Search

Lineage plasticity in small cell lung carcinoma (SCLC) causes therapeutic difficulties. This study aimed to investigate the pathological findings of plasticity in SCLC, focusing on combined SCLC, and elucidate the involvement of YAP1 and other transcription factors. We analysed 100 surgically resected SCLCs through detailed morphological observations and immunohistochemistry for YAP1 and other transcription factors. Component‐by‐component next‐generation sequencing (n = 15 pairs) and immunohistochemistry (n = 35 pairs) were performed on the combined SCLCs. Compared with pure SCLCs (n = 65), combined SCLCs (n = 35) showed a significantly larger size, higher expression of NEUROD1, and higher frequency of double‐positive transcription factors (p = 0.0009, 0.04, and 0.019, respectively). Notably, 34% of the combined SCLCs showed morphological mosaic patterns with unclear boundaries between the SCLC and its partner. Combined SCLCs not only had unique histotypes as partners but also represented different lineage plasticity within the partner. NEUROD1‐dominant combined SCLCs had a significantly higher proportion of adenocarcinomas as partners, whereas POU2F3‐dominant combined SCLCs had a significantly higher proportion of squamous cell carcinomas as partners (p = 0.006 and p = 0.0006, respectively). YAP1 expression in SCLC components was found in 80% of combined SCLCs and 62% of pure SCLCs, often showing mosaic‐like expression. Among the combined SCLCs with component‐specific analysis, the identical TP53 mutation was found in 10 pairs, and the identical Rb1 abnormality was found in 2 pairs. On immunohistochemistry, the same abnormal p53 pattern was found in 34 pairs, and Rb1 loss was found in 24 pairs. In conclusion, combined SCLC shows a variety of pathological plasticity. Although combined SCLC is more plastic than pure SCLC, pure SCLC is also a phenotypically plastic tumour. The morphological mosaic pattern and YAP1 mosaic‐like expression may represent ongoing lineage plasticity. This study also identified the relationship between transcription factors and partners in combined SCLC. Transcription factors may be involved in differentiating specific cell lineages beyond just 'neuroendocrine'. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation is believed to contribute to small cell lung cancer (SCLC) progression, but the underlying relationship remains unclear. Lipocalin‐2, a potential biomarker of inflammation, has been implicated in various cancers but its prognostic value in SCLC is underexplored. Methods: We retrospectively analyzed 191 patients with SCLC (72 with limited‐stage [LD] and 119 with extensive‐stage) treated using platinum‐based chemotherapy. Lipocalin‐2 expression was evaluated using immunohistochemistry. Optimal cutoff values for lipocalin‐2 and neutrophil‐to‐lymphocyte ratio (NLR) were determined using time‐dependent receiver operating characteristic curve analysis. The pectoralis muscle index was used to assess sarcopenia. Results: In LD‐SCLC, high lipocalin‐2 expression was associated with worse progression‐free survival (PFS; median: 7.0 vs. 15.9 months, p = 0.015) and overall survival (OS; median: 12.9 vs. 30.3 months, p = 0.035) compared with low lipocalin‐2 expression. Patients were stratified into three prognostic groups by combining lipocalin‐2 with NLR: low lipocalin‐2/low NLR, high lipocalin‐2/low NLR or low lipocalin‐2/high NLR, and high lipocalin‐2/high NLR (median PFS: 17.3 vs. 11.0 vs. 6.3 months, p = 0.004; median OS: 30.5 vs. 17.3 vs. 8.6 months, p = 0.002). Similar trends were observed when combining lipocalin‐2 with the pectoralis muscle index. High lipocalin‐2 expression was also associated with lower complete response rates (18.9% vs. 34.3%, p = 0.035). No significant prognostic implications were found for lipocalin‐2 in extensive‐stage SCLC. Conclusions: High lipocalin‐2 expression is potentially associated with poorer survival in LD‐SCLC. Combining lipocalin‐2 with other inflammation‐related markers could improve prognostic stratification. [ABSTRACT FROM AUTHOR]

A 69‐year‐old ex‐smoker Japanese man presented with a left mediastinal lymph node and left upper lobe tumour. Bronchoscopic biopsy specimens from the enlarged left mediastinal lymph node and left upper lobe tumour revealed small cell lung carcinoma (SCLC). He was treated with first‐line chemotherapy with carboplatin, etoposide, and atezolizumab for four courses and subsequent atezolizumab maintenance therapy. However, his left upper lobe lung tumour only increased in size, and left upper lobectomy revealed combined SCLC (adenocarcinoma and chondrosarcoma‐like features). Four months after lobectomy, liver metastasis of chondrosarcoma‐like features (similar to pathological findings of the left upper lobe tumour) were observed. Combined SCLC, including sarcomatous components, is rare and poorly responds to chemotherapy. The metastases of combined SCLC in this patient were of only one type of histological component, making diagnosis and treatment difficult. If treatment for SCLC responds inadequately, considering combined SCLC and actively re‐examining histological diagnosis is necessary. [ABSTRACT FROM AUTHOR]

Background: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1–0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features. Aims: We conducted a retrospective cohort study comparing the outcomes of extensive‐stage (ES) SCLC and EPSCC. Methods: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression‐free survival (PFS) and overall response rates (ORRs). Results: Three hundred and eighty‐four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5–1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58–1.46, P = 0.74) and ORR were 73% versus 68%. Conclusions: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is a rapidly progressive neuroendocrine carcinoma that, until recently, had a very small armamentarium of effective treatments. Advances in DNA sequencing and whole transcriptomics have delineated key subtypes; therefore, SCLC is no longer viewed as a homogeneous cancer. Chemoimmunotherapy with PD1 blockade is now the standard of care for advanced disease, and ongoing research efforts are moving this strategy into the limited stage setting. Combination strategies of immunotherapy with radiation are also under active clinical trial in both limited and extensive stage disease. Plain Language Summary: Small cell lung cancer (SCLC) is a rapidly progressive neuroendocrine carcinoma that, until recently, had a very small armamentarium of effective treatments.Chemoimmunotherapy with immune check point inhibitors is now the standard of care for advanced disease.This comprehensive review provides an overview of current treatment strategies for SCLC, unmet needs in this patient population, and emerging treatment strategies incorporating immunotherapy that will hopefully further improve outcomes for patients. Chemoimmunotherapy is the standard of care in front‐line extensive‐stage small cell lung cancer. The addition of immunotherapy for the treatment of patients with limited‐stage small cell lung cancer offers hope for improvement in survival. [ABSTRACT FROM AUTHOR]

Neuroendocrine carcinomas of the lung are currently classified into two categories: small-cell lung carcinoma and large-cell neuroendocrine carcinoma. Diagnostic criteria for small-cell and large-cell neuroendocrine carcinoma are based solely on tumour morphology; however, overlap in histologic and immunophenotypic features between the two types of carcinomas can potentially make their classification challenging. Accurate diagnosis of pulmonary neuroendocrine carcinomas is paramount for patient management, as clinical course and treatment differ between small-cell and large-cell neuroendocrine carcinoma. Molecular-genetic, transcriptomic, and proteomic data published over the past decade suggest that small-cell and large-cell neuroendocrine carcinomas are not homogeneous categories but rather comprise multiple groups of distinctive malignancies. Nuances in the susceptibility of small-cell lung carcinoma subtypes to different chemotherapeutic regimens and the discovery of targetable mutations in large-cell neuroendocrine carcinoma suggest that classification and treatment of neuroendocrine carcinomas may be informed by ancillary molecular and protein expression testing going forward. This review summarizes the current diagnostic criteria, prognostic and predictive correlates of classification, and evidence of previously unrecognised subtypes of small-cell and large-cell neuroendocrine carcinoma. [ABSTRACT FROM AUTHOR]

The IMpower133 regimen, composed of atezolizumab/etoposide (VP‐16)/carboplatin (CBDCA), is the standard first‐line treatment for extensive‐stage small cell lung cancer (ES‐SCLC). However, the safety and efficacy of triplet therapy in patients receiving dialysis have not been sufficiently evaluated. Here, we report two cases of dialysis patients with ES‐SCLC who received the modified IMpower133 regimen. Patient 1 was a 69‐year‐old man, and patient 2 was a 73‐year‐old man who received dialysis because of end‐stage renal failure caused by diabetic nephropathy. Both patients received a modified IMpower133 regimen in the following order: atezolizumab (1200 mg/body) on day 1, VP‐16 (50 mg/m2) on days 1 and 3, and CBDCA (300 mg/m2) on day 1. Four hours of dialysis was performed 1 hour after completing the administration of CBDCA on Day 1 and 2 hours after completing the administration of VP‐16 on Day 3. Both patients achieved a partial response and received atezolizumab maintenance therapy after four cycles of triplet therapy without uncontrollable adverse events. By modifying the dosage, the order of drugs, and the timing of dialysis, the IMpower133 regimen may be tolerable and effective for patients receiving dialysis. [ABSTRACT FROM AUTHOR]

REV7 is involved in multiple biological processes including DNA damage tolerance, cell cycle regulation and gene expression, and is an accessory subunit of the mutation‐prone DNA polymerase ζ. It has been reported that REV7 expression is associated with poor prognosis in several human cancers. The aim of this study is to investigate the significance of REV7 in lung carcinogenesis. Immunohistochemical analyses of surgically resected lung cancer specimens revealed that REV7 shows an increased expression in small cell lung carcinomas (SCLCs) when compared with other histological types of lung carcinoma. Association between REV7 expression levels and clinicopathological factors was investigated using SCLC cases with or without surgical resection. Our analyses revealed that high REV7 expression significantly correlated with tumor cell proliferation, assessed by Ki‐67 labeling indices, and was negatively associated with distant metastasis and extensive‐stage disease. No significant association was detected between REV7 expression and other factors, including prognosis or response to chemoradiotherapy in SCLC. Increase in REV7 expression in SCLC was confirmed using SCLC cell lines. In addition, siRNA‐mediated depletion of REV7 activated the apoptotic pathway and suppressed cell growth in SCLC cells. These results suggest that REV7 plays an important role in tumor cell survival and proliferation in SCLC. [ABSTRACT FROM AUTHOR]

Background: A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study.Methods: The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients).Results: Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule.Conclusions: To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: Clinical impact of the Geriatric Nutritional Risk Index (GNRI) in patients with extensive‐stage disease small cell lung cancer (ED‐SCLC) have not previously been reported. Methods: This study analyzed 352 patients enrolled in a previous randomized phase III trial comparing the efficacy of irinotecan plus cisplatin with that of etoposide plus cisplatin as the first‐line therapy for ED‐SCLC. GNRI values were calculated using serum albumin levels and actual and ideal bodyweights. Patients with a GNRI > 98, 92–98, and <92 were grouped into no, low, and moderate/major risk groups, respectively. Results: The objective response rates were 63.2%, 52.6%, and 49.2% in the no, low, and moderate/major risk groups, respectively (P = 0.024). The median progression‐free survival (PFS) was shorter in patients with a lower GNRI than in those with a higher GNRI (no vs. low vs. moderate/major risk group; 6.5 vs. 5.8 vs. 5.9 months, respectively; P = 0.028). There were significant differences in median overall survival (OS) according to GNRI (no vs. low vs. moderate/major risk group; 13.2 vs. 10.3 vs. 8.4 months, respectively; P < 0.001). Multivariate analysis revealed that being in the moderate/major risk group was an independent poor prognostic factor for PFS (hazard ratio [HR]: 1.300, 95% confidence interval [CI]: 1.012–1.670; P = 0.040) and OS (HR: 1.539; 95% CI: 1.069–2.216; P = 0.020). Conclusions: This prospective study shows that a low GNRI value was associated with a poor prognosis, and it supports the relationship between systemic inflammation, nutritional status, and clinical outcomes in patients with ED‐SCLC.Key points Significant findings of the study: The lower GNRI group had a low response rate to chemotherapy for ED‐SCLC. The HRs for PFS and OS were 1.300 and 1.539 in the patients with GNRI < 92. What this study adds: Low GNRI is associated with poor prognosis in ED‐SCLC. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is a unique tumor that has a distinct clinical behavior and dismal prognosis. If untreated, it can become aggressively malignant, and life expectancy could be limited to weeks. Spontaneous regression of lung cancer has rarely been reported, and among them SCLC is even rarer. The underlying mechanisms of spontaneous regression are poorly understood. Here, we report a case of complete spontaneous SCLC remission in an elderly patient. [ABSTRACT FROM AUTHOR]

Keywords: paraneoplastic cerebellar syndrome; vestibulo-ocular reflex; flocculo-nodular lobe; small cell lung carcinoma EN paraneoplastic cerebellar syndrome vestibulo-ocular reflex flocculo-nodular lobe small cell lung carcinoma 1134 1136 3 10/05/21 20211001 NES 211001 Zinc finger protein 4 (Zic4) antibodies occur as paraneoplastic cerebellar syndrome (PCS) in subjects with small cell lung carcinoma (SCLC).1Oscillopsia as presenting feature of Zic4 antibody associated paraneoplastic neurological syndrome (PNS) has not been reported. Positron emission tomography (PET) CT showed hypermetabolic heterogeneously enhancing lesion in the upper lobe of right lung with ipsilateral mediastinal adenopathy and right adrenal metastasis (Fig. [Extracted from the article]

Background: The aim of this study was to identify subgroups with good or bad prognosis in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) based on immunostaining patterns with neuroendocrine markers and compare them with small cell lung carcinoma (SCLC). Methods: From January 2001 to December 2017, of all patients with resected LCNEC and SCLC, we selected patients whose pathological tumor sizes were ≤30 mm in diameter (defined as small‐sized tumors) and who underwent complete resection with lymphadenectomy. We classified patients with small‐sized LCNEC (sLCNEC) into two subgroups based on immunostaining patterns with three neuroendocrine markers (chromogranin A, synaptophysin, and NCAM) and compared them to small‐sized SCLC (sSCLC). Results: A total of 48 patients with sLCNEC and 39 patients with sSCLC were enrolled. Of 48 patients with sLCNEC, 21 were categorized as the small‐sized triple‐positive group (sTP), whose patients were positive for the three neuroendocrine markers, and 27 patients were categorized as the small‐sized nontriple‐positive group (sNTP), whose patients were not positive for all three neuroendocrine markers. The percentage of lymph node metastasis was significantly lower in sNTP than in sTP and sSCLC. There was no significant difference in overall survival, but recurrence‐free survival (RFS) and tumor‐specific survival (TSS) were significantly poorer in sTP and sSCLC than in sNTP. Multivariate analysis revealed sTP and sSCLC were independent prognostic factors for poorer RFS and TSS than those of sNTP. Conclusions: The sNTP subgroup had a good prognosis and the sTP subgroup a poor prognosis. There were some similarities in clinicopathological features between sTP and sSCLC. [ABSTRACT FROM AUTHOR]

Background: In recent years, insulinoma‐associated protein 1 (INSM1) has been shown to be a key regulator of neuroendocrine development, and it has been evaluated for diagnostic use in some organs. Methods: To evaluate the relationship between INSM1 and synaptophysin, and to confirm the cutoff value using receiver operating characteristic curve (ROC) analysis, the authors performed INSM1 immunocytochemistry using cell block (CB) samples from 53 cases of bronchial brushings and 32 cases of pleural effusions (29 small cell lung cancer [SCLC] specimens and 56 non–small cell lung cancer specimens). The marker expression ratio was calculated by counting the positive tumor cells, and the tumor proportion score (TPS) was applied. Results: INSM1 was expressed in all SCLC specimens, but generally was expressed in <10% of tumor cells in adenocarcinomas. In bronchial brushing samples of SCLC, the INSM1 TPS was 37.5% (staining of >50%), 25.0% (staining of 25%‐50%), 29.5% (staining of 10%‐25%), and 8.3% (staining of 1%‐10%). There were 3 cases (12.5%) with no detectable synaptophysin expression, although the correlation between nuclear INSM1 expression and cytoplasmic synaptophysin expression was statistically significant (P < .001). Receiver operating characteristic curve analysis indicated that 8.68% was the best cutoff value for INSM1, and the sensitivity and specificity between SCLC and non–small cell lung cancer for expression of INSM1 were 95.8% and 100.0%, respectively, in bronchial brushing samples at that cutoff value. Conclusions: INSM1 is a novel diagnostic marker for SCLC, and is useful in both bronchial brushing and pleural effusion cytology specimens. Because INSM1 generally is expressed in <10% of tumor cells in adenocarcinomas, determining an accurate cutoff value for INSM1 is important in the diagnosis of SCLC. Routine cytological evaluation can reliably diagnose small cell lung cancer (SCLC), and immunohistochemistry stains can be used if there is uncertainty regarding the diagnosis. Expression of insulinoma‐associated protein 1 is a novel diagnostic marker for SCLC and is useful in both bronchial brushing and pleural effusion cytology specimens. [ABSTRACT FROM AUTHOR]

Background: In a significant percentage of patients with small cell lung carcinoma (SCLC), cytology samples represent the only source of tumor tissue. Ancillary immunocytochemistry (ICC) for neuroendocrine markers is an important adjunct for the diagnosis of SCLC. Insulinoma‐associated protein 1 (INSM1) is a novel neuroendocrine marker proposed as an economical single‐marker alternative to the traditional 3‐marker panel of chromogranin, synaptophysin, and CD56. To the authors' knowledge, limited studies have evaluated INSM1 immunohistochemistry (IHC) for the diagnosis of SCLC and reported high sensitivities and specificities. The objective of the current study was to evaluate the sensitivity and specificity of INSM1 ICC on direct smears (DS) from patients with SCLC in comparison with IHC on small biopsies (SBs). Methods: All available DS and SBs from patients with SCLC who were diagnosed over the previous year were retrieved. Immunostaining for INSM1 was performed on alcohol‐fixed DS and formalin‐fixed SBs wherever available. A total of 10 DS and SBs from patients with non–small cell lung carcinoma were included for comparison. Nuclear staining for INSM1 in ≥1% tumor cells was interpreted as positive. Results: Among a total of 60 patients with SCLC who were included in the current study, a total of 37 underwent INSM1 IHC on SBs and 36 underwent INSM1 ICC on DS. ICC was noninterpretable in 3 DS due to necrosis. The sensitivity of INSM1 IHC was 97% (36 of 37 cases) whereas the sensitivity of INSM1 ICC was 91% (30 of 33 cases) for the diagnosis of SCLC. Among matched IHC and ICC results available for 11 patients, 91% of cases (10 of 11 patients) demonstrated concordant IHC‐ICC staining. All cases of non–small cell lung carcinoma were negative for INSM1 (100% specificity). Conclusions: INSM1 appears to be a robust and reliable ICC marker for the confirmation of SCLC diagnosis on cytology smears. Immunocytochemistry for insulinoma‐associated protein 1 (INSM1) can be performed reliably on alcohol‐fixed direct smears with high sensitivity and specificity for the confirmatory diagnosis of small cell lung carcinoma. The nuclear localization of INSM1 allows for the easy and objective interpretation of staining results in tumor cells. [ABSTRACT FROM AUTHOR]

Background: The classification of large cell neuroendocrine carcinoma (LCNEC) has generated considerable debate and has been revised since its recognition as a separate entity. Although it shares clinical features with small cell lung carcinoma (SCLC) and was classified with SCLC in the 2015 World Health Organization classification system, numerous studies have revealed inferior treatment outcomes of LCNEC when it was treated as SCLC. Because the incidence of LCNEC is rare, its mutational landscape has not been comprehensively interrogated. Methods: We performed capture‐based ultra‐deep targeted sequencing on tumor samples of LCNEC, large cell carcinoma (LCC), and SCLC to elucidate its biological relationship with these subtypes and to identify potentially targetable molecular alterations. Results: Our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC. A majority (60%) of LCNEC patients harbored copy number variations (CNVs). Interestingly, there were no common CNVs shared among the three subtypes: NFкBIA amplification was shared between LCNEC and LCC, while AKT2 amplification was shared between LCNEC and SCLC. Furthermore, genetic alterations in the PI3K/AKT/mTOR pathway were enriched in all three subtypes. Conclusion: Despite the histological and/or morphological similarities among LCNEC, LCC, and SCLC, our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC, which has the potential to be used as a panel of biomarkers to distinguish LCNEC from a molecular perspective. Furthermore, the molecular distinction among the three subtypes can also be reflected from CNV events. [ABSTRACT FROM AUTHOR]

Atezolizumab was the first immune checkpoint inhibitor (ICI) to be introduced as a first‐line treatment option for extensive‐stage small cell lung cancer (ES‐SCLC), in combination with carboplatin and etoposide (CE) chemotherapy. However, SCLC treatment options after progression to first‐line chemotherapy are limited, warranting the readministration of previously used drugs. In combination with atezolizumab, CE readministration may theoretically be effective, based on two tentative mechanisms: its additive and synergistic effects on cytotoxic chemotherapy. The additive effect is based on the IFCT‐1603 trial in which the Kaplan‐Meier estimates of both progression‐free survival (PFS) and overall survival (OS) in the atezolizumab group exhibited a tail plateau in the selected population. Conversely, an anti‐PD‐L1 antibody synergistic effect on platinum compounds was assessed in a preclinical study, which was reinforced by clinical data. Thus, atezolizumab in combination with CE may be a treatment option in heavily treated patients. Here, we describe the first case of a heavily treated ES‐SCLC patient treated with chemoimmunotherapy, resulting in a partial response and a durable PFS. Key points: Significant findings of the study and what this study adds: CE readministration with atezolizumab may be effective based on two tentative mechanisms. Additive and synergistic effects of atezolizumab on CE have been previously suggested via a clinical trial and preclinical study, respectively. This is reflected in the current case in clinical settings. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is an aggressive disease with a high potential for brain metastases. Treatment for metastatic SCLC is systemic chemotherapy, but the median overall survival remains poor. Cranial irradiation for palliative purposes using whole brain radiotherapy is the standard‐of‐care for patients with symptomatic brain metastases. However, few reports showed a prolonged survival in SCLC patients with solitary brain metastasis treated with a definitive intent. We report a case of a 62‐year‐old man who presented with solitary brain metastasis secondary to SCLC who was successfully treated with definitive radiotherapy to the primary lesion and the solitary brain metastasis, and followed up for 2 years. [ABSTRACT FROM AUTHOR]

Background: The importance of nutritional status and chronic inflammation has been emphasized in cancer. We investigated the impact of Onodera's prognostic nutritional index (OPNI) on clinical outcomes in small cell lung cancer (SCLC) patients. Methods: Data from 220 SCLC patients treated with first‐line platinum‐based chemotherapy from 2006 to 2017 were retrospectively reviewed. The OPNI was calculated as 10 × serum albumin level (g/dL) + 0.005 × absolute lymphocyte count (/mm3). Patients with an OPNI of > 45, 40–45, or < 40 were categorized in high, intermediate, or low OPNI groups, respectively. Results: The proportion of non‐responders to first‐line therapy increased as the OPNI decreased (high, intermediate, low OPNI groups: 6.7%, 18.0%, and 30.8%, respectively; P < 0.001). Early discontinuation of first‐line therapy because of treatment toxicity occurred more frequently in the lower OPNI groups (high, intermediate, low OPNI groups: 5.8%, 21.3%, and 25.6%, respectively; P < 0.001). The one‐year progression‐free and overall survival rates in the high, intermediate, and low OPNI groups were 29%, 19%, and 3%, and 61%, 46%, and 23%, respectively. In multivariate analyses, the low OPNI group was independently associated with poor progression‐free (hazard ratio 1.592; 95% confidence interval 1.009–2.511; P = 0.046) and overall (hazard ratio 1.911; 95% confidence interval 1.208–3.024; P = 0.006) survival compared to the high OPNI group. Conclusion: SCLC patients with an OPNI < 40 showed a low tolerance to chemotherapy and a poor prognosis. Further evaluation is needed to validate these findings. [ABSTRACT FROM AUTHOR]

BACKGROUND Small cell lung cancer (SCLC) is a highly aggressive neoplasm that accounts for approximately 10% to 15% of lung cancers. In most cases, the diagnosis relies on cytology and needs to be confirmed by immunohistochemistry. Although several genetic and molecular abnormalities have been recorded, molecular markers able to predict the prognosis are still lacking. MicroRNA (miRNA) signatures have been recently proposed as useful biomarkers in lung cancer because of their high stability during standard sample processing. METHODS Cytological samples for 50 patients with SCLC were collected from primary tumors (n = 25) and metastases (n = 25) by means of fine-needle aspiration (FNA) or bronchial washing (BW); they were fixed in ethanol (FNA) or Duboscq-Brazil fluid (BW). The 3-miRNA panel expression (miR-192, miR-200c, and miR-205) was quantified with a TaqMan polymerase chain reaction miRNA assay and was compared with overall survival (OS) and clinicopathological data. RESULTS All samples had sufficient RNA for the miRNA expression analysis to be performed, regardless of the sample source or the fixative medium. Patients with a low expression level of the 3-miRNA panel were associated with better OS in univariate ( P = .032) and multivariate analyses ( P = .022). Moreover, in the group of patients older than the mean age of our cohort (65.8 years), a significant OS advantage ( P = .013) was seen for patients with a low expression level of the 3-miRNA panel. CONCLUSIONS A specific 3-miRNA signature is potentially useful for predicting survival for patients with SCLC, and it may be feasible with cytological samples taken during standard diagnostic procedures. Cancer Cytopathol 2016;124:621-9. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Cytology is an accurate, safe, cost-effective, and guideline-recommended method for the diagnosis of small cell lung carcinoma (SCLC), but little is known about whether its use varies by treatment facility and patient characteristics. METHODS Methods of diagnosis (cytology vs histology) for 86,830 patients with SCLC from 1314 facilities that contributed data to a nationwide registry and associations of diagnostic methods with patient and facility characteristics were studied in bivariate and multivariate analyses. RESULTS The percentages of SCLC cases diagnosed by cytology in community cancer programs, comprehensive community cancer programs, academic cancer programs, and National Cancer Institute-designated cancer centers were 13.2%, 15.4%, 23.3%, and 31.3%, respectively ( P < .0001). The corresponding prevalence ratios (and 95% confidence intervals [CIs]) of cytologic diagnosis using multivariate marginal logistic regression models and National Cancer Institute-designated cancer centers as the referent category were 0.45 (95% CI, 0.36-0.57), 0.52 (95% CI, 0.42-0.64), and 0.78 95% CI, (0.62-0.96), respectively. In contrast, the use of cytology varied little by patient demographic and clinical factors. CONCLUSIONS The substantial variation among different types of cancer centers in their use of cytology for the diagnosis of SCLC suggests a need for additional research to study reasons for these differences as well as quality-improvement interventions to encourage adherence to guidelines for SCLC diagnosis. Cancer (Cancer Cytopathol) 2016;124:44-52. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background To investigate whether the response to induction chemotherapy ( IC) would impact the timing of thoracic radiotherapy ( TRT) in limited-stage small-cell lung cancer ( LS-SCLC). Methods A total of 146 patients with LS-SCLC who had received two to six cycles of IC followed by TRT from January 2009 to December 2011 at our hospital were included in this study. Patients were divided into two groups based on the time TRT was administered: early TRT (administered after 2-3 cycles of chemotherapy) or late TRT (administered after 4-6 cycles). Overall survival ( OS) and progression-free survival ( PFS) were analyzed using the Kaplan- Meier method. Multivariate Cox regression analysis was performed to evaluate the independent factors affecting survival. Results The median OS for patients who received early TRT and late TRT was 29.0 and 19.9 months, respectively, ( P = 0.018) and the median PFS was 18.5 and 13.8 months, respectively ( P = 0.049). In patients who achieved complete remission ( CR) or partial remission ( PR) after two to three cycles of IC, the median OS was 36.1 and 22.5 months in the early and late TRT subgroups, respectively ( P = 0.009); the corresponding median PFS was 20.2 and 13.8 months, respectively ( P = 0.038). In the patients who did not achieve CR or PR, no statistic difference was found in OS or PFS between the two subgroups. Conclusion Patients who received early TRT had more favorable outcomes than those who received late TRT. Patients who achieved CR or PR after two to three cycles of IC obtained more benefit from early TRT. [ABSTRACT FROM AUTHOR]

Third and fourth line chemotherapy agents are not helpful in the setting of extensive stage small cell lung cancer ( SCLC). We describe the case of a 43-year-old Korean patient with T4N3M1b extensive stage SCLC who responded remarkably well to treatment and experienced a prolonged progression-free survival ( PFS) period following treatment with fourth line ifosfamide and carboplatin after experiencing disease progression with three previous regimens. Additionally, third line cyclophosphamide, doxorubicin (Adriamycin), and vincristine demonstrated long-term PFS periods. [ABSTRACT FROM AUTHOR]

Airway metastasis from primary lung carcinoma is rare and typically associated with non-small cell histology. While small cell lung cancer is a particularly aggressive form of cancer, few cases of endotracheal or endobronchial metastasis have been reported. Airway involvement can go undetected because of the spread along the perilymphatic drainage system with mostly submucosal involvement causing significant airway compromise before onset of symptoms. We present a patient with recurrent small cell lung cancer, presenting with wheezing, cough, and dyspnea as a result of metastasis to the trachea and bilateral bronchi without significant mediastinal or hilar lymphadenopathy. We discuss the related literature, as well as the suspected pathophysiology causing this unique presentation. [ABSTRACT FROM AUTHOR]

The prognosis of small cell lung cancer ( SCLC) remains poor with a 5-year survival rate of 4-6%. In non-small cell lung cancer ( NSCLC), high levels of intact and cleaved forms of the receptor for urokinase plasminogen activator ( uPAR) are significantly associated with short overall survival. Our aim was therefore to determine the prognostic value of the different uPAR forms in blood from SCLC patients. Serum samples from 92 treatment naive SCLC patients were analysed. Intact uPAR, uPAR(I-III), intact and cleaved uPAR, uPAR(I-III) + uPAR(II-III) and the liberated domain I, uPAR(I) were measured using time-resolved fluorescence immunoassays ( TR- FIA 1-3). Assessment of association of the uPAR forms to overall survival ( OS) was done using Cox regression analysis adjusted for clinical covariates [age, gender, stage, lactate dehydrogenase ( LDH), WHO performance status ( PS)]. Multivariate survival analysis demonstrated that high levels of uPAR(I) were significantly (p = 0.009) associated with short overall survival ( OS). Patients with uPAR(I) levels above the second tertile had a hazard ratio ( HR) of 1.9 (95% confidence interval ( CI): 1.1-3.3), compared to patients with levels below the first tertile. High serum uPAR(I) levels are associated with short OS in SCLC patient, independent of LDH and PS. [ABSTRACT FROM AUTHOR]

The article investigates the efficacy of simvastatin in combination with irinotecan and cisplatin in chemotherapy-naive patients with extensive-disease small-cell lung cancer (ED-SCLC). The results indicate that efficacy of the treatment is affected by smoking status. The study also showed that ever-smokers had a better response rate (RR), a longer progression-free survival (PFS), and had a trend toward an improved overall survival (OS) than those who never smoked.

The aim of the present study was to clarify protein profiling in small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC). The proteomic approach was used, and involved cell lysate from two cell lines (N231 derived from SCLC and LCN1 derived from LCNEC), with 2-D gel electrophoresis (2-DE). In the present study, 25 protein spots with greater than twofold quantitative differences between LCN1 and N231 cells on 2-DE gels were confirmed. Within the 25 identified proteins, cytokeratins (CK) 7, 8, 18 and 19 were upregulated in LCN1 cells compared with N231 cells. The expression of CK7, 8, 18, and 19 was further studied on immunohistochemistry with 81 formalin-fixed and paraffin-embedded pulmonary carcinomas, which included 27 SCLC, 30 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas. Although the expression of CK7, 8, 18, and 19 was observed in all histological types, the mean immunostaining scores of CK7, 8, 18, and 19 were significantly higher in LCNEC than in SCLC ( P < 0.001, P < 0.001, P < 0.01 and P < 0.001, respectively). These data suggest that the biological characteristics of LCNEC and SCLC may be different and the expression of CK may serve as differential diagnostic markers. [ABSTRACT FROM AUTHOR]

Metastasis to palatine tonsils are rare, accounting from only 0.8% of all tonsillar tumors, so far only 100 cases reported in the English literature. Only a few cases have been reported for small cell and non-small cell lung cancer as a primary site. With a diagnosis of small cell lung cancer, a 68-year-old male patient relapsed after six cycles of chemotherapy in tonsilla palatina and cervical lymph nodes. Patients died 26 months after being diagnosed with lung cancer and 2 months after detection of tonsil metastasis. We present the current case report because of the rarity of metastasis to tonsil in lung cancer. [ABSTRACT FROM AUTHOR]

Large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) are high-grade neuroendocrine carcinomas. In order to clarify the similarities and differences between these cancers, 22 cases each of LCNEC and SCLC were collected and a comparative pathological study was carried out. First, their clinicopathological characteristics were confirmed, which were very similar to those previously reported. The 5 year survival rate of LCNEC and SCLC patients was 38.3% and 29.7%, respectively. The morphological characteristics of LCNEC and SCLC were then reviewed with regard to the morphology previously used to differentiate these cancers. As a result, many morphological indicators, such as tumor cell size, nuclear/cytoplasmic ratio, nuclear molding, rosette formation, prominent nucleoli and karyolysis were confirmed to be significant indicators for distinguishing LCNEC from SCLC. On comparative immunohistochemistry, LCNEC had significantly high staining scores for the expression of keratin 7 and 18, E- and P-cadherins, β-catenin, villin 1, retinoblastoma protein (pRB), c-met and α-enolase. These results might reflect the differentiation or deviation of LCNEC toward an epithelial nature irrespective of neuroendocrine tumor lineage. In conclusion, the present comparative study of LCNEC and SCLC defined the similarities and differences between these cancers, and showed the biologically and clinicopathologically overlapping spectrum of the tumor lineage. [ABSTRACT FROM AUTHOR]

Background: Estimates of ideal radiotherapy utilization in lung cancer range from 61% to 74%. Actual utilization rates are lower than this. The aim of the present study was to identify those groups where there was the greatest discrepancy between actual and ideal utilization. Methods: The study population consisted of South-Western Sydney Area Health Service residents who were diagnosed with lung cancer in 1993 or 1996. A clinical audit of medical records was performed to collect details on patient demographics, tumor factors, treatment details and outcome. Results: There were 527 patients diagnosed with lung cancer. Treatment data were available for 499 (95%) patients of which 279 (56%) received radiotherapy. Radiotherapy utilization declined with increasing age and decreasing performance status. When comparing actual with ideal utilization, the greatest shortfall in radiotherapy was seen in small cell lung cancer (55% vs 79%) followed by stage I (35% vs 50%) and IV non-small cell lung cancer (65% vs 83%). There was under-utilization of chest radiotherapy (79% vs 88%) and definitive radiotherapy (14% vs 50%). Conclusions: Definitive chest radiotherapy is underutilized in lung cancer, particularly in patients with limited stage small cell lung cancer and stage I non-small cell lung cancer. This is partly due to non-referral of patients but also a palliative approach by radiation oncologists. These factors have to be addressed in order to optimize survival and quality of life for lung cancer patients. [ABSTRACT FROM AUTHOR]

Aims: Most small cell lung carcinoma (SCLC) patients have metastatic disease at the time of diagnosis and are faced with poor prognosis and limited treatment options. Reports of HER-2/ neu gene amplification and overexpression in this malignancy have raised the possibility of applying targeted immunotherapy with trastuzumab, the monoclonal antibody used to treat metastatic breast cancer. However, a review of the studies measuring HER-2/ neu gene amplification and protein expression in SCLC reveals discordant results. The aim of the present study was to re-examine HER-2/ neu expression in SCLC in relation to gene copy number using the new, highly sensitive, immunofluorescence automated quantitative analysis (AQUA) technology. Methods and results: Fluorescence in situ hybridization (FISH) was used to measure HER-2/ neu gene copy number and amplification status and AQUA was used to measure protein expression in a series of 23 SCLC tumours on a tissue microarray. None of the 17 SCLC specimens assessable by FISH exhibited HER-2/ neu gene amplification as defined by a HER-2/ neu/chromosome 17 ratio = or > 2. Twelve of 17 (70.1%) SCLC samples were polysomic for chromosome 17 with corresponding increases in HER-2/ neu gene copy numbers. Intermediate levels of protein expression corresponding to AQUA scores in the range of 4–24 were detected in all 23 specimens. High protein expression levels corresponding to AQUA scores up to 83, observed previously in association with gene amplification and poor prognosis in breast cancer cases, were not detected in the present study. No statistically significant association was observed between absolute chromosome 17 or HER-2/ neu gene copy numbers and protein expression levels in tumour cells ( P > 0.45). Conclusions: The lack of gene amplification and robust HER-2/ neu protein expression in SCLC tumour cells in this series does not suggest a prominent role for the HER-2/ neu gene in SCLC tumour progression and does not support the general applicability of targeted immunotherapy with trastuzumab to this malignancy. [ABSTRACT FROM AUTHOR]

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a new entity. Besides morphological characteristics, its molecular biological features have been investigated by many researchers and compared to those of other neuroendocrine carcinomas, small cell lung carcinoma (SCLC) and carcinoid tumor (CT). However, there are few reports that show the significantly different genetic characteristics between them. The purpose of the present paper was to study the frequency of loss of heterozygosity (LOH) at chromosome 3p (3p14.2) in 38 neuroendocrine carcinomas of the lung (13 LCNEC, 11 SCLC and 14 CT) and 10 large cell carcinomas (LCC). The frequencies of LOH at 3p14.2 were 69.2% in LCNEC, 81.8% in SCLC, 50.0% in LCC and 7.14% in CT. Those at 22q13.3 were 30.8% in LCNEC, 72.7% in SCLC, 45.5% in LCC and 7.14% in CT. In particular, the frequency of SCLC with LOH at both 3p14.2 and 22q13.3 (63.6%) was significantly higher than that of LCNEC (15.4%). LCNEC and SCLC had different characteristics of LOH patterns at 3p14.2 and 22q13.3. The combined analysis of the LOH at 3p14.2 and 22q13.3 is thought to be useful for differential diagnosis between LCNEC and SCLC. [ABSTRACT FROM AUTHOR]

We report a rare case of metastasis-induced acute pancreatitis (MIAP) from small cell lung cancer (SCLC) diagnosed on autopsy, indicating a diagnosis of MIAP with SCLC. Our case suggests that MIAP can arise as a complication of SCLC and has an extremely poor prognosis. [ABSTRACT FROM AUTHOR]

Lung cancer may rarely appear with a solitary rectal metastasis and no other metastases. We report the first case of primary small cell lung cancer presenting with a solitary rectal metastasis in a 62-year-old man. Chest computed tomography revealed a soft tissue lesion in the subcarinal area. Following bronchoscopic biopsy, the patient was diagnosed with small cell lung cancer. The rectal mass was incidentally found during an imaging study for staging work-up. Histological examination revealed that the rectal mass was consistent with metastasis from small cell lung cancer. We suggest that clinicians should consider the possibility of rectal metastasis in small cell lung cancer patients with rectal masses. [ABSTRACT FROM AUTHOR]