858R mutation. More than 90% of patients were perfectly compliant with prophylactic minocycline administration. Skin toxicities (Grade ≥2) occurred in 43.9% of patients (90% confidence interval [CI], 31.2%-56.7%). The most frequent skin toxicity was acneiform rash in 11 patients (26.8%), followed by paronychia in five patients (12.2%). Due to skin toxicities, eight patients (19.5%) received reduced doses of dacomitinib. The median progression-free survival was 6.8 months (95% CI, 4.0-8.6 months) and median OS was 21.6 months (95% CI, 17.0 months-not reached). CONCLUSION: Although the prophylactic strategy was ineffective, the adherence to prophylactic medication was quite good. Patient education regarding prophylaxis is important and can lead to improved treatment continuity.

Early discontinuation of induction therapy in chemoimmunotherapy as an effective alternative to the standard regimen in patients with non-small cell lung cancer: a retrospective study.

PURPOSE: We aimed to investigate whether induction chemotherapy with less than four courses is as effective as induction chemotherapy with more than four courses in non-small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy. METHODS: We retrospectively enrolled 249 patients with NSCLC who received chemoimmunotherapy at 12 centers in Japan between January and December 2019. The patient group that completed less than four courses owing to adverse events (AEs), and received subsequent maintenance therapy was compared to the group that received at least four courses of induction chemotherapy followed by maintenance therapy. RESULTS: On univariate and multivariate analyses, the patient group that transitioned to maintenance therapy after completing less than four courses of induction chemotherapy had significantly shorter progression-free survival (PFS) than those who completed at least four courses (hazard ratio [HR] 2.15, 95% confidence interval: 1.38-3.37, p < 0.001 and HR 2.32, 95% confidence interval: 1.40-3.84, p = 0.001, respectively). There was no obvious difference in PFS between the group in which induction chemotherapy ended in two or three courses leading to partial or complete response, and the group that continued at least four courses of induction chemotherapy (log-rank test p = 0.53). CONCLUSION: Treatment efficacy may be maintained if induction chemotherapy is completed in less than four courses owing to development of AEs, and is administered for more than two courses with partial or complete response; efficacy is maintained even on transitioning to maintenance therapy.

Impact of maintenance therapy following induction immunochemotherapy for untreated advanced non-small cell lung cancer patients.

PURPOSE: The primary objective of this study was to identify the potential predictors to assess the impact of maintenance therapy after induction immunochemotherapy in the real-world setting of patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively identified 152 patients with advanced NSCLC who received immunochemotherapy at 8 hospitals in Japan between January 2019 and December 2019. Patients who received at least four cycles of induction immunochemotherapy and one cycle of maintenance therapy with immune checkpoint inhibitors were included. We investigated the biomarkers for progression-free survival (PFS) for maintenance therapy after induction immunochemotherapy. RESULTS: Out of the 92 patients with advanced NSCLC included in the study, 42 received maintenance therapy with cytotoxic agents, whereas 50 received maintenance therapy without cytotoxic agents. Among those who received maintenance therapy without cytotoxic agents, responders to prior immunochemotherapy had significantly longer PFS than non-responders (p = 0.004), except those with maintenance therapy with cytotoxic agents. In non-responders to prior immunochemotherapy, patients with maintenance therapy with cytotoxic agents had significantly longer PFS than those with maintenance therapy without cytotoxic agents (log-rank p = 0.007), whereas, among responders to prior immunochemotherapy, there was no significant difference in PFS for different maintenance regimens (log-rank p = 0.31). CONCLUSIONS: This retrospective study showed that response to prior immunochemotherapy was associated with clinical outcomes among patients with advanced NSCLC who received maintenance therapy.

Prognostic Nutritional Index and Lung Immune Prognostic Index as Prognostic Predictors for Combination Therapies of Immune Checkpoint Inhibitors and Cytotoxic Anticancer Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer.

Combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapies (chemoimmunotherapy) is associated with significantly better survival outcomes than cytotoxic chemotherapies alone in patients with advanced non-small cell lung cancer (NSCLC). However, there are no prognostic markers for chemoimmunotherapy. The prognostic nutritional index (PNI) and lung immune prognostic index (LIPI) are prognostic biomarkers for immune checkpoint inhibitor (ICI) monotherapy or cytotoxic chemotherapies. Thus, we aimed to examine whether these factors could also be prognostic markers for chemoimmunotherapy. We retrospectively examined 237 patients with advanced NSCLC treated with chemoimmunotherapy. In the total group, the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 8.6 months. Multivariate analysis of OS and PFS revealed significant differences based on PNI and LIPI. Programmed cell death ligand 1 (PD-L1) was also significantly associated with OS and PFS. PNI and a PD-L1 tumor proportion score (TPS) of <50% and poor LIPI (regardless of PD-L1 TPS) were associated with poor prognosis. PNI and LIPI predicted survival outcomes in patients with advanced NSCLC treated with chemoimmunotherapy, especially in patients with PD-L1 TPS <50%. For patients in this poor category, chemoimmunotherapy may result in a worse prognosis than expected.

Immune-Related Adverse Events Are Associated With Clinical Benefit in Patients With Non-Small-Cell Lung Cancer Treated With Immunotherapy Plus Chemotherapy: A Retrospective Study.

BACKGROUND: The immunotherapy plus chemotherapy combination is one of the most promising treatments in advanced non-small-cell lung cancer (NSCLC). Immunotherapy often causes immune-related adverse events (irAEs), which have been reported to be associated with the good clinical outcomes. However, the effects of immunotherapy plus chemotherapy remain unknown. In this study, we investigated the association between irAEs caused by immunotherapy plus chemotherapy and clinical efficacy in patients with advanced NSCLC. MATERIALS AND METHODS: We retrospectively analyzed the data of patients with advanced NSCLC, who received a combination of immunotherapy plus chemotherapy at six institutions in Japan between January 2019 and September 2019. We examined the effect of irAEs on various clinical outcomes. RESULTS: We included 70 patients with advanced NSCLC. Patients were divided into two groups: patients with irAEs and patients without irAEs. Patients with irAEs had significantly longer progression-free survival than those without irAEs on univariate (hazard ratio 0.53, 95% confidence interval 0.30-0.93, p = 0.026) and multivariate (hazard ratio 0.53, 95% confidence interval 0.29-0.97, p = 0.041) analyses. In addition, patients with grade 1-2 irAEs (mild irAEs) had significantly longer progression-free and overall survival than those with grade 3-5 irAEs (severe irAEs) or without irAEs on univariate (398 days versus 189 days, respectively; p = 0.0061) and multivariate (not reached versus 412 days, respectively; p = 0.021) analyses. CONCLUSION: Patients with NSCLC who experienced mild irAEs showed better response to treatment with immunotherapy plus chemotherapy than those with severe irAEs or without irAEs. Further large-scale research is warranted to confirm these findings.

Prolonged persistence of SARS-CoV-2 infection during A+AVD therapy for classical Hodgkin's lymphoma: A case report.

We describe a case of coronavirus disease 2019 (COVID-19) in a patient with mixed cellularity classical Hodgkin lymphoma (cHL) undergoing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) therapy. A 43-year-old man presented to our hospital with a complaint of fever, for which he was diagnosed with COVID-19 after a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and antiviral therapy with favipiravir and ciclesonide was started subsequently. The fever persisted for the first few days of treatment, but his respiratory status was stable, and he became asymptomatic and afebrile on day 9. Although the PCR tests remained positive, he met the updated discharge criteria of the World Health Organization (WHO) on day 12. However, his fever recurred, and his condition worsened on day 16. A chest X-ray showed a new opacity. It is likely that favipiravir and ciclesonide treatment probably did not completely eliminate the virus in the patient, and therefore the infection persisted. We added remdesivir from day 21, and the improvement was remarkable. He was discharged on day 29 after two consecutive PCR test results were negative. PCR tests are not mandatory for the updated WHO discharge criteria. However, even after antiviral therapy, COVID-19 patients with hematologic malignancies may have prolonged active infection with impaired viral excretion. Depending on the background disease and comorbidities, there may be some patient populations for whom it is not appropriate to simply comply with the current discharge criteria. Therefore, more emphasis may be needed on PCR examinations.

A case of non-small cell lung cancer with danazol-dependent aplastic anemia induced by pembrolizumab.

Programmed cell death protein 1 immune checkpoint inhibitor is an effective treatment for non-small cell lung cancer. Although hematological immune-related adverse events induced by antiprogrammed-cell-death-protein-1 immunotherapy have been reported, they are rare, and there remain many unknowns. We report the case of a 77-year-old woman with non-small cell lung cancer and pembrolizumab-induced danazol-dependent aplastic anemia. Sixteen days after she received pembrolizumab with carboplatin and pemetrexed as first-line treatments, she developed pancytopenia, including severe thrombocytopenia (1 × 109/L) with oral bleeding, epistaxis, and systemic purpura. We initially diagnosed immune-related thrombocytopenia based on an elevated level of platelet-associated immunoglobulin G (922ng/107 cells), but her thrombocytopenia was refractory to prednisolone (1mg/kg) and thrombopoietin receptor agonists. We eventually diagnosed aplastic anemia based on the findings of bone marrow hypoplasia. Treatment with cyclosporine and danazol 300mg (7.5mg/kg) was initiated. Eighteen days later, her blood cell count increased, and we reduced danazol to 100mg. Twenty-four days after the reduction of danazol, her platelet count dropped again to 14 × 109/L; subsequently, increasing danazol improved her platelet count in a few days. Although aplastic anemia was recovered, she died owing to lung cancer progression. In this case, the thrombocytopenia was noticeable initially; however, pancytopenia appeared a month later, and we diagnosed her with aplastic anemia. Platelet counts improved rapidly with the use of danazol. No effective treatment has yet been established for aplastic anemia induced by antiprogrammed-cell-death-protein-1 immunotherapy, but our case suggests that danazol is an effective therapy.

Impact of cancer cachexia on the therapeutic outcome of combined chemoimmunotherapy in patients with non-small cell lung cancer: a retrospective study.

Although previous studies suggest that cancer cachexia is a poor prognostic factor for immune checkpoint inhibitor monotherapy, the impact of cancer cachexia on chemoimmunotherapy is unclear. We investigated the impact of cancer cachexia on the therapeutic outcomes of chemoimmunotherapy for non-small cell lung cancer (NSCLC). We retrospectively analyzed patients' medical records with NSCLC who received chemoimmunotherapy in 12 institutions in Japan between January and November 2019. We defined cancer cachexia as weight loss exceeding 5% of the total body weight or a body mass index of < 20 kg/m2 and weight loss of more than 2% of the total body weight within 6 months before chemoimmunotherapy initiation, with laboratory results exceeding reference values. This study enrolled 235 patients with NSCLC, among whom 196 were eligible for analysis, and 50 (25.5%) met the criteria for cachexia diagnosis. Patients with cancer cachexia had a significantly higher frequency of a programmed death-ligand 1 (PD-L1) expression of ≥ 50% (48%, p = .01) and shorter progression-free survival (PFS; log-rank test: p = .04) than patients without cachexia. There was no significant difference in overall survival (OS) between the cachexia and no-cachexia groups (log-rank test: p = .14). In the PD-L1 ≥ 50% population, there was no significant difference in PFS and OS (log-rank test: p = .19 and p = .79, respectively) between patients with NSCLC in the cachexia or no-cachexia groups. Cancer cachexia might be a poor prognostic factor in patients with NSCLC receiving chemoimmunotherapy.

Clinical impact of pembrolizumab combined with chemotherapy in elderly patients with advanced non-small-cell lung cancer.

OBJECTIVES: Combination therapy of immune checkpoint inhibitors and chemotherapy is considered to be one of the standard treatment options for patients with advanced non-small-cell lung cancer (NSCLC). However, the clinical significance of immune checkpoint inhibitors combined with chemotherapy in elderly patients with NSCLC has not yet been fully understood. Therefore, this study aimed to evaluate how aging affects the therapeutic impact of chemotherapy combine with immune checkpoint inhibitors in elderly patients. MATERIALS AND METHODS: We retrospectively analyzed 203 patients with advanced NSCLC who were treated with the combination therapy of pembrolizumab and chemotherapy between January 2019 and December 2019 at 12 institutions in Japan. We analyzed the clinical impacts of age on the following two groups: those who received pembrolizumab with platinum and pemetrexed (pemetrexed regimen) and those who received pembrolizumab with carboplatin and nab-paclitaxel/paclitaxel (paclitaxel regimen). Progression-free and overall survival were assessed via the Kaplan-Meier method. RESULTS: Multivariate analysis demonstrated that progression-free and overall survival were significantly shorter in elderly patients (aged ≥75 years) with NSCLC than in non-elderly patients (aged <75 years) with NSCLC in the pemetrexed regimen group. In contrast, there were no significant differences in progression-free and overall survival between elderly patients and non-elderly patients with NSCLC in the paclitaxel regimen group. In elderly patients with NSCLC, a programmed death-ligand 1 tumor proportion score of ≥50% was significantly associated with progression-free survival, and performance status of ≥2 was significantly associated with overall survival. Low albumin level (<3.5 g/dL) was significantly associated with both progression-free and overall survival. CONCLUSION: The results of this retrospective study show that the pemetrexed regimen, but not the paclitaxel regimen, was related to poor clinical outcomes in elderly patients with NSCLC.

[A case of Goodpasture's syndrome complicated with cytomegalovirus pneumonia during treatment with plasma exchange and immunosuppressive therapy].

A 63-year-old man presented to another hospital with hematuria and an elevated serum creatinine level. He was admitted, and hemodialysis was initiated. One month after admission, hemoptysis developed and the patient was referred to our hospital for further evaluation. Goodpasture's syndrome was diagnosed on the basis of elevated anti-glomerular basement membrane (anti-GBM) antibody levels. Due to massive alveolar hemorrhage, the patient was treated with plasma exchanges, pulse methylprednisolone and pulse cyclophosphamide followed by oral prednisolone, which lowered his anti-GBM antibody level. However, a chest radiograph obtained on the 56th hospital day showed bilateral ground glass opacities, and his condition deteriorated. Since his blood was positive for the cytomegalovirus pp65 antigen, ganciclovir was started. This improved his condition, with improvement in his chest radiograph and a decrease in the number of antigen-positive cells. It is important to consider the development of cytomegalovirus infection during the treatment of Goodpasture's syndrome with immunosuppressive therapy.

High levels of anti-SSA/Ro antibodies in COVID-19 patients with severe respiratory failure: a case-based review : High levels of anti-SSA/Ro antibodies in COVID-19.

We treated two patients with severe respiratory failure due to coronavirus disease 2019 (COVID-19). Case 1 was a 73-year-old woman, and Case 2 was a 65-year-old-man. Neither of them had a history of autoimmune disease. Chest computed tomography scans before the antiviral therapy showed bilateral multiple patchy ground-glass opacities (GGO) consistent with COVID-19 pneumonia. The GGO regressed over the course of the antiviral treatment; however, new non-segmental patchy consolidations emerged, which resembled those of interstitial lung disease (ILD), specifically collagen vascular disease-associated ILD. We tested the patients' sera for autoantibodies and discovered that both patients had high anti-SSA/Ro antibody titers. In Case 1, the patient recovered with antiviral therapy alone. However, in Case 2, the patient did not improve with antiviral therapy alone but responded well to corticosteroid therapy (methylprednisolone) and made a full recovery. The relationship between some immunological responses and COVID-19 pneumonia exacerbation has been discussed previously; our discovery of the elevation of anti-SSA/Ro antibodies suggests a contribution from autoimmunity functions of the immune system. Although it is unclear whether the elevation of anti-SSA/Ro antibodies was a cause or an outcome of aggravated COVID-19 pneumonia, we hypothesize that both patients developed aggravated the COVID-19 pneumonia due to an autoimmune response. In COVID-19 lung injury, there may be a presence of autoimmunity factors in addition to the known effects of cytokine storms. In patients with COVID-19, a high level of anti-SSA/Ro52 antibodies may be a surrogate marker of pneumonia severity and poor prognosis.

Impact of preexisting antinuclear antibodies on combined immunotherapy and chemotherapy in advanced non-small cell lung cancer patients.

Combined immunotherapy and chemotherapy is a promising standard treatment in patients with advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the relationship between the combined therapy and pretreatment serum antinuclear antibody (ANA) levels as a prognostic indicator in patients with NSCLC. We retrospectively analyzed patients with advanced NSCLC who were treated with combinatorial immunotherapy and chemotherapy between January and December 2019 at six institutions in Japan. Relationship between ANA status and patients' characteristics were reviewed. A total of 77 patients with advanced NSCLC were enrolled in the study. Patients were divided into ANA-positive (ANA ≥ 1:160) and ANA-negative (ANA < 1:160) groups. The ANA-positive group tended to have a shorter progression-free survival and significantly shorter overall survival in univariate (hazard ratio [HR], 2.11, 95% confidence interval [CI] 0.88-5.07, p = 0.093; and HR 3.11, 95% CI 1.14-8.49, p = 0.027, respectively) and multivariate (HR 1.90, 95% CI 0.77-4.68, p = 0.16; and HR 3.37, 95% CI 1.15-9.86, p = 0.027, respectively) analyses than ANA-negative group. The incidence of discontinuation of all treatment components due to severe adverse events was significantly higher in the ANA-positive than in ANA-negative group (50% vs. 15.9%, p = 0.042). The study showed that the presence of antinuclear antibodies may result in a poor prognosis in patients treated with combinatorial immunotherapy and chemotherapy, although further prospective investigations are needed.

Carcinoembryonic antigen and CYFRA 21-1 responses as prognostic factors in advanced non-small cell lung cancer.

BACKGROUND: It is unclear whether changes in serum tumor marker expression post-treatment are of prognostic value. We investigated the associations between changes in serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) after first-line treatment and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: Advanced NSCLC patients (April 2010 to December 2015) with elevated serum CEA or CYFRA 21-1 were included. The associations between tumor marker changes after treatment initiation and OS were analyzed. RESULTS: Ninety-six and 55 patients were CEA- and CYFRA 21-1-positive, respectively. The serum CEA response at 4 months and CYFRA 21-1 responses at 1 and 4 months were significantly associated with OS in the univariate analyses (P=0.025, P=0.016 and P<0.001, respectively). Moreover, in the multivariate analyses, serum CYFRA 21-1 response at 4 months was significantly associated with improved OS (P=0.038). CONCLUSIONS: In NSCLC patients, serum CEA and CYFRA 21-1 responses after treatment initiation may predict longer OS.

Prognostic impact of pleural effusion in EGFR-mutant non-small cell lung cancer patients without brain metastasis.

BACKGROUND: In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), brain metastasis is known as a poor prognosis factor. However, prognostic factors in the patients without brain metastasis remain unclear. In this study, we aimed to clarify the differences between metastatic site and prognosis in common EGFR-mutant NSCLC patients without brain metastasis. METHODS: Chemotherapy-naïve, advanced EGFR-mutant NSCLC patients without brain metastasis diagnosed between January 2010 and March 2016 were enrolled. We evaluated prognosis according to the presence or absence of bone metastases, liver metastasis, and pleural effusion. RESULTS: A total of 50 EGFR-mutant NSCLC patients without brain metastasis were enrolled. The median progression-free survival and overall survival were significantly shorter in patients with pleural effusion than in those patients without (progression-free survival 7.0 months, 95% confidence interval [CI] 3.7-13.0 vs. 13.0 months, 95% CI 9.1-21.7, hazard ratio [HR] 2.29, 95% CI 1.11-4.73, P = 0.020; overall survival 19.5 months, 95% CI 5.7-28.8 vs. 55.3 months, 95% CI 24.0-not evaluable, HR 3.00, 95% CI 1.35-6.68, P = 0.005). Pleural effusion was an independent factor of poor prognosis for progression-free survival (HR 3.44, 95% CI 1.50-7.88, P = 0.003) and overall survival (HR 2.34, 95% CI 1.00-5.44, P = 0.049). CONCLUSION: Pleural effusion might be a poor prognosis factor for advanced EGFR-mutant NSCLC patients without brain metastasis treated with first-generation EGFR-tyrosine kinase inhibitors. Further precision medicine according to the metastatic site is required.

Pulmonary pleomorphic carcinoma with pseudoprogression during nivolumab therapy and the usefulness of tumor markers: A case report.

Pseudoprogression was reported as one of the unconventional responses during immune checkpoint inhibitor therapy. A 70-year-old man with pulmonary pleomorphic carcinoma received nivolumab therapy. Pleural effusion and pulmonary metastasis increased, however then shrank and serum cytokeratin 19 fragment levels decreased. Serum tumor marker might help to distinguish pseudoprogression.

An observational study of the epidermal growth factor receptor-tyrosine kinase inhibitor resistance mechanism in epidermal growth factor receptor gene mutation-positive non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation show a high response to EGFR-tyrosine kinase inhibitor (EGFR-TKI). Clinically, EGFR-positive NSCLC acquires several resistance mechanisms during EGFR-TKI treatment, such as the emergence of a secondary mutation (T790M), MET gene amplification, and transformation to small cell lung cancer. However, the mechanism of resistance to afatinib, a second-generation EGFR-TKI, remains unclear. In this study, we prospectively investigate the mechanism of resistance to afatinib using proteomic analyses.In total, 35 EGFR-positive NSCLC patients of both sexes and ≥20 years old will be included. NSCLC patients with major obstacles in major organs, such as bone marrow, heart, lung, liver, and kidney, will be excluded. Eligible patients will be administered afatinib or gefitinib until disease progression and proteomic analysis will be performed with biopsy samples before treatment and at disease progression.The primary outcome is to detect the potential predictive anomalies in proteins that can be candidates for the resistance factor of afatinib. The secondary outcome is to detect gene and protein abnormalities affecting progression-free survival, response rate, and rate of disease control in afatinib therapy.The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. The results of the study will be disseminated via publications in peer-reviewed journals.Trial registration number is UMIN000031013.

[Surgical management of eight cases of bronchiectasis].

Few reports are currently available on the surgical management of bronchiectasis. We report our experience with 8 cases of bronchiectasis. The indications of pulmonary resection were recurrent pneumonia and/or hemoptysis in spite of medical treatment and the extent mainly limited to the unilateral lung. With the exception of one patient, who died from postoperative pneumonia, all patients showed improvement in symptoms. However, in two cases, hemoptysis recurred; these patients had cystic bronchiectasis, Pseudomonas aeruginosa infections and minimal disease in the contralateral lung, which accounted for the recurrence of hemoptysis. A few reports indicated that cystic bronchiectasis and incomplete resection were adverse prognostic factors and that Pseudomonas aeruginosa infections were related to the development of new bronchiectasis. However, according to some other reports, these factors were not adverse prognostic factors. It is thought that the analysis of many cases is required to determine the indication of lung resection and the appropriate type of resection for bronchiectasis; however, it is difficult to conduct randomized control studies. Since the accumulation of case reports is also considered to be important, we report our series of cases.

[Video assisted thoracic surgery for Mycobacterium avium complex pulmonary disease spread over multiple pulmonary lobe within one lung].

A 75-year-old woman with Mycobacterium avium complex (MAC) pulmonary disease who had been treated by drug therapy for 7 years was admitted on an emergency basis for hemoptysis. Through the previous 7 years, her sputum cultures had been positive for MAC, and her clinical symptoms and examinations, such as chest X-ray and computed tomography, revealed that her condition had worsened. The lesions spread over the right middle lobe, segment 3 (S3) in the right upper lobe, and segment 6 (S6) in the right lower lobe, however, no lesions were present in the left lung. Since we believed that the disease was localized unilaterally, surgical treatment was selected. The surgical procedures that were employed included right middle lobectomy, right S3 segmentectomy and partial resection of right S6 by thoracoscopy. Sixteen months postoperatively, the sputum culture is negative for MAC. Our procedure enabled the preservation of effective lung function and was successful in controlling MAC pulmonary disease. It is believed that surgery for MAC pulmonary disease should be evaluated in more patients to decide the appropriate surgical indication and procedure.