Tumor Necrosis Factor Family Member Profile Predicts Prognosis and Adjuvant Chemotherapy Benefit for Patients With Small-Cell Lung Cancer.

Tumor necrosis factor (TNF) family members participate in the body's antitumor immunity response and influence tumor prognosis and treatment response. However, little is known about the roles of TNF family members in small cell lung cancer (SCLC). Therefore, we conducted the first comprehensive investigation of TNF family members in patients with SCLC, with the goal of using them to predict prognosis and chemotherapy benefit. Abnormal genetic alterations and expression of TNF family members were found to be widespread in SCLC patients. Using LASSO Cox regression analysis, we constructed a TNF family-based signature that separated SCLC patients in the training set (n=77) into high- and low-risk groups with distinct survival and chemotherapy benefit, and the signature was well-validated in the validation set (n=137) by RT-qPCR. Importantly, the signature exhibited superior predictive performance and was identified as a novel independent prognostic factor. Additionally, different immune phenotypes were found between the low-risk and high-risk groups, and high-risk patients had higher CMTM6 expression, suggesting that these patients could benefit from therapeutic methods targeting CMTM6. We constructed the first clinically applicable TNF family-based signature for predicting prognosis and chemotherapy benefit for patients with SCLC. The findings reported here provide a new method for predicting the prognosis of SCLC patients and optimizing clinical management.

Impact of coexistent preserved ratio impaired spirometry on the survival of patients with lung cancer: Analysis of data from the Korean Association for Lung Cancer Registry.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is a common spirometric pattern that is associated with respiratory symptoms and higher mortality rates. However, the relationship between lung cancer and PRISm remains unclear. This study investigated the clinical characteristics of lung cancer patients with PRISm and the potential role of PRISm as a prognostic factor. METHODS: We retrospectively reviewed data collected from 2014 to 2015 in the Korean Association for Lung Cancer Registry. We classified all patients into three subgroups according to lung function as follows: normal lung function; PRISm (forced expiratory volume in 1 s [FEV1 ] < 80% predicted and FEV1 /forced vital capacity [FVC] ≥ 0.7); and chronic obstructive pulmonary disease (COPD; FEV1/FVC < 0.7). In non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the overall survival period was compared among the three subgroups. The prognostic factors were investigated using Cox regression analysis. RESULTS: Of the 3763 patients, 38.6%, 40.1%, and 21.3% had normal lung function, COPD, and PRISm, respectively. Patients with PRISm had poorer overall survival than those with COPD or normal lung function in NSCLC and SCLC (Mantel-Cox log-rank test, p < 0.05). In the risk-adjusted analysis, overall survival was independently associated with COPD (hazard ratio [HR] 1.209, p = 0.027) and PRISm (HR 1.628, p < 0.001) in NSCLC, but was only associated with PRISm (HR 1.629, p = 0.004) in SCLC. CONCLUSIONS: PRISm is a significant pattern of lung function in patients with lung cancer. At the time of lung cancer diagnosis, pre-existing PRISm should be considered a predictive factor of poor prognosis.

ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer.

ASCL1 is a neuroendocrine lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ∼25% of human SCLC are ASCL1-low and associated with low neuroendocrine fate and high MYC expression. Using genetically engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1+ subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9+ mesenchymal/neural crest stem-like state and the emergence of osteosarcoma and chondroid tumors, whose propensity is impacted by cell of origin. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1 and represses genes involved in the Hippo/Wnt/Notch developmental pathways in vivo. Importantly, ASCL1 represses a SOX9/RUNX1/RUNX2 program in vivo and SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Together, in a MYC-driven SCLC model, ASCL1 promotes neuroendocrine fate and represses the emergence of a SOX9+ nonendodermal stem-like fate that resembles neural crest.

Long-term remission of small cell lung cancer after reactivation of tuberculosis following immune-checkpoint blockade: A case report.

Immune-checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune-related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long-term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI-associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.

CT evaluated sarcopenia signals: Shorter survival for small cell lung cancer patients.

Sarcopenia is an independent risk factor for morbidity and mortality in patients suffering from small cell lung cancer (SCLC), however, a universal indicator of sarcopenia usable in clinical practice is still missing. A novel indicator for describing the severity of cancer could be helpful in tailoring the anti-tumor therapy. The aim of this study was to evaluate the computed tomography (CT) scans of total muscle area and radiation attenuation in patients suffering from small cell lung cancer. We used staging CT scans performed at the time of diagnosis to measure total muscle area (TMA) and average psoas density (PD) at level of the 3rd lumbar vertebra. TMA and PD were statistically evaluated in association with overall survival and disease staging. We used Mann-Whitney test and Spearman´s correlation coefficient for statistical testing and p-value under 0.05 was considered statistically significant. Retrospectively we examined 47 patients suffering from SCLC (mean age 65.05+/-7.3 years, BMI 23.97+/-4.4 kg/m2, BSA 1.77+/-0.2 m2, 30-day mortality was 4.3 % with 10 months median survival). As sarcopenia was pointed TMA under 55 and 39 cm2/m2 for men and women respectively. The sarcopenic patients had significantly shorter median survival (7 vs. 11 months, p=0.05). We observed a significant relationship between survival and performance status (Spearman´s correlation, R=-0.39, p=0.05). The patients were divided into two groups according to the extensive (ED, n=34) or limited (LD, n=13) form of the disease. We observed significant difference in PD (42.49+/-6.1 vs. 47.67+/-4.5 HU, p=0.006) between ED vs. LD groups.

Impact of Early Prophylactic Cranial Irradiation With Hippocampal Avoidance on Neurocognitive Function in Patients With Limited Disease Small Cell Lung Cancer. A Multicenter Phase 2 Trial (SAKK 15/12).

PURPOSE: Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC). METHODS AND MATERIALS: In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment. RESULTS: Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%). CONCLUSIONS: The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.

Coexistence of Anti-SOX1 and Anti-GABAB Receptor Antibodies with Autoimmune Encephalitis in Small Cell Lung Cancer: A Case Report.

Anti-γ-aminobutyric acid B receptor (anti-GABABR) encephalitis is a rare type of autoimmune encephalitis (AE). Although it responds well to immunomodulating therapy and has favorable prognosis, anti-GABABR AE has often been misdiagnosed as infectious encephalitis. Herein, we present a case of a 59-year-old female with anti-GABABR AE associated with small cell lung cancer (SCLC) that was once misdiagnosed as infectious encephalitis. Our findings increase the awareness that patients presenting with a clinical trial of cognitive impairment, seizures and SCLC may harbor AE. Our case also highlights the importance of anti-SOX1 antibody in the detection of SCLC.

Axon-like protrusions promote small cell lung cancer migration and metastasis.

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A+/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.

Antrodia Cinnamomea Prolongs Survival in a Patient with Small Cell Lung Cancer.

Introduction: Antrodia cinnamomea (AC) is an extremely rare medicinal fungus native to forested regions of Taiwan. It possesses numerous biological activities, especially anti-tumor effects shown in various in vitro cancer cells and in vivo animal models. However, there are few clinical reports about AC as a treatment for cancer patients. This report attempts to demonstrate the therapeutic effect of dish-cultured AC (DAC) on a small cell lung cancer (SCLC) patient taken orally for an extended duration. Patient concerns: An 88-year-old male with a history of diabetes mellitus and hypertension visited the outpatient department with the symptoms of dyspnea and a cough for two weeks. After a diagnosis of SCLC, the patient declined both chemotherapy and radiotherapy because of the side effects and only accepted supportive care without additional therapy. Diagnosis: Limited-stage SCLC (T4N2M1a, stage IV) after the chest radiograph, computed tomography-guided biopsy, and pathological diagnosis. Interventions: The patient was prescribed DAC with an increasing dosage, from 5 g/d up to 10 g/d DAC, for six months, without radiation or chemotherapy treatment. Outcomes: DAC caused the tumor to shrink substantially. Surprisingly, the patient survived for 32 months without relapse after six months of DAC treatment. Laboratory examinations indicated that the patient's health had improved significantly, reverting to near normal levels. Notably, he had a good quality of life with a high Barthel index score. Unfortunately, this patient died of septic shock caused by acute cholangitis. Conclusion: DAC may exert an anti-cancer effect, which can lead to tumor regression. This is supposed to be achieved by the combined DAC's immunomodulatory, anti-angiogenic, anti-metastatic, anti-proliferative, and pro-apoptotic effects mediated through multiple signaling pathways. We propose that DAC can be used as a complementary medicine to prolong the life expectancy and improve the life quality of SCLC patients.

The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score in Patients with Small Cell Lung Cancer Before First-Line Treatment with Etoposide and Progression-Free Survival.

BACKGROUND The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a prognostic factor in patients who have some types of malignant tumors. The aim of this study was to investigate the prognostic significance of the HALP score in patients with small cell lung cancer (SCLC) before first-line treatment with etoposide. MATERIAL AND METHODS A retrospective study included 178 patients with SCLC who received first-line chemotherapy with etoposide between September 2015 and May 2019. The baseline clinical characteristics and blood parameters were recorded. Univariate and multivariate analysis and Kaplan-Meier plots were used to identify the factors associated with progression-free survival (PFS). RESULTS The optimal cut-off values of the HALP score was determined by X-tile software to be 25.8. Univariate and multivariate analysis showed that in 178 patients, the HALP score, body mass index (BMI), and serum albumin levels had no prognostic significance. In the patient age group <65 years, a BMI ≥24 kg/m² was an independent prognostic factor (HR, 1.943; 95% CI, 1.251-3.018) (P=0.003). In the patient age group ≥65 years, a HALP score >25.8 was an independent positive prognostic factor for outcome following first-line treatment with etoposide (HR, 0.483; 95% CI, 0.270-0.865) (P=0.014). CONCLUSIONS In patients <65 years with SCLC who underwent first-line treatment with etoposide, a BMI ≥24 kg/m² an independent prognostic factor, and in patients ≥65 years, a HALP score >25.8 was an independent predictor of improved outcome, associated with increased PFS.

Effects of cognitive education on the perceived control and symptom distress of lung cancer patients receiving chemotherapy: A randomised controlled trial.

AIM: A randomised controlled trial (RCT) was implemented to verify the feasibility and acceptability of cognitive education in the format of mind maps for increasing perceived control and decreasing the symptom distress of lung cancer patients who were receiving chemotherapy. METHODS: A total of 136 lung cancer patients who were receiving chemotherapy were randomised using stratified blocks (1:1 ratio, from March 2016 to April 2017). The intervention group was given cognitive education in the format of mind maps. The control group was provided conventional education. The primary outcomes were perceived control, including cancer experience and cancer efficacy; the secondary outcomes included symptom distress (arising from fatigue, distress, sleep disturbance, poor appetite, drowsiness, shortness of breath, etc.). The Mann-Whitney U test, chi-squared test, two-sample t test and repeated measurement analysis of variance were used. RESULTS: Ninety-four patients completed the final study. The results of the repeated measurement analysis of variance indicated that at the 8th or 12th week following cognitive education intervention in the format of mind maps, the cancer experience, cancer efficacy (except personal efficacy) and symptom distress (arising from fatigue, distress, sleep disturbance, and sadness and its total scores) of the patients in the intervention group were considerably improved compared with those of the control group (p < 0.05). The longer the intervention was, the higher the level of the patients' perceived control was and the lower the degree of patient symptom distress was (p < 0.05). CONCLUSIONS: Our findings suggest that cognitive education in the format of mind maps could improve perceived control and decrease the symptom distress of lung cancer patients who were receiving chemotherapy and that it was feasible and acceptable. Cognitive education in the format of mind maps was found to be an effective teaching tool for lung cancer patients who were receiving chemotherapy.

Body Mass Index (BMI), BMI Change, and Overall Survival in Patients With SCLC and NSCLC: A Pooled Analysis of the International Lung Cancer Consortium.

INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.

Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.

OBJECTIVE: To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABAB receptor antibodies (GABABR-Abs). METHODS: Retrospective clinical study of CSF-confirmed cases of GABABR-Abs encephalitis. RESULTS: We identified 22 patients (4 female) with GABABR-Abs, with a median age of 64 years (range 55-85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10 days (range 1-30), the recurrent seizures' phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26 days (range 6-65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2 years). CONCLUSION: Paraneoplastic GABABR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.

Regional Changes in Brain 18F-FDG Uptake After Prophylactic Cranial Irradiation and Chemotherapy in Small Cell Lung Cancer May Reflect Functional Changes.

Chemotherapy followed by prophylactic cranial irradiation (PCI) is associated with increased survival in patients with small cell lung cancer but is associated with fatigue and cognitive impairment. This retrospective study evaluated regional differences in 18F-FDG uptake by the brain before and after PCI. The null hypothesis was that direct toxic effects on the brain from PCI and chemotherapy are symmetric; thus, asymmetric deviations may reflect functional changes due to therapy. Methods: Electronic medical records from 2013 to 2016 were reviewed for patients with small cell lung cancer, MRI of brain negative for metastasis, and 18F-FDG PET/CT scans before and after PCI. As the standard of care, patients received first-line chemotherapy or chemoradiation to the thorax followed by PCI. The 18F-FDG PET/CT scans nearest the PCI were selected. Sixteen patients met these initial criteria. Commercially available PET software was used to register and subtract the PET scans before and after PCI to obtain difference maps. Occipital and cerebellar regions were excluded from the final statistical analysis given the known high variability and misregistration. The χ2 test was used to analyze the data. Results: Two patients had 18F-FDG uptake differences only in the occipital and cerebellar regions. The software registration failed on 1 patient's scans. Therefore, 13 patients were included in the final analysis. Nine of 13 patients demonstrated significant unilateral changes in only 1 region of the brain, and 3 of 13 showed significant changes unilaterally in 2 regions. The χ2 test revealed a significant unilateral regional difference on a patient level (χ2 = 6.24, P = 0.025). The most commonly affected brain region was the frontal lobe. Conclusion: Significantly more patients had unilateral than bilateral regional differences (both increases and decreases) in 18F-FDG uptake in the brain before and after PCI. This finding suggests that differences in unilateral distribution are related to functional changes, since direct toxicity alone from PCI and chemotherapy would be symmetric. The frontal region was the most commonly affected, suggesting a potential contributing etiology for cognitive impairment and decreased executive function after therapy.

Identifying a missing lineage driver in a subset of lung neuroendocrine tumors.

Tumor heterogeneity of a primary histologic cancer type has major implications for cancer research and therapeutics. An important and understudied aspect of this heterogeneity is the role of transcription factors that serve as "lineage oncogenes" in a tumor type. A demonstration that different subgroups have distinct dependencies on lineage-specific transcription factors is highlighted in a relatively homogenous cancer type: the pulmonary neuroendocrine cancer small cell lung carcinoma (SCLC). Identification of these factors is providing new insights into the origin of the heterogeneity and subtype-specific vulnerabilities in SCLC and provides a template for studying heterogeneity in other cancer types.

Feasibility of an eight-week outpatient-based pulmonary rehabilitation program for advanced lung cancer patients undergoing cytotoxic chemotherapy in Korea.

The scientific evidence supporting pulmonary rehabilitation (PR) for lung cancer patients undergoing cytotoxic chemotherapy is accumulating; however, the feasibility of outpatient-based PR in these patients has not yet been evaluated in Korea. We conducted an eight-week outpatient-based PR feasibility study in a tertiary referral hospital setting. Patients with advanced lung cancer (non-small cell lung cancer IIIB-IV and small-cell lung cancer extensive disease) scheduled to undergo first-line cytotoxic chemotherapy underwent PR consisting of 60-minute sessions twice a week under the guidance and supervision of a physical therapist, for a total of eight weeks. Feasibility was assessed based on completion of the PR program. In total, 12 patients (median age 68 years) were enrolled; 11 (91.7%) were male with a history of smoking. Among these 12 patients, 9 (75%) completed the eight-week outpatient-based PR program. Three patients could not complete the PR program: two were unwilling and one died from complications of lung cancer. This study showed a 75% completion rate of an eight-week outpatient-based PR program for advanced lung cancer patients undergoing cytotoxic chemotherapy, which supports its feasibility.

Small cell lung cancer mimicking lymphoma in CT and 68Ga-DOTA-NOC PET/CT: A case report.

RATIONALE: Small cell lung cancer accounts for 15-20% of all lung cancers and is the most common pulmonary neuroendocrine neoplasm. Most small cell lung cancers arise from lobar or main bronchi, the most common manifestations of small cell lung cancer is a large mass centrally located within the lung parenchyma or a mediastinal mass involving the hilus. Small cell lung cancer is easily ignored by clinicians without lung parenchyma and hilus involvement. Here, we report a case of small cell lung cancer, which was misdiagnosed as the lymphoma in contrast enhanced CT and Ga-DOTA-NOC PET/CT imagings. PATIENT CONCERNS: A 49-year-old male with chief complaint of discontinuous cough for 1 month. DIAGNOSES: Small cell lung cancer. INTERVENTIONS: Radiotherapy and chemotherapy were given thereafter. OUTCOMES: The case had multiple enlarged lymph nodes due to tumor progression. LESSONS: Small cell lung cancer is a malignant and progressive disease, and easy to be ignored in clinical. The case of small cell lung cancer without parenchyma and hilus involvement has never been reported before. Here, we report it and hope it provides a differential diagnosis for clinicians in the following similar cases.

POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer.

Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a trans-differentiation event in this disease.