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• W2981994259 abstract "SCLC is an aggressive disease with a dismal outcome and 5-year survival rates rarely exceeding 10%. Although the armamentarium of antineoplastic agents was recently expanded with immunotherapeutic options, only a minority of patients experience durable treatment benefits. The written history of neurologic paraneoplastic syndromes (PNSs) that were clearly associated with malignancies of the lung starts as early as in 1948, when two cases of progressing ataxia and sensory loss showed the diagnosis of lung cancer at autopsy and were subsequently reported by Denny-Brown after having lost the medical records for 10 years as a result of the disasters of the Second World War.1Denny-Brown D. Primary sensory neuropathy with muscular changes associated with carcinoma.J Neurol Neurosurg Psychiatry. 1948; 11: 73-87Crossref PubMed Scopus (262) Google Scholar Since then, our understanding of PNSs has evolved and a wide variety of endocrine, dermatologic, hematologic, rheumatologic, and ophthalmological syndromes, as well as glomerulopathy and coagulopathy, have been recognized. PNSs occur in various cancer types but predominately in SCLC. Neurologic PNSs occur in 3% to 5% of patients with SCLC. They are considered clinical manifestations of humoral or cellular antitumor autoimmune responses against neuronal proteins expressed by tumor cells. The discovery that onconeural autoantibodies are present in up to 50% of patients with neurologic PNS2Honnorat J. Antoine J.-C. Paraneoplastic neurological syndromes.Orphanet J Rare Dis. 2007; 2: 22Crossref PubMed Scopus (217) Google Scholar has both granted insight into its pathogenesis and facilitated making the correct diagnosis.3Graus F. Delattre J.Y. Antoine J.C. et al.Recommended diagnostic criteria for paraneoplastic neurological syndromes.J Neurol Neurosurg Psychiatry. 2004; 75: 1135-1140Crossref PubMed Scopus (1235) Google Scholar The diagnosis of PNS, however, remains challenging, often requires an interdisciplinary approach, and often is finally made after the exclusion of other plausible causes. With the recognition of PNS as a tumor-associated phenomenon, its prognostic impact has been investigated. Endocrinologic PNSs are correlated with higher tumor burden and advanced-disease stage and are associated with an inferior prognosis.4Hiraki A. Ueoka H. Takata I. et al.Hypercalcemia-leukocytosis syndrome associated with lung cancer.Lung Cancer. 2004; 43: 301-307Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 5Takai E. Yano T. Iguchi H. et al.Tumor-induced hypercalcemia and parathyroid hormone-related protein in lung carcinoma.Cancer. 1996; 78: 1384-1387Crossref PubMed Scopus (43) Google Scholar, 6Collichio F.A. Woolf P.D. Brower M. Management of patients with small cell carcinoma and the syndrome of ectopic corticotropin secretion.Cancer. 1994; 73: 1361-1367Crossref PubMed Scopus (40) Google Scholar, 7Dimopoulos M.A. Fernandez J.F. Samaan N.A. Holoye P.Y. Vassilopoulou-Sellin R. Paraneoplastic Cushing's syndrome as an adverse prognostic factor in patients who die early with small cell lung cancer.Cancer. 1992; 69: 66-71Crossref PubMed Scopus (63) Google Scholar Additionally, a relevant number of patients eventually die of complications related to the PNS (e.g., fatal infections in Cushing syndrome). In contrast, the presence of neurologic PNS has been linked to a favorable outcome in some reports. Notably, in approximately 80% of all cases, neurologic PNS precedes clinically overt cancer, allowing diagnosis and treatment of SCLC in earlier disease stages.2Honnorat J. Antoine J.-C. Paraneoplastic neurological syndromes.Orphanet J Rare Dis. 2007; 2: 22Crossref PubMed Scopus (217) Google Scholar Although superior outcome related to neurologic PNS may thus be a result of lead time bias, there are also several anecdotal reports on spontaneous regression of SCLC without treatment in patients with onconeural antibodies.8Mawhinney E. Gray O.M. McVerry F. McDonnell G.V. Paraneoplastic sensorimotor neuropathy associated with regression of small cell lung carcinoma.BMJ Case Rep. 2010; PubMed Google Scholar, 9Hirano S. Nakajima Y. Morino E. et al.A case of spontaneous regression of small cell lung cancer with progression of paraneoplastic sensory neuropathy.Lung Cancer. 2007; 58: 291-295Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 10Gill S. Murray N. Dalmau J. Thiessen B. Paraneoplastic sensory neuronopathy and spontaneous regression of small cell lung cancer.Can J Neurol Sci. 2003; 30: 269-271Crossref PubMed Scopus (45) Google Scholar Given the autoimmune nature of neurologic PNS, there is a possibility that an effective host immune response directed against both the cancer and the nervous system may modulate the course of the disease. In this issue of the Journal of Thoracic Oncology, Iams et al.11Iams W.T. Shiuan E. Meador C.B. et al.Improved prognosis and increased tumor-infiltrating lymphocytes in patients who have SCLC with neurologic paraneoplastic syndromes.J Thorac Oncol. 2019; 14: 1970-1981Abstract Full Text Full Text PDF Scopus (29) Google Scholar describe and analyze what is to date the largest cohort of patients with SCLC with neurologic or endocrinologic PNS. In a retrospective analysis, they identified 25 patients with SCLC with neurologic PNS, 30 patients with SCLC with endocrinologic PNS, and 90 control patients with SCLC without any clinical signs of PNS. Patients with neurologic PNS showed favorable overall survival compared with patients with endocrinologic PNS and controls (median overall survival 24 months versus 12 months versus 13 months, respectively). Despite the limitations of a single-center retrospective study and a heterogeneous, partly unbalanced study population, these findings are remarkable and hypothesis generating. Here, Iams et al.11Iams W.T. Shiuan E. Meador C.B. et al.Improved prognosis and increased tumor-infiltrating lymphocytes in patients who have SCLC with neurologic paraneoplastic syndromes.J Thorac Oncol. 2019; 14: 1970-1981Abstract Full Text Full Text PDF Scopus (29) Google Scholar hypothesize that improved prognosis in patients with neurologic PNS is related to tumor-infiltrating lymphocytes and programmed cell death 1 (PD-1) –programmed death ligand 1 (PD-L1) interactions. The authors therefore performed immunohistochemistry on formalin-fixed, paraffin-embedded tumor biopsy samples available from a subset of patients. Indeed, they found increased CD3 levels and trends toward increased levels of CD4- and CD8-positive T-cell infiltrates in tumors from patients with SCLC with neurologic PNS compared with in tumors from controls. Samples from patients with SCLC with neurologic PNS also showed increased CD3-, CD4-, and CD8-positive tumor cell infiltrates as compared with samples from patients with SCLC with endocrinologic PNS. Evaluation of a PD-1–PD-L1 interaction score revealing coexpression of both markers on cells in close proximity to each other showed increased PD-1–PD-L1 interactions in samples from patients with neurologic PNS versus in samples from patients with endocrinologic PNS, but not versus in samples from patients with no PNS. Consequently, in this study, Iams et al.11Iams W.T. Shiuan E. Meador C.B. et al.Improved prognosis and increased tumor-infiltrating lymphocytes in patients who have SCLC with neurologic paraneoplastic syndromes.J Thorac Oncol. 2019; 14: 1970-1981Abstract Full Text Full Text PDF Scopus (29) Google Scholar provide the first evidence that neurologic PNSs are associated with a proinflammatory “hot” microenvironmental tumor signature. This in turn has recently been identified as an independent beneficial prognostic marker in SCLC.12Carvajal-Hausdorf D. Altan M. Velcheti V. et al.Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung cancer (SCLC).J Immunother Cancer. 2019; 7: 65Crossref PubMed Scopus (77) Google Scholar, 13Muppa P. Parrilha Terra S.B.S. Sharma A. et al.Immune cell infiltration may be a key determinant of long-term survival in small cell lung cancer.J Thorac Oncol. 2019; 14: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Interestingly, the isolated presence of onconeural antibodies in the absence of a clinically overt neurologic PNS is not associated with a more favorable prognosis.14Zekeridou A. Majed M. Heliopoulos I. Lennon V.A. Paraneoplastic autoimmunity and small-cell lung cancer: neurological and serological accompaniments.Thorac Cancer. 2019; 10: 1001-1004Crossref PubMed Scopus (26) Google Scholar However, no data exist regarding the microenvironment of these tumors. The idea that neurologic PNS may serve as a surrogate marker for clinically significant host defense against the tumor is intriguing and provides a potential rationale for immunotherapy in these patients. However, patients with existing autoimmune disorders are regularly excluded from immuno-oncology (IO) clinical trials, and it is important to consider possible exacerbations of neurologic PNS as a side effect. Of 216 treated patients within the CheckMate 032 trial, for example, three patients discontinued study treatment with checkpoint inhibitors permanently on account of neurologic PNS. In the work by Iams et al.,11Iams W.T. Shiuan E. Meador C.B. et al.Improved prognosis and increased tumor-infiltrating lymphocytes in patients who have SCLC with neurologic paraneoplastic syndromes.J Thorac Oncol. 2019; 14: 1970-1981Abstract Full Text Full Text PDF Scopus (29) Google Scholar the only patient with SCLC with neurologic PNS who had received immunotherapy had no reported neurologic toxicity and died of pneumonitis and disease progression after four courses of nivolumab. What have we learned with these data? The presence of neurologic PNS is a prognostic marker in SCLC, the isolated presence of onconeural antibodies alone does not predict outcome in these patients, and the T-cell–mediated inflammatory milieu seems to be essential for improving the prognosis of these patients. Whether the presence of a hot tumor in patients with SCLC and PNS is a promising potential predictive marker for treatment with checkpoint inhibitors remains absolutely uncertain. Keeping in mind the more favorable prognosis of patients with SCLC with neurologic PNS, the use of IO compounds has to be carefully evaluated given the potential risk of higher frequencies of immune-related adverse events. In other tumor types such as melanoma, the baseline status of tumor-infiltrating lymphocytes is not predictive, and in patients with SCLC and PNS, toxicity of IO compounds has to be evaluated extremely carefully, keeping in mind the favorable prognosis and the potentially higher frequency of immune-related adverse events in this patient population. Carefully designed trials are needed to evaluate checkpoint inhibition in the light of these findings. Improved Prognosis and Increased Tumor-Infiltrating Lymphocytes in Patients Who Have SCLC With Neurologic Paraneoplastic SyndromesJournal of Thoracic OncologyVol. 14Issue 11PreviewApproximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition. Full-Text PDF Open Access" @default.
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