Setting Of Small Cell Lung Cancer Research Articles

Engineering Cancer Antigen-Specific T Cells to Overcome the Immunosuppressive Effects of TGF-β.

Adoptive T cell therapy with T cells expressing affinity-enhanced TCRs has shown promising results in phase 1/2 clinical trials for solid and hematological tumors. However, depth and durability of responses to adoptive T cell therapy can suffer from an inhibitory tumor microenvironment. A common immune-suppressive agent is TGF-β, which is secreted by tumor cells and cells recruited to the tumor. We investigated whether human T cells could be engineered to be resistant to inhibition by TGF-β. Truncating the intracellular signaling domain from TGF-β receptor (TGFβR) II produces a dominant-negative receptor (dnTGFβRII) that dimerizes with endogenous TGFβRI to form a receptor that can bind TGF-β but cannot signal. We previously generated specific peptide enhanced affinity receptor TCRs recognizing the HLA-A*02-restricted peptides New York esophageal squamous cell carcinoma 1 (NY-ESO-1)157-165/l-Ag family member-1A (TCR: GSK3377794, formerly NY-ESO-1c259) and melanoma Ag gene A10254-262 (TCR: ADP-A2M10, formerly melanoma Ag gene A10c796). In this article, we show that exogenous TGF-β inhibited in vitro proliferation and effector functions of human T cells expressing these first-generation high-affinity TCRs, whereas inhibition was reduced or abolished in the case of second-generation TCRs coexpressed with dnTGFβRII (e.g., GSK3845097). TGF-β isoforms and a panel of TGF-β-associated genes are overexpressed in a range of cancer indications in which NY-ESO-1 is commonly expressed, particularly in synovial sarcoma. As an example, immunohistochemistry/RNAscope identified TGF-β-positive cells close to T cells in tumor nests and stroma, which had low frequencies of cells expressing IFN-γ in a non-small cell lung cancer setting. Coexpression of dnTGFβRII may therefore improve the efficacy of TCR-transduced T cells.

A Multicenter Blinded Study Evaluating EGFR and KRAS Mutation Testing Methods in the Clinical Non–Small Cell Lung Cancer Setting—IFCT/ERMETIC2 Project Part 1: Comparison of Testing Methods in 20 French Molecular Genetic National Cancer Institute Platforms

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have limited use as first-line treatment for mutated EGFR metastatic non-small cell lung cancer. The French National Cancer Institute has installed molecular genetics platforms implementing EGFR and KRAS testing. However, there is considerable uncertainty as to which detection methods should be applied for routine diagnosis. This study aimed to compare the EGFR and KRAS genotyping methods developed by the IFCT/ERMETIC2 network platforms in two blind panels: 25 samples of serial dilutions of cell line DNA (20 centers) and 74 FFPE lung tumor samples (10 centers). The best threshold of mutation detection on cell lines was obtained using allele-specific amplification-based technologies. Nonamplifiable tissue samples were significantly less common when using alternative testing versus direct sequencing [15%; 95% confidence interval (CI), 14%-16% versus 40%; 95% CI, 39%-42%; P < 0.001]. Mutated cases increased from 42% (95% CI, 31%-54%) to 53% (95% CI, 41%-64%), with three supplementary EGFR mutations (p.G179A at exon 18 and p.L858R and p.L861Q at exon 21) and five supplementary KRAS mutations, when using alternative testing instead of direct sequencing. False-positive results were observed when using a PCR-based sizing assay, high-resolution melting, or pyrosequencing. Concordance analysis returned good kappa test scores for EGFR exon 19 and KRAS analysis when comparing sequencing with alternative methods and revealed no difference between alternative techniques themselves.

Prognostic Effect of Early Treatment of Paraneoplastic Limbic Encephalitis in a Patient with Small-Cell Lung Cancer

Paraneoplastic neurologic syndrome (pns) is an uncommon manifestation of cancer and may present before any symptoms of malignant disease. This syndrome occurs in fewer than 1 of every 10,000 patients diagnosed with a malignancy. Anti-neural antibodies have been associated with pns, suggesting that this condition may reflect immune mechanisms. Depending on the region of the nervous system that has been affected, pns can have a number of manifestations. Paraneoplastic limbic encephalitis (ple) stems from involvement of the limbic system and may present with seizures and changes in mood, memory, and personality. The present report describes the case of a 55-year-old man presenting with ple in the setting of small-cell lung cancer, with subsequent improvement of his neurologic symptoms. The value of rapid diagnosis and multidisciplinary management of this syndrome are discussed.

Subacute Sensorimotor Polyneuropathy as Sole Manifestation of Occult Non Hodgkin’s Lymphoma: Infiltrative or Paraneoplastic?

Sir, The mechanisms of peripheral neuropathy in any malignancy can be because of a direct effect of the cancer by invasion or compression of nerves, a remote or paraneoplastic effect, or an iatrogenic effect of treatment. Focal or multifocal cranial neuropathies, radiculopathies, and plexopathies typically result from tumor infiltration, herpes zoster infection, or radiation-induced injury. Apart from sensorimotor polyneuropathies, which are the most frequently encountered peripheral nerve syndromes, motor neuropathies, sensory neuronopathies, polyradiculoneuropathies, and autonomic neuropathies can also occur. Although uncommon, paraneoplastic mechanisms should be considered in a patient with malignancy and an associated peripheral nerve disorder, especially in the setting of small-cell lung cancer or lymphoproliferative cancer [1]. A 63 years old, non alcoholic, male presented to us with chief complaints of tingling paresthesias in glove and stocking distribution of the limbs and mild weakness in feet since 3 months. The complaints were insidious in onset and were progressive. He gave history of inability to hold the chappals and frequent slipping of the chappals from feet. There were no weakness in the hands. He did not give any history suggestive of proximal muscle weakness. He was nondiabetic and was not taking any drugs. There was no history of fever of weight loss. General examination did not reveal anything significant apart from mild pallor. There was no evidence of postural hypotension. Examination of skin was normal and there were no thickened/tender nerves on palpation. Other systems examination was normal. In CNS examination higher functions, cranial nerves were normal. Motor system examination revealed mild weakness in plantar flexors of the ankle (patient was unable to stand on the ball of feet without support). Bilateral ankle and knee reflexes were lost. Sensory examination showed hyperasthesia in both legs up to knee joints, position sense was intact and vibration sensation was impaired up to both medial malleolus. On investigations Hb was 9 gm%, TLC 5500/mm3, DLC polymorphs 62%, lymphocytes 34%, monocytes 2%, eosinophil 2%, few atypical lymphocytes were seen. Absolute platelet count 225000/mm3. All red cell indices (MCV, MCH, MCHC) were within normal limits. Urine examination was normal. Liver and kidney function tests were normal. Fasting blood sugar 98 mg%, PPBS 138 mg%. Serum electrophoresis did not reveal any M spike. ELISA for HIV was negative. Bone marrow examination revealed marrow hyperplasia with some places showing infiltration by atypical lymphocytes. Thyroid profile was normal. CXR showed rounded, homogenous opacity in the left hilar region suggestive of mass (Fig. 1). USG abdomen was normal. EMG/NCV was conducted which revealed decreased nerve conduction velocities, prolonged distal latencies without any conduction block. Compound muscle action potential (CMAP) was normal, suggesting a predominantly demyelinating type of neuropathy. HRCT of thorax revealed left hilar mass (Fig. 2). A CT-guided FNA was done from the left hilar mass for cytological analysis and non Hodgkin’s lymphoma (NHL) was diagnosed (Fig. 3a, b). Immunophenotyping was carried out which was positive for CD 20 and CD 22 suggesting that the lymphoma was of B cell origin. Patient did not give consent for sural nerve biopsy and immunophenotyping. Anti neuronal antibodies status was not done because the patient could not afford. Fig. 1 Chest X-ray PA view showing left sided hilar opacity suggestive of mass Fig. 2 HRCT of thorax highlighting the mass and mediastinal lymphadenopathy Fig. 3 a, b Cytological smears 10× and 40× view stained with MGG stain showing cellular smears with predominant lymphocytic population. Lymphocytes are large and atypical with coarse chromatin and prominent nuclei, there is also presence of macrophages, ... He was started with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), regime. He tolerated the first cycle well though there was no significant improvement in the symptoms of neuropathy and awaits the second cycle.

Paraneoplastic limbic encephalitis presenting as a neurological emergency: a case report

IntroductionParaneoplastic limbic encephalitis remains a challenging clinical diagnosis with poor outcome if it is not recognized and treated early in the course of the disease.Case PresentationA 65-year-old Caucasian woman presented with generalized tonic-clonic seizures and increasing confusion shortly after a lung biopsy that led to the diagnosis of small-cell lung cancer. She had a complicated hospital course, and had recurrent respiratory distress due to aspiration pneumonia, and fluctuating mental status and seizures that were refractory to anti-epileptic drug treatment. Routine laboratory testing, magnetic resonance imaging of the brain, electroencephalogram, lumbar puncture, serum and cerebrospinal fluid tests for paraneoplastic antibodies, and chest computed tomography were performed on our patient. The diagnosis was paraneoplastic limbic encephalitis in the setting of small-cell lung cancer with positive N-type voltage-gated calcium channel antibody titer. Anti-epileptic drugs for seizures, chemotherapy for small-cell lung cancer, and intravenous immunoglobulin and steroids for paraneoplastic limbic encephalitis led to a resolution of her seizures and improved her mental status.ConclusionEarly recognition of paraneoplastic limbic encephalitis and prompt intervention with immune therapies at the onset of presentation will probably translate into more favorable neurological outcomes.

Neuropathies associated with malignancy.

Patients with malignancy can develop peripheral neuropathies as (1) a direct effect of the cancer by invasion or compression of nerves, (2) a remote or paraneoplastic effect, or (3) an iatrogenic effect of treatment. Focal or multifocal cranial neuropathies, radiculopathies, and plexopathies typically result from tumor infiltration, herpes zoster infection, or radiation-induced injury. Sensorimotor polyneuropathies are the most frequently encountered peripheral nerve syndromes, but motor neuropathies, sensory neuronopathies, polyradiculoneuropathies, and autonomic neuropathies can also occur. Although uncommon, paraneoplastic mechanisms should be considered in a patient with malignancy and an associated peripheral nerve disorder, especially in the setting of small-cell lung cancer or lymphoproliferative cancer. Toxic neuropathies occur with exposure to several chemotherapeutic agents, including the vinca alkaloids, cisplatin, taxanes, and suramin. These neuropathies are usually dose-related, sensory-predominant, and at least partially reversible, with an axonopathic or ganglionopathic mechanism. Suramin is unique in causing subacute, demyelinating polyradiculoneuropathy.