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Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.
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Primary pituitary diffuse large B-cell lymphoma (PPL) has been regarded as a subtype of primary central nervous system lymphoma (PCNSL); however, the pituitary gland is located outside the blood brain barrier (BBB) with neural and vascular connections to the brain. Given its unique anatomic location, a combination of non-central nervous system (CNS)-penetrating and CNS-penetrating therapeutic agents can be employed to treat PPL. We report a female patient with PPL who was successfully managed with anatomy-adapted therapy incorporating non-CNS penetrating chemoimmunotherapy [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)] alternating with CNS-penetrating chemoimmunotherapy [rituximab, high-dose methotrexate, and high-dose cytarabine (RMA)]. She received a total of eight cycles of treatment with four cycles of each regimen following partial transsphenoidal resection. She achieved a complete response after two cycles and has remained in complete remission for the last eight years. To our knowledge, this is the longest documented survival in a patient with PPL. Targeted genomic profiling with Next-Generation Sequencing (NGS) was recently performed on the lymphoma tissue. The genomic profile of PPL in this patient is quite different from the findings typically associated with PCNSL. We suggest that PPL may be biologically distinct from PCNSL and should be treated with an anatomy adapted approach. Additional research is necessary to confirm our findings.
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The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations.
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INTRODUCTION: The development of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) concurrently or sequentially in the same patient is a rare clinical scenario and can be labeled as a poly-lymphomatous syndrome (PLS). METHODS: We report clinico-pathologic characteristics and survival outcomes of 7 such cases from our institution. In concurrent PLS, HL is present with NHL in the same location (composite PLS) or in separate locations (discordant PLS). Sequential presentations were seen with HL following NHL or vice versa (sequential PLS). CONCLUSIONS: It is essential to perform adequate biopsies in supposedly relapsed or refractory settings to diagnose PLS. We suggest that the incidence of PLS is likely underestimated due to the under-utilization of repeat biopsies. In patients with concurrent PLS, the treatment should ideally cover both types of lymphoma with an emphasis on tailoring the treatment towards the more aggressive lymphoma. In patients with sequential PLS, the treatment should target the new lymphoma. Consolidation treatments such as autologous hematopoietic cell transplant should be considered when there is a component of relapsed cHL or aggressive NHL. Based on our experience, PLS does not appear to be associated with a poor prognosis. Further research is necessary for better understanding of the biology and management of PLS.
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Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Linfoma no Hodgkin , Linfoma , Humanos , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/terapia , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/terapia , Trasplante AutólogoRESUMEN
Primary cranial vault lymphoma (PCVL) is a rare lymphoma involving the skull with or without extra- and intracranial extension. Most cases of PCVL are diffuse large B-cell lymphoma (DLBCL). We report a case of primary cranial vault diffuse large B-cell lymphoma (PCV-DLBCL) that was successfully treated with anthracycline-based chemoimmunotherapy (CIT) alternating with central nervous system (CNS)-directed CIT with high-dose methotrexate and high-dose cytarabine. CNS-centric therapy was given for suspected cerebral cortical involvement and presumed elevated risk of CNS recurrence. The patient has remained in complete remission for 4.25 years following treatment. We suggest that PCV-DLBCL is potentially curable with CNS-directed therapy. Additionally, we provide genomic profiling results indicating an indeterminate cell of origin and multiple genetic mutations which are not frequently seen in DLBCL.
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Secondary central nervous system involvement by systemic diffuse large B-cell lymphoma (DLBCL) carries a very poor prognosis. We present a female patient who had two episodes of intracerebral central nervous system (CNS)-only relapse of systemic non-germinal center diffuse large B-cell lymphoma (NGC-DLBCL). Her treatment at initial diagnosis consisted of induction with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and intrathecal (IT) - methotrexate (MTX) followed by consolidation with autologous stem cell transplant (ASCT) after high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy. She had the first CNS-only relapse 1.5 years post-ASCT and received whole brain radiation therapy (WBRT). She developed the second intracerebral CNS-only relapse 2 years post-WBRT. A CNS-centric therapeutic approach with salvage chemoimmunotherapy incorporating rituximab, high-dose methotrexate (HD-MTX), high-dose cytarabine (HiDAC), and ibrutinib was utilized for her second CNS-only relapse. She underwent consolidation with a second ASCT following high-dose carmustine (BCNU) and thiotepa chemotherapy. Given her high risk of CNS recurrence, she was started on maintenance ibrutinib. To date, she has remained in complete remission for 3 years. In our experience, multiply relapsed secondary CNS lymphoma (SCNSL) with this response is very rare. We suggest one CNS-centric therapeutic approach that can potentially salvage patients with SCNSL who have not had prior exposure to adequate CNS-directed therapies but acknowledge that additional research is necessary to validate our findings.
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Hyperviscosity syndrome (HVS) is an emergent complication of Waldenström macroglobulinemia (WM) characterized by visual, neurologic, and rarely auditory impairment. We report a 69-year-old female with MYD88 and CXCR4-mutant WM who developed HVS resulting in bilateral blindness and deafness associated with neurologic manifestations including confusion, severe generalized weakness, and imbalance. Ophthalmologic evaluation revealed bilateral central retinal vein occlusion (CRVO), diffuse retinal hemorrhages, macular edema, and serous macular detachments (SMD). Magnetic resonance imaging of the brain showed bleeding in the inner ears. Management was challenging as her WM was resistant to systemic therapies including bendamustine + rituximab (BR) and rituximab + bortezomib + dexamethasone (RVD). Bruton's tyrosine kinase inhibitors could not be used initially due to ongoing lower gastrointestinal bleeding. She required five total sessions of plasma exchange and was finally initiated on zanubrutinib, achieving a partial response. She also received intravitreal bevacizumab with rapid resolution of the retinal hemorrhages but with little improvement of the SMD. She had partial restoration of her hearing in the right ear and only slight improvement in her bilateral visual deficits. The management of HVS in frail, elderly patients with therapy-resistant WM can be challenging. In these cases, plasma exchange is required until an effective systemic therapy can be safely instituted. Genomic profiling is important in the management of WM as it can predict treatment resistance and guide therapeutic decisions.
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Diffuse large B-cell lymphoma (DLBCL) is well known for selectively involving certain extranodal locations such as the central nervous system (CNS), testes, and skin. DLBCL or high-grade B-cell lymphoma selectively involving the bone marrow is rare and has been sparsely reported in the medical literature. We report two cases of lymphoma presenting with primary bone marrow involvement without evidence of involvement of any other sites. The first case represents de novo DLBCL. The patient achieved complete remission with initial treatment, had a bone marrow-only relapse three years later, and achieved a second complete remission following non-transplant salvage therapy. The second case had findings consistent with "double hit" Richter's transformation of chronic lymphocytic leukemia with translocation of c-MYC and BCL-2. This patient had an aggressive clinical course characterized by rapid progression with CNS involvement within three months resulting in the demise of the patient. These two cases represent two distinct subtypes of primary bone marrow lymphoma: de novo and transformed. Further research is necessary to gain a better understanding of this rare lymphoma entity and develop novel therapies.
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The immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/terapia , Animales , Humanos , Inmunoterapia/métodos , Neoplasias/inmunología , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Co-stimulatory and co-inhibitory molecules play a critical role in T cell function. Tumor cells escape immune surveillance by promoting immunosuppression. Immunotherapy targeting inhibitory molecules like anti-CTLA-4 and anti-PD-1/PD-L1 were developed to overcome these immunosuppressive effects. These agents have demonstrated remarkable, durable responses in a small subset of patients. The other mechanisms for enhancing anti-tumor activities are to target the stimulatory pathways that are expressed on T cells or other immune cells. In this review, we summarize current phase I/II clinical trials evaluating novel immunotherapies targeting stimulatory pathways and outline their advantages, limitations, and future directions.
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Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Microambiente Tumoral/inmunología , Humanos , Persona de Mediana Edad , Neoplasias/inmunologíaRESUMEN
INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers. Progress has been made in treatment of HCC; however, improved outcomes are much needed. The increased metabolic needs of cancer cells underscore the importance of metabolic pathways in cancer cell survival. Lipid metabolism has a role in HCC development; aberrant overexpression of several key enzymes is seen in many solid human tumors. Areas covered: We discuss aberrant lipid metabolism and the promise of multiple targets, in particular related to HCC treatment. We searched PubMed and clinicaltrials.gov for published and unpublished studies from 2000 to 2019. These terms were used: lipids, fatty acid metabolism, lipid metabolism, liver cancer, HCC, de novo fatty acid synthesis, ATP citrate lyase, stearoyl CoA denaturase, fatty acid synthase, acetyl coenzyme A carboxylase, CD147, KLF4, monoglyceride lipase, AMP activated protein kinase. Expert opinion: The importance of dysregulation of fatty acid synthesis in cancer is a growing area of research. HCC demonstrates significant alteration in lipid metabolism, representing great potential as a target for novel therapeutics. Various agents have demonstrated promising anti-neoplastic activity. This strategy deserves further development for improved outcomes.