Hyperprogressive disease under anti-PD-1 rechallenge after initial response to anti-PD-1 treatment for non-small cell lung cancer: a case report.

Background: Hyperprogressive disease is an unexpected response pattern observed in immune checkpoint therapy and associated with poor prognosis. The rechallenge of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors can be a treatment option in non-small cell lung cancer (NSCLC) patients who once responded to them. Here, we reported the hyperprogressive phenomenon after PD-1/PD-L1 rechallenge in a patient with NSCLC. Case Description: This case report described a patient with recurrent large cell lung cancer undergoing hyperprogressive disease with pleural and pericardial dissemination shortly after the pembrolizumab rechallenge, although he had a favorable response to the initial pembrolizumab treatment. A lower ratio of CD8+ T cells to Foxp3+ regulatory T cells was distributed in the cell blocks of pleural and pericardial effusion which were taken after hyperprogressive disease, compared to the resected tumor microenvironment. Neutrophil-to-lymphocyte ratio (NLR) was lower in peripheral blood when the disease was controlled and it rose when the disease progressed. Notably, NLR increased dramatically when hyperprogression occurred. Conclusions: For the first time, we reported that a patient who showed a favorable response to initial anti-PD-1 treatment underwent hyperprogressive disease when rechallenging the same immunotherapy. The increased Foxp3+ regulatory T cells in the tumor microenvironment and the longitudinal change of NLRs in peripheral blood were suggested to be associated with hyperprogressive disease.

Pulmonary Erdheim-Chester Disease With BRAF-AGAP3 Fusion: Late-Onset Osteolytic Femoral Lesions Despite Long-Term Pulmonary Stabilization With Corticosteroid.

Erdheim-Chester disease (ECD) is a rare inflammatory myeloid neoplasm affecting multiple systems and organs. The patient is a 38-year-old male with ECD complicated with pulmonary and cutaneous manifestations but without bone lesions diagnosed in 2008. Initial treatment with oral and inhaled corticosteroids achieved persistent favorable disease remission. However, atypical late-onset bone lesions developed in the bilateral femur in 2021. Although BRAF-V600E mutation was negative in the lung specimen at diagnosis, the next-generation gene sequence using biopsied bone lesions revealed a rare BRAF-AGAP3 fusion, leading to the administration of trametinib. This is the first report describing ECD harboring BRAF-AGAP3 fusion successfully treated with trametinib. Our case presents a unique clinical course in which late-onset osteolytic bone lesions developed despite a long-term stabilization of pulmonary lesions with low-dose oral and inhaled corticosteroids.

An elderly woman with Birt-Hogg-Dubé syndrome having multiple pulmonary cysts mimicking lymphangioleiomyomatosis.

The characteristics of the pulmonary cysts on the high-resolution computed tomography (HRCT) chest images are an important diagnostic clue to distinguish among cystic lung diseases. The diagnostic accuracy of HRCT was reported to be as high as 90% by experienced pulmonologists and radiologists. Herein, we report the case of an elderly woman with Birt-Hogg-Dubé syndrome (BHDS) whose HRCT images displayed lymphangioleiomyomatosis-like features of the pulmonary cysts, rendering it difficult for us to diagnose BHDS. This case illustrates the significance of a thorough anamnesis, physical examination, and skin biopsy of facial papules to establish an accurate diganosis.

Late relapse of ulcerative colitis presenting as tracheobronchitis: a case report.

BACKGROUND: Lung involvement in inflammatory bowel diseases usually follows colitis. However, the time to lung involvement onset varies depending on the case, and pulmonary lesions are usually not parallel to exacerbations of the colitis. CASE PRESENTATION: A 67-year-old Asian woman with a 38-year history of ulcerative colitis presented to our hospital with a complaint of prolonged dry cough for 2 months. The colitis had remained quiescent for > 35 years with low-dose salazosulfapyridine treatment. Chest computed tomography indicated circumferential thickening of the tracheal wall, while bronchoscopy examination revealed widespread erythematous edema and diffuse narrowing of the bronchial lumen. Biopsy of the bronchial mucosa showed submucosal lymphocytic infiltration. She was diagnosed with ulcerative-colitis-related tracheobronchitis and successfully treated with corticosteroids. CONCLUSIONS: Tracheobronchitis, in our case, occurred despite the longest remission period previously reported. Careful follow-up is necessary for the early recognition and treatment of pulmonary disease in patients with ulcerative colitis, regardless of the disease duration and long-term remission of colitis.

Dramatic, significant metabolic response to a one-time pembrolizumab treatment following a relapse of pre-existing organizing pneumonia in a patient with advanced non-small cell lung cancer: A case report.

Immune checkpoint inhibitors can often trigger immune-related adverse events (irAEs), such as relapse of pre-existing interstitial pneumonia. Here, we report the case of an 88-year-Japanese man diagnosed with advanced lung adenocarcinoma with a high tumor proportion score of programmed death-ligand 1. Six years earlier, he had developed organizing pneumonia (OP), a subtype of interstitial pneumonia, that was treated with steroid pulse therapy maintained with prolonged prednisolone administration. We initiated pembrolizumab as the first-line treatment. One month after the first pembrolizumab administration, high resolution computed tomography (HRCT) of the chest demonstrated ground-glass opacities and consolidations. We suspected pembrolizumab-induced OP relapse, an irAE. His oxygenation was normal; therefore, we discontinued pembrolizumab without additional treatment for OP relapse. Four months after OP relapse, HRCT showed no new findings. After significant amelioration of OP, although the size of the tumor shadow remained the same on HRCT, positron emission tomography-computed tomography demonstrated the disappearance of the standardized uptake value of the primary tumor, mediastinal lymph nodes, and pleural nodules. In conclusion, this is the first report of a dramatic, significant metabolic response after a single pembrolizumab treatment despite the relapse of pre-existing OP in a patient with advanced lung adenocarcinoma.

Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells.

Birt-Hogg-Dubé syndrome (BHDS), an autosomal dominant inheritance disease caused by folliculin (FLCN) mutations, is associated with lung cysts and spontaneous pneumothorax. The possibility of FLCN haploinsufficiency in pleural mesothelial cells (PMCs) contributing to development of pneumothorax has not yet been clarified. Electron microscopy revealed exposed intercellular boundaries between PMCs on visceral pleura and decreased electron density around the adherens junctions in BHDS. To characterize cellular function of PMCs in BHDS patients (BHDS-PMCs), during surgery for pneumothorax, we established the flow cytometry-based methods of isolating high-purity PMCs from pleural lavage fluid. BHDS-PMCs showed impaired cell attachment and a significant decrease in proliferation and migration, but a significant increase in apoptosis compared with PMCs from primary spontaneous pneumothorax (PSP) patients (PSP-PMCs). Microarray analysis using isolated PMCs revealed a significant alteration in the expression of genes belonging to Gene Ontology terms "cell-cell adhesion junction" and "cell adhesion molecule binding". Gene set enrichment analysis demonstrated that CDH1, encoding E-cadherin, was identified in the down-regulated leading edge of a plot in BHDS-PMCs. AMPK and LKB1 activation were significantly impaired in BHDS-PMCs compared with PSP-PMCs. Our findings indicate that FLCN haploinsufficiency may affect the E-cadherin-LKB1-AMPK axis and lead to abnormal cellular function in BHDS-PMCs.

Isolation and characterisation of lymphatic endothelial cells from lung tissues affected by lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.

Uncommon radiologic computed tomography appearances of the chest in patients with lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by multiple thin-walled pulmonary cysts. The currently proposed diagnostic algorithm emphasizes the characteristic cystic appearance on high-resolution computed tomography (HRCT) so uncommon HRCT appearances present challenges to establishing the proper LAM diagnosis. The objective of this study is to accrue uncommon chest HRCT appearances, determine frequencies in both tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM (S-LAM) patients. 311 females referred to our hospital, including 272 S-LAM patients (mean age 39.2 years) and 39 TSC-LAM patients (mean age 38.3 years), were retrospectively evaluated. We found 2 types of radiologic findings likely to make HRCT cyst appearance atypical: characteristics of the cyst itself and uncommon findings in addition to cysts. We found that approximately 80% of LAM patients, whether TSC-associated or sporadic, showed typical HRCT appearance with mild to severe cystic destruction. The remaining 20% displayed unusual profiles in cyst appearance as well as additional findings aside from cyst: the former includes large cyst, thickened walls, and irregularly shaped whereas the latter includes ground glass attenuation and diffuse noncalcified nodules. It is important to be aware of various radiologic findings that make HRCT cystic appearance atypical of LAM.

Transbronchial lung biopsy for the diagnosis of lymphangioleiomyomatosis: the severity of cystic lung destruction assessed by the modified Goddard scoring system as a predictor for establishing the diagnosis.

BACKGROUND: A guide of patient selection for establishing the diagnosis of lymphangioleiomyomatosis (LAM) by transbronchial lung biopsy (TBLB) has not been established, although the pathological confirmation of LAM by lung biopsy is desirable, particularly when patients have no additional test results except typical findings of computed tomography (CT) of the chest. METHODS: We retrospectively reviewed the medical records of LAM patients who visited at our hospital from January 2010 to September 2018. We found 19 patients who underwent TBLB and collected the following data to investigate which parameters could predict the TBLB diagnostic positivity for LAM: age, degree of exertional dyspnea, pulmonary function test, cystic lung destruction visually assessed by the modified Goddard scoring system (MGS), serum level of vascular endothelial growth factor-D, and TBLB-related data. RESULTS: The diagnosis of LAM was established by TBLB in 15 of 19 patients (78.9%) and no serious complications occurred. MGS was significantly higher in the TBLB-positive group than the TBLB-negative group. In LAM patients without pulmonary lymphatic congestion on CT (N = 16), multivariable logistic regression analysis revealed that MGS and FEV1/FVC were independent contributing parameters for TBLB diagnostic positivity. However, the analysis of Bayesian inference demonstrated that MGS is a better predictor than FEV1/FVC; the probability of establishing diagnosis exceeds 80% if MGS is > 2 (i.e., area of cystic destruction occupies > 25% of lung parenchyma on CT). CONCLUSIONS: MGS may be a helpful and convenient tool to select candidates for TBLB to establish the diagnosis of LAM pathologically.

Protein-losing Enteropathy Caused by Intestinal or Colonic Lymphangiectasia Complicated by Sporadic Lymphangioleiomyomatosis: A Report of Two Cases.

This report describes two patients with sporadic lymphangioleiomyomatosis complicated by protein-losing enteropathy (PLE). Imaging studies indicated retroperitoneal lymphangioleiomyomas and abnormalities of the adjacent digestive tract. Endoscopic mucosal biopsy revealed colonic lymphangiectasia in one patient; whereas the site in the other patient was intestinal. Treatment with sirolimus led to the complete resolution of PLE within several months; additionally, marked shrinkage was observed in the lymphangioleiomyomas of both cases. These findings suggest that colonic or intestinal lymphatic congestion due to neighboring lymphangioleiomyomas was the mechanism for the development of PLE. At the time of writing this report, the beneficial effect of sirolimus has lasted for more than 3 years.

Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant inherited disorder caused by germline mutations in the FLCN gene, and characterized by skin fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax, and renal neoplasms. Pulmonary manifestations frequently develop earlier than other organ involvements, prompting a diagnosis of BHDS However, the mechanism of lung cyst formation and pathogenesis of pneumothorax have not yet been clarified. Fibroblasts were isolated from lung tissues obtained from patients with BHDS (n = 12) and lung cancer (n = 10) as controls. The functional abilities of these lung fibroblasts were evaluated by the tests for chemotaxis to fibronectin and three-dimensional (3-D) gel contraction. Fibroblasts from BHDS patients showed diminished chemotaxis as compared with fibroblasts from controls. Expression of fibronectin and TGF-ß1 was significantly reduced in BHDS fibroblasts when assessed by qPCR Addition of TGF-ß1 in culture medium of BHDS lung fibroblasts significantly restored these cells' abilities of chemotaxis and gel contraction. Human fetal lung fibroblasts (HFL-1) exhibited reduced chemotaxis and 3-D gel contraction when FLCN expression was knocked down. To the contrary, a significant increase in chemotactic activity toward to fibronectin was demonstrated when wild-type FLCN was overexpressed, whereas transduction of mutant FLCN showed no effect on chemotaxis. Our results suggest that FLCN is associated with chemotaxis in lung fibroblasts. Together with reduced TGF-ß1 expression by BHDS lung fibroblasts, a state of FLCN haploinsufficiency may cause lung fibroblast dysfunction, thereby impairing tissue repair. These may reveal one mechanism of lung cyst formation and pneumothorax in BHDS patients.

[A case of Stage IV gastric cancer in which a partial response was maintained for four years with multidisciplinary treatment].

The patient was a 63-year-old man with Stage IV gastric cancer (cT3, cNX, cM1[LYN]). After chemotherapy with S-1 plus paclitaxel (PTX), a partial response was achieved, and distal gastrectomy was subsequently performed. During continued chemotherapy with S-1 plus PTX after surgery, enlarged lymph nodes (#16) were observed. Metastasis was detected and treated with radiation therapy. Ten months after the cervical and Virchow lymph node metastases were detected, lymph node dissection was performed. After the second surgery, chemotherapy with S-1 plus cisplatin (CDDP) was selected, but the regimen was changed to S-1 alone because of cerebral infarction. This treatment resulted in the maintenance of a partial response for one year. However, lymph node metastases around the right iliac artery and left cervix subsequently appeared, and lymph node dissection was performed. Since the metastatic lesions remained inside the left parotid gland, radiation therapy to the cervical region was performed again. However, the right inguinal and iliac lymph node metastases enlarged, and we again attempted to treat them with radiation therapy. The patient died due to peritoneal dissemination four years and two months after his first visit.