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Management of acquired immunodeficiency syndrome (AIDS)-related diffuse large B-cell (DLBCL) and plasmablastic lymphomas (PBL) poses significant challenges. The evidence supports use of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) with or without rituximab as first-line therapy. The need for central venous access, growth factors and significant toxicities limits its use in resource-constrained settings. To address these challenges, we have developed a novel regimen, CVEP (cyclophosphamide, vinblastine, etoposide, and prednisolone) based on the pharmacodynamic principles of dose-adjusted EPOCH. This single-centre phase II study evaluated the efficacy and safety of CVEP regimen in patients with de novo systemic AIDS-related DLBCL and PBL. The primary objective was complete response (CR) rates as assessed by positron emission tomography-computed tomography. The secondary objectives were incidence of Grade 3/4 toxicities, toxicities requiring hospitalisation, and disease-free survival. From May 2011 to February 2017, 42 patients were enrolled. At the end of therapy the CR rates were 69% (29/42) in the intention-to-treat population and 80.5% (29/36) in evaluable patients. At a median follow-up of 69 months, the 5-year disease-free survival was 65.3%. Out of 217 cycles administered, febrile neutropenia occurred in 19.3% and hospitalisation was required in 18.3% of cycles. There were two treatment-related deaths. The CVEP regimen is an active and safe regimen for AIDS-related DLBCL and PBL.
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Síndrome da Imunodeficiência Adquirida , Linfoma Difuso de Grandes Células B , Humanos , Etoposídeo/efeitos adversos , Vimblastina/efeitos adversos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Prednisolona/efeitos adversos , Ciclofosfamida/efeitos adversos , Prednisona/uso terapêutico , Vincristina/efeitos adversos , Doxorrubicina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: The COVID-19 pandemic has disrupted health-care systems, leading to concerns about its subsequent impact on non-COVID disease conditions. The diagnosis and management of cancer is time sensitive and is likely to be substantially affected by these disruptions. We aimed to assess the impact of the COVID-19 pandemic on cancer care in India. METHODS: We did an ambidirectional cohort study at 41 cancer centres across India that were members of the National Cancer Grid of India to compare provision of oncology services between March 1 and May 31, 2020, with the same time period in 2019. We collected data on new patient registrations, number of patients visiting outpatient clinics, hospital admissions, day care admissions for chemotherapy, minor and major surgeries, patients accessing radiotherapy, diagnostic tests done (pathology reports, CT scans, MRI scans), and palliative care referrals. We also obtained estimates from participating centres on cancer screening, research, and educational activities (teaching of postgraduate students and trainees). We calculated proportional reductions in the provision of oncology services in 2020, compared with 2019. FINDINGS: Between March 1 and May 31, 2020, the number of new patients registered decreased from 112 270 to 51 760 (54% reduction), patients who had follow-up visits decreased from 634 745 to 340 984 (46% reduction), hospital admissions decreased from 88 801 to 56 885 (36% reduction), outpatient chemotherapy decreased from 173634 to 109 107 (37% reduction), the number of major surgeries decreased from 17 120 to 8677 (49% reduction), minor surgeries from 18 004 to 8630 (52% reduction), patients accessing radiotherapy from 51 142 to 39 365 (23% reduction), pathological diagnostic tests from 398 373 to 246 616 (38% reduction), number of radiological diagnostic tests from 93 449 to 53 560 (43% reduction), and palliative care referrals from 19 474 to 13 890 (29% reduction). These reductions were even more marked between April and May, 2020. Cancer screening was stopped completely or was functioning at less than 25% of usual capacity at more than 70% of centres during these months. Reductions in the provision of oncology services were higher for centres in tier 1 cities (larger cities) than tier 2 and 3 cities (smaller cities). INTERPRETATION: The COVID-19 pandemic has had considerable impact on the delivery of oncology services in India. The long-term impact of cessation of cancer screening and delayed hospital visits on cancer stage migration and outcomes are likely to be substantial. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.
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COVID-19/terapia , Prestação Integrada de Cuidados de Saúde/tendências , Acessibilidade aos Serviços de Saúde/tendências , Oncologia/tendências , Neoplasias/terapia , Assistência Ambulatorial/tendências , COVID-19/diagnóstico , Diagnóstico Tardio , Detecção Precoce de Câncer/tendências , Hospitalização/tendências , Hospitais com Alto Volume de Atendimentos/tendências , Humanos , Índia/epidemiologia , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Aceitação pelo Paciente de Cuidados de Saúde , Fatores de Tempo , Tempo para o Tratamento , Listas de EsperaRESUMO
The MHC class I Ag presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II Ag presentation pathway in melanoma cells is less clear. In Ag-presenting cells, IFN-γ-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma Ags. Although not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas cutaneous melanoma data set showed that high GILT mRNA expression was associated with improved overall survival. Expression of IFN-γ, TNF-α, and IL-1ß was positively associated with GILT expression in melanoma specimens. These cytokines were capable of inducing GILT expression in human melanoma cells in vitro. GILT protein expression in melanocytes was induced in halo nevi, which are nevi undergoing immune-mediated regression, and is consistent with the association of GILT expression with improved survival in melanoma. To explore potential mechanisms of GILT's association with patient outcome, we investigated pathways related to GILT function and expression. In contrast to healthy skin specimens, in which the MHC class II pathway was nearly uniformly expressed and intact, there was substantial variation in the MHC class II pathway in the The Cancer Genome Atlas melanoma specimens. Both an active and intact MHC class II pathway were associated with improved overall survival in melanoma. These studies support a role for GILT and the MHC class II Ag presentation pathway in melanoma outcome.
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Apresentação de Antígeno/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Melanoma/imunologia , Melanoma/mortalidade , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Adolescente , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Interferon gama/metabolismo , Interferon gama/farmacologia , Masculino , Melanoma/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/farmacologia , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
Aims: To analyze outcomes in primary anorectal melanoma, a rare disease with limited data and treatment guidelines. Materials & methods: We analyzed 305 subjects in the National Cancer Database from 2004 to 2015. The primary end point was overall survival (OS). Results: Surgery was predictive of OS (median 2.24 vs 1.18 years; p = 0.009) with no survival difference between local and transabdominal approaches (p = 0.77). No OS benefit was seen with chemotherapy (p = 0.16), radiotherapy (p = 0.31) or adjuvant therapy post surgery (p > 0.05 for all groups). Targeted therapy trended toward higher survival in metastatic patients (1.33 vs 0.55 years; p = 0.06). Conclusion: In nonmetastatic patients, surgery of any method is associated with a survival benefit. The trend for improved survival following targeted therapy in metastatic patients merits further exploration.
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Neoplasias do Ânus/epidemiologia , Neoplasias do Ânus/terapia , Melanoma/epidemiologia , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/mortalidade , Terapia Combinada , Gerenciamento Clínico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/diagnóstico , Melanoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Modelos de Riscos Proporcionais , Vigilância em Saúde Pública , Estudos Retrospectivos , Fatores Socioeconômicos , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Aim: To explore management trends in preinvasive and cT1-T3 penile cancer. Materials & methods: The National Cancer Database was queried (2004-2013) for cT1-T3 M0 penile cancer with specified nonpalliative surgical techniques and histologies (n = 5,728). Results: Local excision (39%) and partial penectomy (38%) were most commonly utilized. Patients with cTis/Ta or cT1 disease more often received nonpenectomy approaches (p < 0.05); cT2-T3 cases more likely underwent penectomy (p < 0.001). No survival differences were observed between penectomy (49.3 months) and nonpenectomy approaches (50.3 months) in the overall cohort (p = 0.107) and when stratifying by T-stage (p > 0.20 for all). Conclusion: This study provides contemporary insight into the landscape for management of this rare disease and can serve as a benchmark for future evaluation of treatment trends.
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Neoplasias Penianas/terapia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Penianas/diagnóstico , Neoplasias Penianas/epidemiologia , Prognóstico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In the past decade, the study of mechanisms of cancer immunity has seen a prominent boom, which paralleled the increased amount of research on the clinical efficacy of immune checkpoint blockade in several lethal types of cancers. This conspicuous effort has led to the development of successful immunotherapy treatment strategies, whose medical impact has been recognized by the awarding of 2018 Nobel Prize in Physiology or Medicine to the two pioneers of check point inhibitor research, Tasuku Honjo and James Allison. Despite these promising achievements, the differences in the clinical response rate in different cancer patients and the high risk of toxicity of immune-based therapies represent crucial challenges. More remarkably, the causes responsible for different outcome (success vs failure) in patients with tumor having same histotype and clinical characteristics remain mostly unknown. MicroRNAs (miRNAs), small regulatory noncoding RNA molecules representing the most studied component of the dark matter of the human genome, are involved in the regulation of many pathways of cancer and immune cells. Therefore, understanding the role of miRNAs in controlling cancer immunity is necessary, as it can contribute to reveal mechanisms that can be modulated to improve the success of immunetherapy in cancer patients. Here, we discuss the latest findings on immune pathways regulated by miRNAs in cancer, miRNA-mediated regulation of immune cells in the tumor microenvironment, and miRNAs as potential target for immunotherapies.
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Imunoterapia/métodos , MicroRNAs/genética , Neoplasias/imunologia , Animais , Humanos , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/terapiaRESUMO
Clinical trials have shown that early and deeper cytogenetic/ molecular responses to tyrosine kinase inhibitors (TKIs) help in achieving improved long-term outcomes including lower rates of disease progression in chronic myeloid leukaemia (CML). However, the level of molecular responses achieved with TKI therapy in patients with CML is variable and this could be explained by differences in adherence to CML therapy. A systematic literature review of CML studies reporting adherence to BCR-ABL inhibitors from the USA, Asia and Europe (19 articles: 9 retrospective, 4 prospective, rest cross-sectional) showed that average adherence varies from 19% to 100% of the proportion of prescribed drug taken. Some factors that contribute to non-adherence include patient attitudes, adverse events associated with therapy, treatment complexities and socioeconomic issues. This article focuses on the problem of non-adherence to therapy in CML, especially from an Indian perspective, and offers suggestions for its mitigation.
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Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Transversais , Humanos , Índia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND & OBJECTIVES: Multiple myeloma (MM) is a plasma cell malignancy characterized by cytogenetic heterogeneity. In comparison with conventional karyotyping, fluorescence in situ hybridization (FISH) can efficiently detect various genetic changes in non-cycling plasma cells in 50-90 per cent of MM cases. The present study was undertaken in MM patients to evaluate the frequency and clinico-pathological significance of various cytogenetic abnormalities in the Indian population. METHODS: Interphase FISH was applied on purified plasma cells of 475 patients with MM using specific probes. Interphase FISH for 1q gain/1q amplification was performed on a separate group of 250 newly diagnosed MM patients. RESULTS: Low frequency of Δ13 [-13/del(13q)] (32%) and t(11;14) (5%) was observed in our 475 patients probably due to ethnic diversity. Clustering of Δ13, del(17)(p13.1) and IgH translocations in non-hyperdiploidy confirmed prognostic significance of ploidy in MM. t(4;14) and del(17)(p13.1) were high-risk groups due to correlation with high serum ß2-microglobulin, increased plasma cells and advanced disease. Hyperdiploidy and t(14;16) were associated with higher age group. In a separate group of 250 patients, 1q amplification [amp(1q)] in combination with Δ13 and/or del(17p) with t(4;14) revealed association with adverse clinico-laboratory features, which confirmed progressive role of amp(1q) with adverse prognostic impact. Amp(1q) was clustered at 1q21 and 1q25 loci. INTERPRETATION & CONCLUSIONS: Based on our findings, it appears that comprehensive analysis of various cytogenetic aberrations by interphase FISH is a powerful strategy being adapted for risk stratification of MM.
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Citodiagnóstico , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Aberrações Cromossômicas , Deleção Cromossômica , Análise Citogenética , Feminino , Humanos , Hibridização in Situ Fluorescente , Índia , Cariotipagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Translocação GenéticaRESUMO
Plasmacytoma classified into solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) is characterized by infiltrate of plasma cells of diverse maturity and by their monoclonal immunoglobulin products. Both SPB and EMP represent different groups of neoplasm in terms of location, tumor progression, and overall survival rate. There is a need for features that indicate likelihood of myeloma in patients with plasmacytoma without other manifestations. This study was an attempt to study the morphologic patterns of plasmacytoma (SPB and EMP), MIB1 proliferation index, and correlation of these with clinicopathologic features and survival of the patients. The study group comprised of 134 cases of plasmacytoma (88 SPB and 46 EMP) over duration of 8 years and were graded as per Bartl's histologic grading system. Commonest site was vertebral body in SPB (36%) and upper aerodigestive tract in EMP (48%). On serum electrophoresis, overall M band was detected in 41% cases. Both SPB and EMP on histology revealed similar morphologic features. MIB1 proliferation index ranged from less than 1% to 80%. It was slightly higher in EMP in comparison with SPB (P value = .002). Seventy percent of cases, which progressed to multiple myeloma (MM) showed MIB1 labeling index more than 10%; however, it was not statistically significant in predicting the disease progression. With the median follow-up of 19 months (range, 1-99 months), 10 SPB had disease progression of which 7 converted to MM, and 3 developed EMP, with a median interval of 21 months (range, 8-75 months) for the development of MM and 3 months (range, 3-9 months) for the progression to EMP. Five-year survival for EMP varied by site, with poorest survival in brain/central nervous system EMP as compared with EMP at other sites. To conclude, grade and MIB1 proliferation index help in predicting aggressive course in plasmacytoma.
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Anticorpos Antinucleares/metabolismo , Anticorpos Monoclonais/metabolismo , Plasmocitoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antinucleares/sangue , Anticorpos Monoclonais/sangue , Eletroforese das Proteínas Sanguíneas , Progressão da Doença , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Plasmocitoma/sangue , Plasmocitoma/epidemiologia , Plasmocitoma/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Taxa de Sobrevida , Adulto JovemRESUMO
Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952).
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Minimal residual disease (MRD) has become an essential tool in the management of B-cell acute lymphoblastic leukemia (B-ALL) and aids in tailoring treatment strategies to suit specific patient needs. Although much progress has been made in this area, there is limited data on the use of MRD in the Indian context. Our objective was to identify relevant literature that discusses the utility of MRD in the management of B-cell ALL in adolescents and young adults (AYA) and adults in Indian settings. A systematic search and screening of articles were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary data source was PubMed followed by Google Scholar for articles and conference proceedings. Of the 254 records screened, 24 records were retained for analysis. MRD monitoring had a significant role in the management of AYA/adult B-cell ALL patients. Variability of results was observed across these studies with respect to methods, techniques, and use. However, these studies evidenced and validated the importance of MRD assessment in risk-adapted management of B-cell ALL and highlighted the need for optimization. The advances in MRD diagnostics and applications are yet to be tested and adopted in Indian settings. Hence, there is a need for in-depth research to develop and optimize approaches for calibrating country-specific management strategies. The potential role of MRD assessments in anticipating relapse or treatment failures warrants more attention for the preemptive positioning of novel strategies involving immunotherapies.
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PURPOSE: The purpose of this work was to evaluate whether inter-fraction imaging and replanning enhance treatment delivery adherence to clinical planning objectives in the context of a 5-fraction template-based interstitial brachytherapy (TISB) approach for gynecologic cancer treatment. METHODS AND MATERIALS: This retrospective study analyzed nineteen patients who underwent 5 fractions of interstitial brachytherapy over 3 days using the Syed-Neblett template. A verification CT scan was acquired for applicator assessment and reviewed by a radiation oncologist and medical physicist before each fraction. Eleven patients required replanning at least once during the treatment course. Replanning on the verification CT scan consisted of generating new target and organ-at-risk contours, digitizing catheter positions, and optimizing source dwell times to meet planning objectives. Dwell times and positions from the initial treatment plan were evaluated on the new contours to assess the dose that would have been delivered without replanning (nonadapted). Significance of nonadapted versus adapted dose differences were evaluated using a 2-sided Wilcoxon sum rank test. RESULTS: The average (min, max) change in dose (Gy) between the clinically delivered plans and the nonadapted plans were HR-CTV D90%: -6.5 (-0.6, -15.1), HR-CTV D98%: -6.5 (-0.4, -12.6), Bladder D2cc: -0.5 (0.0, -2.8), Bowel D2cc: -0.8 (0.0, -3.2), Rectum D2cc: -1.1 (0.0, -11.5), Sigmoid D2cc: -1.4 (-0.1, -5.4). Dosimetric changes in HR-CTV coverage were significantly improved with replanning while organ-at-risk differences were nonsignificant (p > 0.05). Fraction 3 was the most common fraction indicated for replanning. CONCLUSIONS: Replanning template-based interstitial brachytherapy can improve target coverage and adherence to planning goals.
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Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease.
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Bleomicina , Linhagem da Célula , Interleucina-4 , Pulmão , Fatores de Transcrição SOX9 , Animais , Interleucina-4/metabolismo , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOX9/genética , Camundongos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Células-Tronco Adultas/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/efeitos dos fármacos , Envelhecimento/metabolismo , Diferenciação Celular , Transdução de Sinais , Humanos , Macrófagos/metabolismoRESUMO
Single-cell RNA sequencing predominantly employs short-read sequencing to characterize cell types, states and dynamics; however, it is inadequate for comprehensive characterization of RNA isoforms. Long-read sequencing technologies enable single-cell RNA isoform detection but are hampered by lower throughput and unintended sequencing of artifacts. Here we develop Single-cell Targeted Isoform Long-Read Sequencing (scTaILoR-seq), a hybridization capture method which targets over a thousand genes of interest, improving the median number of on-target transcripts per cell by 29-fold. We use scTaILoR-seq to identify and quantify RNA isoforms from ovarian cancer cell lines and primary tumors, yielding 10,796 single-cell transcriptomes. Using long-read variant calling we reveal associations of expressed single nucleotide variants (SNVs) with alternative transcript structures. Phasing of SNVs across transcripts enables the measurement of allelic imbalance within distinct cell populations. Overall, scTaILoR-seq is a long-read targeted RNA sequencing method and analytical framework for exploring transcriptional variation at single-cell resolution.
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Neoplasias Ovarianas , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Análise de Célula Única , Humanos , Feminino , Análise de Célula Única/métodos , Neoplasias Ovarianas/genética , Análise de Sequência de RNA/métodos , Linhagem Celular Tumoral , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Transcriptoma/genética , Isoformas de RNA/genética , Desequilíbrio Alélico/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão GênicaRESUMO
High-grade B-cell NHL's are more common in seropositive patients. They are biologically different from their seronegative counterparts. We report our analysis on our cohort of patients who were treated with DA-EPOCH(+/-R). We retrospectively analyzed treatment-naïve HIV-associated High-grade B-cell NHL patients (aged ≥ 18) treated with DA-EPOCH(+/-R) regimen from 2011 to 2015. Descriptive statistics were summarized with median and range; survival outcomes were analyzed with Kaplan-Meier method. The cohort comprised of 40 patients [DLBCL(19), Burkitt's Lymphoma(16), High-grade B-Cell Lymphoma-Unclassifiable(09), and Plasmablastic Lymphoma(01)] and the median CD4 + T cell count was 202/mm3. CNS prophylaxis was administered with intrathecal methotrexate to 90% of patients. With a median follow-up of 72 months, an estimated 5-year OS was 82.5%, and 5-PFS was 77.5%. There were 9 deaths, and 9 patients had progression. At least 4 cycles of chemotherapy were administered to 35 (93%) patients, with 28 (70%) receiving 6 cycles. Grade 3-4 toxicities were seen in 33 (83%) patients- febrile neutropenia (65%) being the most common followed by mucositis (25%) and peripheral neuropathy (13%). There was no difference in survival based on IPI, CD 4 + T cell count, CDI, or duration of HIV. DA-EPOCH(+/-R) is a highly effective regimen in seropositive high-grade B-cell lymphoma, even in the presence of adverse features. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01652-3.
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Objective To study the results of only posterior decompression and instrumentation in dorsal and dorsolumbar spine tuberculosis. Methods The patients ( n = 30) who were included in this study had dorsal or dorsolumbar spine tuberculosis, with or without neurological deficit, and with or without deformity. All 30 patients were managed by only posterior approach decompression and instrumentation. We studied cases for correction and maintenance of deformity at dorsal and dorsolumbar spine, functional outcome by the Oswestry disability index (ODI) and visual analogue scale (VAS) scores, as well as neurological outcome by the Frankel grade. Results In the current series, 30 patients were operated with single stage posterior decompression and instrumentation, and showed significant improvement in neurological status and functional outcomes, which were accessed by the ODI score, VAS score, and Frankel grade. Conclusion The posterior (extracavitary) approach provides optimum access to the lateral and anterior aspects of the spinal cord for good decompression. It facilitates early mobilization and avoids problems of prolonged recumbency, provides better functional outcome, and significantly better sagittal plane kyphosis correction.
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Objective To evaluate the risk factors and outcomes in patients surgically treated for subaxial cervical spine injuries with respect of the timing of surgery and preoperative physiological parameters of the patient. Methods 26 patients with sub-axial cervical spine fractures and dislocations were enrolled. Demographic data of patients, appropriate radiological investigation, and physiological parameters like respiratory rate, blood pressure, heart rate, PaO2 and ASIA impairment scale were documented. They were divided pre-operatively into 2 groups. Group U with patients having abnormal physiological parameters and Group S including patients having physiological parameters within normal range. They were further subdivided into early and late groups according to the timing of surgery as U early , U late, S early and S late . All the patients were called for follow-up at 1, 6 and 12 months. Results 56 percent of patients in Group S had neurological improvement by one ASIA grade and a good outcome irrespective of the timing of surgery. Patients in Group U having unstable physiological parameters and undergoing early surgical intervention had poor outcomes. Conclusion This study concludes that early surgical intervention in physiologically unstable patients had a strong association as a risk factor in the final outcome of the patients in terms of mortality and morbidity. Also, no positive association of improvement in physiologically stable patients with respect to the timing of surgery could be established.
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The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that ß-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.
Assuntos
Neurônios Adrenérgicos , Imunidade Inata , Mucosa Intestinal , Linfócitos , Regeneração , Animais , Transdução de Sinais , Neurônios Adrenérgicos/fisiologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/inervação , Mucosa Intestinal/fisiologia , Camundongos , Interleucina 22RESUMO
Primary CNS lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma with the worst outcomes amongst all extranodal lymphomas. There is a scarcity of data on real-world outcomes of primary CNS lymphoma (PCNSL) owing to the rarity of the disease. This study analyzed the demographic patterns, risk stratification, treatment regimens used, & outcomes of patients treated at Tata Memorial Center Mumbai, India. This is a retrospective analysis of newly diagnosed primary CNS lymphoma patients treated at our centre over seven years from January 2013 to December 2019. A total of 142 patients with PCNSL were diagnosed during this period. Thirty (21.1%) patients were deemed ineligible for any systemic or local therapies,ten patients were referred to other hospitals, two patients had relapsed disease, and one was excluded because age less than 18 years. Finally 99 patients were included in the final analysis. Among these 99 patients,72 patients (72.7%) were < 60 years,70 (70.7%) patients had Eastern cooperative oncology group (ECOG) performance status (PS) less than equal to 2. DLBCL was the most common histology (86.4%) while rests were high grade B cell NHL NOS (11.4%),Burkitt's Lymphoma(1%),Peripheral T-cell Lymphoma NOS (1.2%). Only one of 99 patients was positive for HIV serology. Multiple intracranial lesions were found in 59.5%. Surgical resection was performed in 28.4% of patients. Out of 63 patients in whom the International extranodal lymphoma study group (IELSG) score is available, 34(54%) were IELSG high-risk groups. As per Memorial Sloan Kettering Cancer Center (MSKCC) risk grouping, patients were almost equally distributed in all the risk groups, with 32(32.3%) patients in risk group 1 (age < 50 years), 36(36.4%) patients in risk group 2 (age > 50 years, KPS > = 70), and 31(31.3%) patients in risk group 3 age > 50 years, KPS < 70). First-line treatment with high dose methotrexate (HD-MTX) based regimens was administered to 92 (92.9%) patients, and 72.8% of these patients received rituximab. Of these 92 patients, 59 (64.1%) patients could complete induction, and 52 patients received consolidation. Thirty-one patients received high dose cytarabine based chemo consolidation, one patient underwent high dose chemotherapy followed by autologous stem cell transplantation (ACST), and 19 patients received whole-brain radiotherapy (WBRT) and 1 patient received temozolomide as consolidation regimen. Thus only 52 patients completed the entire course of induction with consolidation therapy. The response to treatment was assessed using International PCNSL Collaborative Group Criteria. Post completion of consolidation, 49(94.2%) patients had a complete response. With a median follow-up duration of 39.2 months, the median progression-free survival (PFS) and the median overall survival (OS) of the patients taken into the analysis (N = 99) were 21 and 37 months respectively. On multivariate analysis, age < 60 yrs, > = 5 HD-MTX cycles received & the use of rituximab predicted better OS.Outcomes of patients with PCNSL treated with HD-MTX based therapy are comparable to reported literature however a large proportion of patients do not undergo required treatment despite the curable nature of disease. Supplementary Information: The online version supplementary material available at 10.1007/s12288-022-01557-7.
RESUMO
BACKGROUND: Mantle cell lymphoma (MCL) is a rare type of mature B-cell lymphoid malignancy with the pathologic hallmark of translocation t(11;14) (q13, q32), which leads to an overexpression of Cyclin D1 (CCND1). The disease is also characterized by the presence of a high number of recurrent genetic alterations, which include aberrations in several cellular pathways. MCL is a heterogeneous disease with a wide range of clinical presentations and a majority presenting with aggressive disease in advanced stages. RECENT FINDINGS: Management of MCL is bereft with challenges due to its resistant and relapsing pattern. Despite improvements in remission durations, the disease is currently incurable with standard therapy and has a median survival of about 3-5 years. The use of small molecules like the bruton tyrosine kinase (BTK) and BCL2 inhibitors, for treating relapsed MCL has been established leading to a diminishing role for conventional chemotherapy. Combinations of small molecule inhibitors with or without chemoimmunotherapy, are showing promising results. Cellular therapy in the form of CAR-T cell therapy, has been approved recently. CONCLUSIONS: Personalized cancer treatment and chemo-free regimens are showing promise and results from well-planned long-term studies are evolving. In India, there is a paucity of epidemiological, clinical, and research data in this field.