Smoking exposure-induced bronchus-associated lymphoid tissue in donor lungs does not prevent tolerance induction after transplantation.

The presence of bronchus-associated lymphoid tissue (BALT) in donor lungs has been suggested to accelerate graft rejection after lung transplantation. Although chronic smoke exposure can induce BALT formation, the impact of donor cigarette use on alloimmune responses after lung transplantation is not well understood. Here, we show that smoking-induced BALT in mouse donor lungs contains Foxp3+ T cells and undergoes dynamic restructuring after transplantation, including recruitment of recipient-derived leukocytes to areas of pre-existing lymphoid follicles and replacement of graft-resident donor cells. Our findings from mouse and human lung transplant data support the notion that a donor's smoking history does not predispose to acute cellular rejection or prevent the establishment of allograft acceptance with comparable outcomes to nonsmoking donors. Thus, our work indicates that BALT in donor lungs is plastic in nature and may have important implications for modulating proinflammatory or tolerogenic immune responses following transplantation.

Characteristics of donor lungs declined on site and impact of lung allocation policy change.

OBJECTIVE: National and institutional data suggest an increase in organ discard rate (donor lungs procured but not implanted) after a new lung allocation policy was introduced in 2017. However, this measure does not include on-site decline rate (donor lungs declined intraoperatively). The objective of this study is to examine the impact of the allocation policy change on on-site decline. METHODS: We used a Washington University (WU) and our local organ procurement organization (Mid-America Transplant [MTS]) database to abstract data on all accepted lung offers from 2014 to 2021. An on-site decline was defined as an event in which the procuring team declined the organs intraoperatively, and the lungs were not procured. Logistic regression models were used to investigate potentially modifiable reasons for decline. RESULTS: The overall study cohort comprised 876 accepted lung offers, of which 471 donors were at MTS with WU or others as the accepting center and 405 at other organ procurement organizations with WU as the accepting center. At MTS, the on-site decline rate increased from 4.6% to 10.8% (P = .01) after the policy change. Given the greater likelihood of non-local organ placement and longer travel distance after policy change, the estimated cost of each on-site decline increased from $5727 to $9700. In the overall group, latest partial pressure of oxygen (odds ratio [OR], 0.993; 95% confidence interval [CI], 0.989-0.997), chest trauma (OR, 2.474; CI, 1.018-6.010), chest radiograph abnormality (OR, 2.902; CI, 1.289-6.532), and bronchoscopy abnormality (OR, 3.654; CI, 1.813-7.365) were associated with on-site decline, although lung allocation policy era was unassociated (P = .22). CONCLUSIONS: We found that nearly 8% of accepted lungs are declined on site. Several donor factors were associated with on-site decline, although lung allocation policy change did not have a consistent impact on on-site decline.

Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis.

Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored and there are currently no therapeutics to target fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 38 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. Pro-fibrotic fibroblasts were transcriptionally similar to cancer associated fibroblasts and expressed high levels of collagens and periostin (POSTN), thymocyte differentiation antigen 1 (THY-1), and endothelin receptor A (EDNRA) predicted to be driven by a RUNX1 gene regulatory network. We assessed the applicability of experimental systems to model tissue fibrosis and demonstrated that 3 different in vivo mouse models of cardiac injury were superior compared to cultured human heart and dermal fibroblasts in recapitulating the human disease phenotype. Ligand-receptor analysis and spatial transcriptomics predicted that interactions between C-C chemokine receptor type 2 (CCR2) macrophages and fibroblasts mediated by interleukin 1 beta (IL-1ß) signaling drove the emergence of pro-fibrotic fibroblasts within spatially defined niches. This concept was validated through in silico transcription factor perturbation and in vivo inhibition of IL-1ß signaling in fibroblasts where we observed reduced pro-fibrotic fibroblasts, preferential differentiation of fibroblasts towards myofibroblasts, and reduced cardiac fibrosis. Herein, we show a subset of macrophages signal to fibroblasts via IL-1ß and rewire their gene regulatory network and differentiation trajectory towards a pro-fibrotic fibroblast phenotype. These findings highlight the broader therapeutic potential of targeting inflammation to treat tissue fibrosis and restore organ function.

Pulmonary Carcinoid Tumorlet in the Explanted Lungs for Lung Transplantation: A Case Series of 15 Patients.

BACKGROUND: Pulmonary carcinoid tumorlet (PCT) is defined as small proliferation of neuroendocrine cells that invade the adjacent basement membrane. It is often associated with chronic pulmonary inflammatory processes. However, the characteristics of PCT in end-stage lung diseases remain unclear. METHODS: We conducted a retrospective cohort study of the explanted lungs after transplantation at our institution between January 1999 and October 2020. Patients who underwent re-transplantation were excluded. RESULTS: Pulmonary carcinoid tumorlet was incidentally discovered in the explanted lungs from 15 patients (1.1%) out of 1367 lung transplants performed during the study period. Nine patients (60.0 %) were women, with a median age of 59 years (IQR: 57-62) at transplant. Underlying pulmonary indications for lung transplantation were chronic obstructive pulmonary disease (9/15, 60.0%), interstitial lung disease (2/15, 13.0%), pulmonary vascular disease (2/15, 13.0%), alpha-1 antitrypsin deficiency (1/15, 7.0%), and bronchiectasis (1/15, 7.0%). Of the patients who underwent bilateral lung transplantation (13/15, 86.7%), PCT was found in the right lung in 10 patients (10/13, 76.9%). Thirteen patients had one lesion, 1 patient had 2 lesions and 1 patient had multiple lesions. CONCLUSION: Our study shows that PCT is generally uncommon, but when it occurs, it occurs more frequently on the right side and in female patients with end-stage pulmonary disease. Chronic obstructive pulmonary disease may be a predisposing factor for developing PCT.

Outcomes of Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of death in the first 30 days after lung transplantation and is also associated with worse long-term outcomes. Outcomes of patients with PGD grade 3 requiring extracorporeal membrane oxygenation (ECMO) support after lung transplantation have yet to be well described. We sought to describe short- and long-term outcomes for patients with PGD grade 3 who required ECMO support. METHODS: This is a single-center retrospective cohort study of patients undergoing lung transplantation. We stratified patients with PGD grade 3 into non-ECMO, venoarterial (VA) ECMO, and venovenous (VV) ECMO groups after transplantation. We then compared the outcomes between the groups. RESULTS: Of 773 lung transplant recipients, PGD grade 3 developed in 204 (26%) at any time in the first 72 hours after lung transplantation. Of these, 13 (5%) required VA ECMO and 25 (10%) required VV ECMO support. The 30-day, 1-year, and 5-year survival in the VA ECMO group was 62%, 54%, and 43% compared with 96%, 84%, and 65% in the VV ECMO group and 99%, 94%, and 71% in the non-ECMO group. Multivariable Cox regression analysis showed that VA ECMO was associated with increased mortality (hazard ratio, 2.37; 95% CI, 1.06-5.28; P = .04). CONCLUSIONS: Patients who required VA ECMO support for PGD grade 3 have significantly worse survival compared with those who did not require ECMO and those who required VV ECMO support. This suggests that VA ECMO treatment of patients with PGD grade 3 after lung transplantation can be a predictable risk factor for mortality.

Donor Macrophages Modulate Rejection After Heart Transplantation.

BACKGROUND: Cellular rejection after heart transplantation imparts significant morbidity and mortality. Current immunosuppressive strategies are imperfect, target recipient T cells, and have adverse effects. The innate immune response plays an essential role in the recruitment and activation of T cells. Targeting the donor innate immune response would represent the earliest interventional opportunity within the immune response cascade. There is limited knowledge about donor immune cell types and functions in the setting of cardiac transplantation, and no current therapeutics exist for targeting these cell populations. METHODS: Using genetic lineage tracing, cell ablation, and conditional gene deletion, we examined donor mononuclear phagocyte diversity and macrophage function during acute cellular rejection of transplanted hearts in mice. We performed single-cell RNA sequencing on donor and recipient macrophages and monocytes at multiple time points after transplantation. On the basis of our imaging and single-cell RNA sequencing data, we evaluated the functional relevance of donor CCR2+ (C-C chemokine receptor 2) and CCR2- macrophages using selective cell ablation strategies in donor grafts before transplant. Last, we performed functional validation that donor macrophages signal through MYD88 (myeloid differentiation primary response protein 88) to facilitate cellular rejection. RESULTS: Donor macrophages persisted in the rejecting transplanted heart and coexisted with recipient monocyte-derived macrophages. Single-cell RNA sequencing identified donor CCR2+ and CCR2- macrophage populations and revealed remarkable diversity among recipient monocytes, macrophages, and dendritic cells. Temporal analysis demonstrated that donor CCR2+ and CCR2- macrophages were transcriptionally distinct, underwent significant morphologic changes, and displayed unique activation signatures after transplantation. Although selective depletion of donor CCR2- macrophages reduced allograft survival, depletion of donor CCR2+ macrophages prolonged allograft survival. Pathway analysis revealed that donor CCR2+ macrophages are activated through MYD88/nuclear factor kappa light chain enhancer of activated B cells signaling. Deletion of MYD88 in donor macrophages resulted in reduced antigen-presenting cell recruitment, reduced ability of antigen-presenting cells to present antigen to T cells, decreased emergence of allograft-reactive T cells, and extended allograft survival. CONCLUSIONS: Distinct populations of donor and recipient macrophages coexist within the transplanted heart. Donor CCR2+ macrophages are key mediators of allograft rejection, and deletion of MYD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograft survival. This highlights the therapeutic potential of donor heart-based interventions.

Clinical features and outcomes of unplanned single lung transplants.

OBJECTIVE: The decision to perform single lung transplants or double lung transplants is usually made before the operation. We have previously reported that a proportion of single lung transplants were unexpectedly performed in the setting of an aborted double lung transplant, and these patients may be at a higher risk of worse short-term outcomes. Long-term outcomes in unplanned single lung transplants remain unknown. METHODS: We analyzed a single-center database of lung transplants from 2000 to 2020. Single lung transplants were classified into planned and unplanned groups after reviewing operative notes. Root cause analysis was performed for unplanned single lung transplants. RESULTS: Of the 1326 lung transplants, 1265 (95%) were double lung transplants and 61 (5%) were single lung transplants (22 planned [36%], 39 unplanned [64%]). Underlying indications for transplant were significantly different; planned single lung transplant: chronic obstructive pulmonary disease (55%) and idiopathic pulmonary fibrosis (45%); unplanned single lung transplants: chronic obstructive pulmonary disease (23%), idiopathic pulmonary fibrosis (39%), and bronchiolitis obliterans syndrome (13%). The primary reasons for unplanned single lung transplant were donor-related (3, 7.7%), recipient-related (31, 80%), and donor and recipient-related factors (5, 13%). Unplanned single lung transplants were more likely to require cardiopulmonary bypass during the operation (planned: 4/22, 18% vs unplanned: 20/39, 51%) but had shorter ischemic times (planned: 251 ± 58 minutes vs unplanned: 221 ± 48 minutes). The 5-year overall survival was 53% in the planned and 58% in the unplanned groups, respectively (P = .323). No difference in chronic lung allograft dysfunction-free survival (P = .995) was observed. CONCLUSIONS: Unplanned single lung transplants in the setting of aborted double lung transplant may be associated with acceptable long-term outcomes.

Lung Transplant for Pulmonary Fibrosis With Dendriform Ossification.

Dendriform pulmonary ossification (DPO) is a rare condition defined as disseminated, widespread heterotopic bone formation within the lungs. This condition is associated with restrictive pulmonary disease, such as interstitial pneumonia or fibrosis. The clinical features and pathophysiologic mechanism of DPO remain unclear, however. We report a case of a 66-year-old man with idiopathic pulmonary fibrosis accompanied by DPO who was treated with a double-lung transplant. His postoperative course was uneventful without recurrence of DPO.

Incidentally Detected Chronic Lymphocytic Leukemia in Hilar Lymph Nodes at the Time of Lung Transplantation: A Case Report.

A 68-year-old man with interstitial pulmonary fibrosis underwent bilateral lung transplantation. Histopathologic examination of hilar lymph nodes in the explanted lungs showed effacement of normal nodal architecture by the proliferation of small lymphocytes, consistent with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Unexpectedly discovered malignancies at the time of lung transplantation is uncommon, especially in the lymph nodes. The clinical management was challenging because of attempts to balance treatment of CLL and immunosuppressive treatment to prevent graft rejection. Here, we report a case of incidentally detected CLL in hilar lymph nodes with explanted lungs and review the relevant literature.

Clinical Features and Outcomes of Combined Pulmonary Fibrosis and Emphysema After Lung Transplantation.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is recognized as a characteristic syndrome of smoking-related interstitial lung disease that has a worse prognosis than idiopathic pulmonary fibrosis (IPF). However, outcomes after lung transplantation for CPFE have not been reported. The aim of this study is to describe the clinical features and outcomes of CPFE after lung transplantation. RESEARCH QUESTION: What are the clinical features and outcomes of CPFE after lung transplantation? STUDY DESIGN AND METHODS: This is a single-center retrospective cohort study of patients with CPFE and IPF who underwent lung transplantation at our center between January 2011 and December 2016. We defined CPFE as ≥10% emphysema in the upper lung fields combined with fibrosis on high-resolution CT scan. We characterized the clinical features of patients with CPFE and compared their outcomes after lung transplantation with those with IPF. RESULTS: Twenty-seven of 172 (16%) patients with IPF met criteria for CPFE. Severe pulmonary hypertension was present in 16 of 27 (59%) patients with CPFE. On logistic regression analysis, CPFE was significantly associated with primary graft dysfunction (PGD) grade 3 (OR, 3.14; 95% CI, 1.18-8.37; P = .02). On competing risk regression analysis, CPFE was associated with acute cellular rejection (ACR) grade ≥ A2, and chronic lung allograft dysfunction (CLAD) (hazard ratio [HR], 1.89; 95% CI, 1.10-3.25; P = .02; HR, 1.96; 95% CI, 1.02-3.77; P = .04, respectively). Five-year survival was 79.0% for the CPFE group and 75.4% for the IPF group (log-rank P = .684). INTERPRETATION: After transplantation, patients with CPFE were more likely to develop PGD, ACR, and CLAD compared with those with IPF. However, survival was not significantly different between the two groups.

Clinical Outcomes of Lung Transplants From Donors With Unexpected Pulmonary Embolism.

BACKGROUND: Pulmonary embolism (PE) is unexpectedly detected in some donor lungs during organ procurement for lung transplantation. Anecdotally, such lungs are usually implanted; however, the impact of this finding on recipient outcomes remains unclear. We hypothesized that incidentally detected donor PE is associated with adverse short-term and long-term outcomes among lung transplant recipients. METHODS: We analyzed a prospectively maintained database of all lung donors procured by a single surgeon and transplanted at our institution between 2009 and 2018. A standardized approach was used for all procurements and included antegrade and retrograde flush. Pulmonary embolism was defined as macroscopic thrombus seen in the pulmonary artery during the donor procurement operation. RESULTS: A total of 501 consecutive lung procurements were performed during the study period. The incidence of donor PE was 4.4% (22 of 501). No organs were discarded owing to PE. Donors with PE were similar to donors without PE in baseline characteristics and Pao2. Recipients in the two groups were also similar. Pulmonary embolism was associated with a higher likelihood of acute cellular rejection grade 2 or more (10 of 22 [45.5%] vs 120 of 479 [25.1%], P = .03). Multivariable Cox modeling demonstrated an association between PE and the development of chronic lung allograft dysfunction (hazard ratio 2.02; 95% confidence interval, 1.23 to 3.30; P = .005). CONCLUSIONS: Lungs from donors with incidentally detected PE may be associated with a higher incidence of recipient acute cellular rejection as well as reduced chronic lung allograft dysfunction-free survival. Surgeons must use caution when transplanting lungs with incidentally discovered PE. These preliminary findings warrant corroboration in larger data sets.

Clinical impact of the radiological indeterminate for usual interstitial pneumonia pattern on the diagnosis of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease associated with significant morbidity and mortality. The international clinical practice guidelines for the diagnosis of IPF have recently been revised. METHODS: In this single-center retrospective study conducted between June 2006 and March 2018, 27 patients with a newly classified indeterminate for usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) who had undergone surgical lung biopsy were enrolled at the Japanese Red Cross Medical Center. Clinical and pathological characteristics and prognosis were retrospectively analyzed from patient records. RESULTS: On the basis of multidisciplinary discussion (MDD), IPF was diagnosed in six patients (22%), unclassifiable interstitial pneumonia in 5 (19%), chronic hypersensitivity pneumonitis in 10 (37%), collagen vascular disease-associated interstitial lung disease in 5 (19%), and lymphoproliferative disorder in 1 (4%) patient. Ground-glass opacity, peribronchovascular distribution, upper or middle lobe distribution, mosaic attenuation, consolidation patterns, and honeycombing were found on HRCT. Histological UIP or probable UIP was observed in seven patients. The median survival time from the initial visit was 2770 days (92.3 months). There was a significant difference in survival time in the GAP stage and honeycombing on HRCT according to the log-rank test. CONCLUSIONS: Patients with an indeterminate for UIP pattern on HRCT were more likely to have non-IPF than IPF through pathological diagnosis and MDD. GAP stage and honeycombing on HRCT may be significant risk factors for all-cause mortality.

Role of donor macrophages after heart and lung transplantation.

Since the 1960s, heart and lung transplantation has remained the optimal therapy for patients with end-stage disease, extending and improving quality of life for thousands of individuals annually. Expanding donor organ availability and immunologic compatibility is a priority to help meet the clinical demand for organ transplant. While effective, current immunosuppression is imperfect as it lacks specificity and imposes unintended adverse effects such as opportunistic infections and malignancy that limit the health and longevity of transplant recipients. In this review, we focus on donor macrophages as a new target to achieve allograft tolerance. Donor organ-directed therapies have the potential to improve allograft survival while minimizing patient harm related to global suppression of recipient immune responses. Topics highlighted include the role of ontogenically distinct donor macrophage populations in ischemia-reperfusion injury and rejection, including their interaction with allograft-infiltrating recipient immune cells and potential therapeutic approaches. Ultimately, a better understanding of how donor intrinsic immunity influences allograft acceptance and survival will provide new opportunities to improve the outcomes of transplant recipients.

Impact of preoperative pathological confirmation on surgical and postoperative outcomes of lung resection for early stage lung cancer.

INTRODUCTION: The frequency of detection of peripheral pulmonary lesion (PPL) in suspected early lung cancer has been increasing, and whether preoperative pathological diagnosis (PPD) for small PPLs should always be established before their surgical resection can become a worrisome problem for physicians. The aim of the study was to clarify the impact of obtaining PPD on surgical and postoperative outcomes of lung resection for early stage lung cancer. MATERIAL AND METHODS: This was a retrospective review of cases that underwent surgical resection for known or suspected primary lung cancer presenting pathological stage 0 or I, enrolled from June 2006 to May 2016. The patients divided into two groups according to PPD group (n = 57) and non-PPD group (n = 157) were compared. The procedure, node dissection, operation time, amount of bleeding, postoperative complications, postoperative length of stay, and postoperative recurrences were analyzed. RESULTS: Among the 214 patients, no significant differences in operation time (248.5 ± 88.6 versus 257.6 ± 89.0, min, mean ± SD, p = 0.328), amount of bleeding (195.3 ± 176.5 vs 188.1 ± 236.1, ml, p = 0.460), postoperative complication (5.2% vs 4.5%, p = 0.728), postoperative length of stay (10.6 ± 6.3 vs 10.4 ± 5.3, days, p = 0.827), or postoperative recurrences (21.0% vs 17.2%, p = 0.550) were seen between PPD and non-PPD groups. CONCLUSION: Therefore, PPD had less impact on surgical and postoperative outcomes of pathological stage 0 or I lung cancer; direct surgical resection without non-surgical biopsy would be acceptable with careful selection of cases.

Spread through air spaces is an independent predictor of recurrence in stage III (N2) lung adenocarcinoma.

OBJECTIVES: Spread through air space (STAS) is recognized as a pattern of invasion in lung adenocarcinoma and has been reported to be a predictor of recurrence and survival in patients with early-stage lung adenocarcinoma. However, this parameter has not been studied well in stage III (N2) lung adenocarcinoma. In this study, we evaluated the association between STAS invasion patterns and recurrence and survival in stage III (N2) lung adenocarcinoma. METHODS: We retrospectively reviewed data from 76 patients at University of Tokyo with stage III (N2) lung adenocarcinoma who underwent surgery from August 1998 to December 2013. Statistical analysis was performed to determine the impact of STAS invasion clinicopathological features and clarify the relationship between this pattern of invasion and survival. RESULTS: Tumour STAS was observed in 46 of 76 patients (60.5%) and was significantly associated with the presence of lymphatic invasion (P < 0.001), papillary components (P < 0.001) and micropapillary components (P < 0.001). STAS was also significantly associated with recurrence (5-year recurrence-free probability: 19.0% vs 46.1%, P < 0.05). Univariate analyses showed that STAS was a significant risk factor for recurrence (hazard ratio 1.94, 95% confidence interval 1.07-3.51; P = 0.029). CONCLUSIONS: The presence of STAS invasion pattern is a significant risk factor for recurrence in stage III (N2) lung adenocarcinoma.

Rapid effects of benralizumab on severe asthma during surgery for residual tumor after advanced lung squamous cell carcinoma treatment with pembrolizumab.

Severe bronchial asthma is a chronic disorder of the airways that may be accompanied by comorbid diseases. Invasive treatment, including surgery, in patients with severe asthma has limitations depending on the degree of control of the asthma. A 71-year-old woman was diagnosed with squamous cell carcinoma with high programmed death-ligand 1 (PD-L1) expression and cT3N0M1a. After 13 cycles of pembrolizumab every 3 weeks, chest computed tomography (CT) revealed a dramatic decrease in the lesion size in the left upper lobe, but the size of the lesion in the right lower lobe was significantly increased. The pathological findings of the right residual tumor by CT-guided transthoracic needle biopsy (CTNB) revealed squamous cell carcinoma with no PD-L1 expression, and right lower lobectomy was recommended. However, because the patient had frequent asthma attacks and cough, surgery was considered risky. Increased blood eosinophil count was observed, and benralizumab was administered for asthma control. The symptoms disappeared 2 days after benralizumab administration, and peak flow increased. Surgery was performed 5 days after benralizumab administration. There was a marked reduction in the eosinophil count of the surgical tissue compared with the preoperative CTNB tissue. No asthma attacks were observed during and after surgery, and the control of asthma and lung cancer was stable. Benralizumab is considered promising for the treatment of eosinophilic severe uncontrolled asthma.

Nivolumab and stereotactic radiation therapy for the treatment of patients with Stage IV non-small-cell lung cancer.

BACKGROUND: Radiation therapy might modify the cancer immune environment to enhance the antitumor effect of immune checkpoint inhibitors. We performed a feasibility study of nivolumab following stereotactic radiation therapy for chemotherapy pretreated advanced non-small-cell lung cancer. PATIENTS AND METHODS: Pretreated advanced/recurrent non-small-cell lung cancer patients received stereotactic radiation therapy to one of the disease sites. Nivolumab at a dose of 3 mg/kg was given within 2 weeks after the completion of stereotactic radiation therapy and continued every 2 weeks thereafter until disease progression or unacceptable toxicities. The primary endpoint was the occurrence rate of Grade 3 pneumonitis (within 12 weeks) or other non-hematological toxicity (within 8 weeks). RESULTS: From September 2016 to September 2017, six patients were enrolled. Five received stereotactic radiation therapy to their primary lesions. All patients received nivolumab on the following day after stereotactic radiation therapy completion. Grade 3 pneumonitis occurred in one patient, but no other serious adverse events were reported for the other patients. One complete response and two partial responses were achieved. Four patients had measurable lesions outside the irradiated area, of whom three patients responded to the treatment. The initial progression sites were mainly outside the irradiated field, including one brain metastasis. CONCLUSIONS: Nivolumab therapy immediately following stereotactic radiation therapy was well tolerated. This sequential combination warrants further study.

The Significant Antitumor Activity of Nivolumab in Lung Adenocarcinoma with Choriocarcinomatous Features.

We report the case of a 60-year-old Japanese man with a metastatic brain tumor that caused ataxia. As a consequence of resection of a cerebellar tumor, the tumor was diagnosed as a poorly differentiated adenocarcinoma with choriocarcinomatous features. The patient underwent bronchoscopy, leading to a diagnosis of the same histology as the brain tumor. After the administration of first-line chemotherapy and maintenance therapy due to progressive disease, he was given nivolumab and obtained a partial response; however, 11-months later, computed tomography showed tumor progression. Our experience suggests that nivolumab has strong activity, even in patients with a rare form of lung cancer.

Squamous cell carcinoma of the lung showing a ground glass nodule on high-resolution computed tomography associated with pneumoconiosis: a case report.

BACKGROUND: Adenocarcinoma with lepidic growth pattern presents as a ground glass nodule (GGN) on high resolution computed tomography (CT), whereas peripheral pulmonary squamous cell carcinoma (SCC) usually presents as a solid nodule. We herein report a rare case of pulmonary SCC extending along the alveolar lumen representing as a GGN on a CT scan in a patient with pneumoconiosis. CASE PRESENTATION: A 77-year-old man with pneumoconiosis was found to have a gradually enlarging GGN in the right lower lobe of the lung on CT. An adenocarcinoma of the lung was suspected. The GGN was successfully resected by thoracoscopic segmentectomy. Pathological examination of the resected specimen was pathologically diagnosed as a stage IA SCC extending along the alveolar lumen. The patient had no evidence of recurrence 19 months after surgery. CONCLUSIONS: SCC should be included in the differential diagnosis of peripherally located GGNs, especially in patients at high risk of SCC of the lung such as those with pneumoconiosis.

Efficacy and safety of stereotactic body radiotherapy using CyberKnife in Stage I primary lung tumor.

BACKGROUND: CyberKnife® (CK) is a new, advanced radiotherapy technique. This study aimed to evaluate its efficacy and toxicity in Japanese patients with early-stage primary lung tumor who were medically unfit and inoperable. METHODS: This retrospective study investigated patients who received CK treatment for medically inoperable Stage І primary lung tumor at the Japanese Red Cross Medical Center between June 2011 and September 2016. Each patient received a total of 36-48 Gy (median, 43 Gy) administered by CK in 4-5 fractions. RESULTS: Totally, 40 patients (T1a, n = 19; T1b, n = 15; T2a, n = 6) were included. Their median age was 86 (range, 56-95) years. Tracking required the use of fiducial markers in 28 patients and the Xsight Spine Tracking System in 12. The median follow-up was 14.5 (range, 1-51) months. Local recurrence occurred in seven (17.5%) patients. The local progression-free survival rates at 1 and 2 years were 83.9% and 74.0%, respectively. Distant recurrence occurred in regional lymph nodes (n = 5), the lung outside the radiation field (n = 3), and the bone (n = 1). Seven patients died. Overall survival rates at 1 and 2 years were 93.6% and 73.1%, respectively. Radiation pneumonitis was identified in 28 (70%) patients (Grade 1, n = 25; Grade 2, n = 2; Grade 5, n = 1). CONCLUSIONS: CK showed good local control with limited toxicity and could be an alternative treatment modality in medically inoperable patients with Stage І primary lung tumor.