RESUMO
BACKGROUND: Radiation-associated soft tissue sarcomas (RA-STS) are rare complications of patients receiving radiation therapy (RT) and are generally associated with a poor prognosis. Most of the literature surrounding RA-STS of the chest is centered on angiosarcoma. Therefore, we aim to document the management and outcome of patients with non-angiosarcoma RA-STS of the chest. METHODS: We reviewed 17 patients (all female, median age 65 years) diagnosed with RA-STS. The most common primary malignancy was breast carcinoma (n = 15), with a median RT dose of 57.9 Gy. All patients underwent surgical resection; five patients (29%) received radiotherapy; and five patients (29%) received peri-operative chemotherapy. RESULTS: The 5-year local recurrence and metastatic-free survival were 61% and 60%, while the 5-year disease-specific survival was 53%. Local recurrence was associated with death due to disease (HR 9.06, p = 0.01). Complications occurred in nine of patients, most commonly due to a wound complication (n = 7). At the most recent follow-up, the median Musculoskeletal Tumor Society Score was 63%. CONCLUSION: RA-STS involving the chest wall are aggressive tumors with a high risk of local relapse and death due to disease. Local recurrence was associated with death due to disease; as such, we recommend aggressive surgical management with evaluation for adjuvant therapies.
Assuntos
Recidiva Local de Neoplasia , Sarcoma , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Sarcoma/radioterapia , Sarcoma/patologia , Sarcoma/mortalidade , Sarcoma/terapia , Sarcoma/cirurgia , Recidiva Local de Neoplasia/patologia , Neoplasias Induzidas por Radiação/patologia , Neoplasias Induzidas por Radiação/mortalidade , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/cirurgia , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Adulto , Neoplasias Torácicas/radioterapia , Neoplasias Torácicas/patologia , Neoplasias Torácicas/mortalidade , Parede Torácica/patologia , Parede Torácica/efeitos da radiação , Seguimentos , Neoplasias de Tecidos Moles/radioterapia , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Neoplasias de Tecidos Moles/cirurgia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapiaRESUMO
BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
Assuntos
Doenças Raras , Doenças não Diagnosticadas , Estados Unidos , Humanos , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/terapia , Atenção Terciária à Saúde , Medicina Genômica , Testes Genéticos , Aconselhamento GenéticoRESUMO
Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colina/análogos & derivados , Reparo do DNA/efeitos dos fármacos , Hidrazinas/farmacologia , Carioferinas/antagonistas & inibidores , Linfoma não Hodgkin/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Salicilatos/farmacologia , Triazóis/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Colina/administração & dosagem , Colina/efeitos adversos , Colina/farmacologia , Replicação do DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Ftalazinas/administração & dosagem , Ftalazinas/farmacologia , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Distribuição Aleatória , Salicilatos/administração & dosagem , Salicilatos/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína Exportina 1RESUMO
PURPOSE: Extraskeletal Ewing sarcoma (EES), is a rare soft tissue sarcoma. Treatment for EES commonly involves chemotherapy and surgical resection (ST) or less commonly combined chemotherapy, surgery, and radiotherapy (ST + RT). The purpose of the current study was to evaluate our institutional experience treating EES. METHODS: We reviewed 36 (18 males:18 females) patients (mean age 30 years) with a nonretroperitoneal/visceral EES treated with either ST (n = 24, 67%) or ST + RT (n = 12, 33%). All patients were treated with chemotherapy, most commonly vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide (VDC/IE, n = 23, 66%) Radiotherapy was mostly delivered preoperatively (n = 9). The mean follow-up was 8 years. RESULTS: The 10-year disease specific survival for patients was 78%, with no difference in the survival between patients in the ST versus the ST + RT groups (83% vs. 71%, p = 0.86). There was no difference in the 10-year local recurrence (91% vs. 100%, p = 0.29) or metastatic free survival (87% vs. 75%, p = 0.45) between the ST and ST + RT groups. CONCLUSION: The results of the current study highlight the ability to achieve excellent local control with chemotherapy and surgery for EES. We recommend for multidisciplinary management of patients with EES, including chemotherapy and surgery, with use of radiotherapy if there is concern for a potentially close margin of resection.
Assuntos
Neoplasias Ósseas , Sarcoma de Ewing , Sarcoma , Adulto , Feminino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida , Doxorrubicina , Etoposídeo/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patologia , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Compared to other sarcomas, myxoid liposarcoma (ML) is known to be radiosensitive, with improved oncologic outcomes. Although these tumors "shrink" following radiotherapy, there is a paucity of data examining the degree of radiosensitivity and oncologic outcome. The purpose of the study was to evaluate pre- and postradiotherapy tumor volume to determine if size reduction impacts outcome. METHODS: We reviewed 62 patients with ML undergoing surgical resection combined with preoperative radiotherapy, with pre- and postradiotherapy MRI. This included 34 (55%) males, with a mean age of 47 ± 14 years. All tumors were deep to the fascia, and 12 (19%) patients had tumors with a >5% round-cell component. RESULTS: The mean volume reduction was 54% ± 29%. Compared to patients with >25% volume reduction, patients with reduction ≤25% had worse 10-year disease specific survival (86% vs. 37%, p < 0.01), in addition to an increased risk of metastatic disease (HR 4.63, p < 0.01) and death due to disease (HR 4.52, p < 0.01). CONCLUSION: Lack of volume reduction is a risk factor for metastatic disease and subsequent death due to disease in patients with extremity ML treated with combined preoperative radiotherapy and surgery. This data could be used to stratify patients for adjuvant therapies and follow-up intervals.
Assuntos
Lipossarcoma Mixoide , Lipossarcoma , Sarcoma , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Combinada , Extremidades/patologia , Lipossarcoma/patologia , Lipossarcoma Mixoide/radioterapia , Lipossarcoma Mixoide/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Extraskeletal Ewing sarcoma are rare tumors within the Ewing sarcoma family. Initial staging studies for extraskeletal Ewing sarcoma historically have included imaging and bone marrow aspiration and biopsy (BMAB). However, recent studies on Ewing sarcoma of bone have questioned the utility of BMAB in the initial staging of patients, but no studies of which we are aware have evaluated the role of BMAB in extraskeletal Ewing sarcoma. We suspected that BMAB was of low diagnostic yield in patients with extraskeletal Ewing sarcoma and exposed patients to potential morbidity without an impact on their clinical course. QUESTION/PURPOSE: Is BMAB a useful test in the staging of extraskeletal Ewing sarcoma? METHODS: Between January 1996 and December 2021, our institution evaluated 109 patients with a listed diagnosis of extraskeletal Ewing sarcoma. Those patients were retrospectively reviewed for this study. Of those, we considered patients with biopsy-confirmed diagnosis of extraskeletal Ewing sarcoma. Biopsy was performed based on institutional protocols, with all diagnoses assigned by a board-certified pathologist. Based on that criteria, 96% (105 of 109) were eligible. An additional 18% (20 of 109) were excluded because records of their initial diagnostic and staging workup were not available. This left 78% (85 of 109) for analysis. Of those, 52% (44 of 85) were male. The average age was 32 ± 16 years. Primary tumor locations included extremities in 26% (22 of 85), paraspinal in 20% (17 of 85), chest in 19% (16 of 85), retroperitoneum in 13% (11 of 85), intraabdominal in 12% (10 of 85), intrapelvic in 7% (6 of 85), and head or neck in 4% (3 of 85). Initial diagnostic and staging information, including the use of PET-CT, bone scan, CT chest, and BMAB, was collected. Metastatic disease at the time of presentation or during follow-up was noted. The utility of BMAB was determined by the rate of positive tests in those undergoing BMAB during the initial staging process. Descriptive statistical analysis was sufficient to address the study question, and therefore no comparative statistics were performed. RESULTS: BMAB was obtained during the initial staging process in 64% (54 of 85) of patients. This BMAB was negative in all 54 patients, including those with known metastatic disease. CONCLUSION: Diagnosing metastatic disease in extraskeletal Ewing sarcoma is important as the presence of metastases at diagnosis adversely affects prognosis. The routine use of BMAB in the staging process of extraskeletal Ewing sarcoma is of low diagnostic yield. BMAB is unlikely to diagnose metastatic involvement even in patients with known metastases to bone. We do not have enough data to suggest whether other modalities, such as PET-CT, might be more useful. Similar studies should be pursued to determine the utility of the remainder of staging modalities in patients with extraskeletal Ewing sarcoma to elucidate the most efficient and effective staging protocol. LEVEL OF EVIDENCE: Level III, diagnostic study.
Assuntos
Neoplasias Ósseas , Sarcoma de Ewing , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Feminino , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Neoplasias Ósseas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medula Óssea/patologia , Estudos Retrospectivos , Relevância Clínica , Biópsia , Tomografia Computadorizada por Raios X , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma. METHODS: This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort. RESULTS: 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients. CONCLUSIONS: In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Indazóis/administração & dosagem , Osteossarcoma/tratamento farmacológico , Pirimidinas/administração & dosagem , Sarcoma/tratamento farmacológico , Sulfonamidas/administração & dosagem , Topotecan/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Humanos , Indazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Topotecan/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Musculoskeletal interventions are increasingly used with palliative and curative intent in the multidisciplinary treatment of oncology patients with bone and soft-tissue tumors. There is an unmet need for high-quality evidence to guide broader application and adoption of minimally invasive interventional technologies to treat these patients. Therefore, the Society of Interventional Radiology Foundation and the Society of Interventional Oncology collaborated to convene a research consensus panel to prioritize a research agenda addressing the gaps in the current evidence. This article summarizes the panel's proceedings and recommendations for future basic science and clinical investigation to chart the course for interventional oncology within the musculoskeletal system. Key questions that emerged addressed the effectiveness of ablation within specific patient populations, the effect of combination of ablation with radiotherapy and/or immunotherapy, and the potential of standardization of techniques, including modeling and monitoring, to improve the consistency and predictability of treatment outcomes.
Assuntos
Radiologia Intervencionista , Neoplasias de Tecidos Moles , Consenso , Humanos , Oncologia , Cuidados PaliativosRESUMO
Primary pulmonary artery sarcoma (PPAS) is a rare malignancy that is commonly mistaken for pulmonary embolism due to similarities in clinical presentation and radiographic findings. Distinct radiographic findings to help differentiate between the two diseases are highlighted in the case presented. (1) Several nuances in various imaging modalities have been identified to help distinguish pulmonary artery sarcoma from pulmonary thromboembolic disease. (2) The wall eclipsing sign is considered pathognomonic for pulmonary artery sarcoma. (3) Positron emission tomography/computed tomography may help reduce time between diagnosis and treatment, which may ultimately prolong survival. (4) Providers should be well versed on the subtle differences on imaging to prevent future delays in diagnosis and treatment.
Assuntos
Embolia Pulmonar , Sarcoma , Neoplasias Vasculares , Diagnóstico Diferencial , Humanos , Imagem Multimodal , Artéria Pulmonar/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Sarcoma/diagnóstico por imagem , Neoplasias Vasculares/diagnóstico por imagemRESUMO
A variety of analytical approaches have indicated that melanoma cell line UCLA-SO-M14 (M14) and breast carcinoma cell line MDA-MB-435 originate from a common donor. This indicates that at some point in the past, one of these cell lines became misidentified, meaning that it ceased to correspond to the reported donor and instead became falsely identified (through cross-contamination or other means) as a cell line from a different donor. Initial studies concluded that MDA-MB-435 was the misidentified cell line and M14 was the authentic cell line, although contradictory evidence has been published, resulting in further confusion. To address this question, we obtained early samples of the melanoma cell line (M14), a lymphoblastoid cell line from the same donor (ML14), and donor serum preserved at the originator's institution. M14 samples were cryopreserved in December 1975, before MDA-MB-435 cells were established in culture. Through a series of molecular characterizations, including short tandem repeat (STR) profiling and cytogenetic analysis, we demonstrated that later samples of M14 and MDA-MB-435 correspond to samples of M14 frozen in 1975, to the lymphoblastoid cell line ML14, and to the melanoma donor's STR profile, sex and blood type. This work demonstrates conclusively that M14 is the authentic cell line and MDA-MB-435 is misidentified. With clear provenance information and authentication testing of early samples, it is possible to resolve debates regarding the origins of problematic cell lines that are widely used in cancer research.
Assuntos
Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Melanoma/patologia , Neoplasias da Mama/genética , DNA de Neoplasias/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Melanoma/genéticaRESUMO
This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on treatment and management considerations for AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for AYA Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.
Assuntos
Neoplasias/diagnóstico , Neoplasias/terapia , Adolescente , Comportamento , Terapia Combinada/métodos , Gerenciamento Clínico , Feminino , Fertilidade , Humanos , Incidência , Neoplasias/epidemiologia , Neoplasias/etiologia , Cuidados Paliativos , Gravidez , Complicações Neoplásicas na Gravidez , Assistência Terminal , Adulto JovemRESUMO
PURPOSE: Local control for Ewing sarcoma (ES) has improved in modern studies. However, it is unclear if these gains have also been achieved for pelvis tumors. The purpose of this study is to evaluate local control and survival in pelvis ES patients treated in the modern era. METHODS: All pelvis ES patients diagnosed from 1990 to 2012 and seen at Mayo Clinic were identified. Factors relevant to survival and local control were analyzed. RESULTS: The cohort consisted of 48 patients. Fifty-two percent had metastatic disease at diagnosis. The 5-year overall survival and event-free survival was 73% and 65%, respectively, for localized disease. The 5-year cumulative incidence of local recurrence was 19%, with a 26% incidence for radiation, 13% for surgery, and 0% for surgery + radiation (P = 0.54). All local failures occurred in-field. Sacral involvement by tumor trended toward a higher incidence of local recurrence (hazard ratio 3.06, P = 0.09). Patients treated with definitive radiation doses ≥5,600 cGy had a lower incidence of local recurrence (17% vs. 28%, P = 0.61). CONCLUSIONS: Our study demonstrates excellent survival for localized tumors in the modern era. Anatomical localization within the pelvis likely correlates with outcomes. Local control remains problematic, especially for patients treated with definitive radiation. Though statistically not significant, surgery + radiation and definitive radiation dose ≥5,600 cGy were associated with the lowest incidence of local failure, suggesting treatment intensification may improve local control for pelvis ES.
Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Sarcoma de Ewing/patologia , Sarcoma de Ewing/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/mortalidade , Criança , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Pelve , Radioterapia , Estudos Retrospectivos , Sarcoma de Ewing/mortalidade , Adulto JovemRESUMO
To characterize the gene expression profile of regenerated melanocytes in the narrow band UVB (NBUVB)-treated vitiligo epidermis and their precursors in the hair follicle, we present here a strategy of RNA isolation from in situ melanocytes using human frozen skin. We developed a rapid immunostaining protocol using the NKI-beteb antibody, which labels differentiated and precursor melanocytes, followed by fluorescent laser capture microdissection. This technique enabled the direct isolation, from melanocyte and adjacent keratinocyte populations, of satisfactory quality RNA that was successfully amplified and analysed by qRT-PCR. The melanocyte-specific gene transcripts TYR, DCT, TYRP1 and PMEL were significantly upregulated in our NBUVB-treated melanocyte samples as compared with the keratinocyte samples, while keratinocyte-specific genes (KRT5 and KRT14) were expressed significantly higher in the keratinocyte samples as compared with the melanocyte samples. Furthermore, in both NBUVB-treated vitiligo skin and normal skin, when bulge melanocytes were compared with epidermal melanocytes, we found significantly lower expression of melanocyte-specific genes and significantly higher expression of three melanocytic stem cell genes (SOX9, WIF1 and SFRP1), while ALCAM and ALDH1A1 transcripts did not show significant variation. We found significantly higher expression of melanocyte-specific genes in the epidermis of NBUVB-treated vitiligo, as compared to the normal skin. When comparing bulge melanocyte samples from untreated vitiligo, NBUVB-treated vitiligo and normal skin, we did not find significant differences in the expression of melanocyte-specific genes or melanocytic stem cell genes. These techniques offer valuable opportunities to study melanocytes and their precursors in vitiligo and other pigmentation disorders.
Assuntos
Microdissecção e Captura a Laser , Melanócitos/metabolismo , RNA/isolamento & purificação , Vitiligo/metabolismo , Estudos de Casos e Controles , Humanos , RNA/metabolismo , Vitiligo/radioterapiaRESUMO
Seizures occur in most patients with primary malignant tumors and are associated with poor quality of life. To our knowledge, no previous studies have sought descriptions of quality of life in patients' own words. Patients with a history of a malignant primary brain tumor and seizures participated in semi-structured interviews, which were analyzed with qualitative methodology. Twenty-seven patients participated, most with high grade brain tumors. Most were receiving anti-seizure medication. Three distinct themes emerged: (1) the first seizure as a sentinel event, as manifested in part by how patients described their first seizure in remarkable detail ("I clearly remember the date "); (2) seizures as inextricably tied to the brain tumor itself; for example, one patient explained how he "always wondered what was happening with my brain tumor" with each seizure; and (3) adaptation and acceptance-or lack therefore-to seizures. With respect to this third theme, patients conveyed frustration from an inability to work, to drive, and to take care of their children ("It's like you are 15 all over again.") Others described frustration with taking antiseizure medications ("I felt like an 80 year old, now taking her pills every day"). However, some patients had adapted or resigned themselves (" so much of life is out of control-you just gotta take what you get."). These findings have future research implications but should also serve to make healthcare providers more aware of the heavy emotional burden that seizures thrust upon brain tumor patients.
Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/psicologia , Convulsões/etiologia , Convulsões/psicologia , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Qualidade de Vida , Convulsões/tratamento farmacológicoRESUMO
Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies.
Assuntos
Apoptose/genética , Regulação da Expressão Gênica/genética , Genoma Humano/genética , Melanoma/genética , Proteínas Musculares/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sequência de Bases , Western Blotting , Primers do DNA/genética , Exoma/genética , Vetores Genéticos/genética , Células HEK293 , Humanos , Imunoprecipitação , Lentivirus , MicroRNAs/genética , Dados de Sequência Molecular , Proteínas Musculares/metabolismo , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/metabolismoRESUMO
Sarcomas are a rare and highly diverse group of malignancies of mesenchymal origin. While sarcomas are generally considered resistant to immunotherapy, recent studies indicate subtype-specific differences in clinical response to checkpoint inhibitors (CPIs) that are associated with distinct immune phenotypes present in sarcoma subtypes. Oncolytic viruses (OVs) are designed to selectively infect and kill tumor cells and induce intratumoral immune infiltration, enhancing immunogenicity and thereby sensitizing tumors to immunotherapy. Herein we review the accumulated clinical data evaluating OVs in sarcoma. Small numbers of patients with sarcoma were enrolled in early-stage OV trials as part of larger solid tumor cohorts demonstrating safety but providing limited insight into the biological effects due to the low patient numbers and lack of histologic grouping. Several recent studies have investigated talimogene laherparepvec (T-VEC), an approved oncolytic herpes simplex virus (HSV-1), in combination therapy regimens in sarcoma patient cohorts. These studies have shown promising responses in heavily pre-treated and immunotherapy-resistant patients associated with increased intratumoral immune infiltration. As new and more potent OVs enter the clinical arena, prospective evaluation in subtype-specific cohorts with correlative studies to define biomarkers of response will be critical to advancing this promising approach for sarcoma therapy.
RESUMO
Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = -0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.
Assuntos
Glioblastoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Vírus do Sarampo/genética , Antígeno Carcinoembrionário/genética , Recidiva Local de Neoplasia/terapia , Vacina contra Sarampo , Microambiente TumoralRESUMO
Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.
Assuntos
Aldeído Desidrogenase/genética , Transformação Celular Neoplásica/genética , Melanoma/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Cutâneas/genética , Aldeído Desidrogenase/antagonistas & inibidores , Família Aldeído Desidrogenase 1 , Aldeído Oxirredutases , Animais , Apoptose/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Melanoma/enzimologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno/genética , Elementos de Resposta , Retinal Desidrogenase , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Temozolomida , Tretinoína/química , Tretinoína/farmacologiaRESUMO
BACKGROUND: There are several modifications in the technique for the placement of mesh during laparoscopic inguinal hernia repair. One of these is a slit on the mesh to surround the cord structures which proponents of it suggest that it decreases the recurrence rate due to better anchoring of the mesh and lower risk of displacement. There is only low-level evidence in current literature examining the two methods. The present study aimed to provide stronger evidence in establishing whether the slit mesh technique is superior to the non-slit mesh technique. METHODS: The reporting of this systematic review was guided by the standards of the preferred reporting items for systematic review and meta-analysis statement and registered with PROSPERO (ID: CRD42022300629). Eligible studies had to compare the two methods of mesh placement slit Vs nonslit in laparoscopic Inguinal hernia repair and also report on at least one outcome. The outcomes were expressed in odd ratios with their 95% confidence intervals. Where significant heterogeneity existed a random effects model was used otherwise a fixed effects model was used. RESULTS: Five studies met the criteria for inclusion in quantitative analysis. Overall, there were 10 (1.5%) recurrences in the slit group compared to 12 (2.5%) in the non-slit group OR 0.62, 95% CI (0.27-1.41). There was no difference in the incidence of post-operative bleeding (OR 1.21, 95%CI 0.4-3.66), seroma formation (OR1.5, 95% CI 0.81-2.76), or post-operative neuralgia (OR 0.98, 95%CI 0.11-8.92) between the two groups. CONCLUSION: There was no difference between the two methods.