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1.
Ann Surg Oncol ; 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39150618

RESUMEN

BACKGROUND: Atypical intradermal smooth muscle neoplasm, also commonly termed cutaneous leiomyosarcoma, is a soft tissue tumor with a low risk of aggressive behavior. These lesions arise in the dermis with possible superficial subcutaneous extension, demonstrate cytologic atypia, and often show mitotic activity. METHODS: A retrospective review of patient demographics, tumor characteristics, and treatment methods was conducted in a consecutive series of patients presenting to MD Anderson Cancer Center (MDACC) from 2002 to 2021 (n = 95). All pathology was reviewed by MDACC pathologists and determined to be atypical intradermal smooth muscle neoplasm. RESULTS: Median age at diagnosis was 58 years (range 22-86), and 74% were male. Ninety-five percent (n = 90) of patients identified as White, non-Hispanic. Most tumors were slow-growing, solitary, and painless nodules. Tumors were in the lower extremities (44.2%), followed by the upper extremity (28.4%), trunk (22.1%), and head and neck (5.2%). All patients (n = 44, 46.3%) who had a punch/incisional biopsy for diagnostic purposes had a subsequent tumor excision. Unplanned excision or excisional biopsy was performed on the remaining 46 (48%) patients. Of this subset, 41 of the 46 aforementioned patients (89%) had positive margins and underwent re-excision. Final pathology in 25/38 (66%) re-excision specimens was negative for residual tumor despite an initial positive margin. Two patients in the cohort had local recurrence 2 and 3 years after initial surgery. Both patients had positive margins, underwent excision of the recurrent tumor, and remain free of disease. After median follow-up of 6.9 years (range 1 day-18 years), 5-year recurrence-free survival was 96% and overall survival (OS) of the entire cohort was 78%. CONCLUSION: In this study of consecutive patients presenting with atypical intradermal smooth muscle neoplasm, we found good OS and local control after definitive surgical excision with negative margins, including excisional biopsy with close margins. Atypical intradermal smooth muscle neoplasm is unlikely to metastasize and has an excellent prognosis. Guidelines to determine optimal surveillance strategies for these patients should be revisited.

4.
Nat Cancer ; 5(4): 625-641, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38351182

RESUMEN

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Liposarcoma , Terapia Neoadyuvante , Neoplasias Retroperitoneales , Humanos , Liposarcoma/tratamiento farmacológico , Liposarcoma/inmunología , Terapia Neoadyuvante/métodos , Neoplasias Retroperitoneales/tratamiento farmacológico , Neoplasias Retroperitoneales/inmunología , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Anciano , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Sarcoma/terapia , Sarcoma/inmunología , Sarcoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacos
5.
Ann Surg Oncol ; 31(6): 4138-4147, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38396039

RESUMEN

BACKGROUND: Although social vulnerability has been associated with worse postoperative and oncologic outcomes in other cancer types, these effects have not been characterized in patients with soft tissue sarcoma. This study evaluated the association of social vulnerability and oncologic outcomes. METHODS: The authors conducted a single-institution cohort study of adult patients with primary and locally recurrent extremity or truncal soft tissue sarcoma undergoing resection between January 2016 and December 2021. The social vulnerability index (SVI) was measured on a low (SVI 1-39%, least vulnerable) to high (60-100%, most vulnerable) SVI scale. The association of SVI with overall survival (OS) and recurrence-free survival (RFS) was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. RESULTS: The study identified 577 patients. The median SVI was 44 (interquartile range [IQR], 19-67), with 195 patients categorized as high SVI and 265 patients as low SVI. The median age, tumor size, histologic subtype, grade, comorbidities, stage, follow-up time, and perioperative chemotherapy and radiation utilization were similar between the high and low SVI cohorts. The patients with high SVI had worse OS (p = 0.07) and RFS (p = 0.016) than the patients with low SVI. High SVI was independently associated with shorter RFS in the multivariate analysis (hazard ratio, 1.64; 95% confidence interval, 1.06-2.54) but not with OS (HR, 1.47; 95% CI 0.84-2.56). CONCLUSION: High community-level social vulnerability appears to be independently associated with worse RFS for patients undergoing resection of extremity and truncal soft tissue sarcoma. The effect of patient and community-level social risk factors should be considered in the treatment of patients with extremity sarcoma.


Asunto(s)
Extremidades , Recurrencia Local de Neoplasia , Sarcoma , Humanos , Femenino , Masculino , Sarcoma/cirugía , Sarcoma/mortalidad , Sarcoma/patología , Persona de Mediana Edad , Extremidades/cirugía , Extremidades/patología , Tasa de Supervivencia , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Recurrencia Local de Neoplasia/mortalidad , Anciano , Estudios de Seguimiento , Pronóstico , Adulto , Poblaciones Vulnerables , Torso/cirugía , Torso/patología , Estudios Retrospectivos , Factores de Riesgo , Neoplasias de los Tejidos Blandos/cirugía , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/patología
6.
Ann Surg Oncol ; 30(6): 3668-3676, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36723723

RESUMEN

BACKGROUND: Regional lymph node metastasis in extremity and trunk soft tissue sarcoma (ETSTS) is rare with no standardized management. We sought to determine management patterns for regional lymph node metastasis in ETSTS. METHODS: A survey regarding the management of ETSTS lymph node metastasis was distributed to the membership of the Musculoskeletal Tumor Society (MSTS) and the Society of Surgical Oncology (SSO) in January 2022. The survey queried the type of training (surgical oncology, orthopedic oncology), details of their practice setting, and management decisions of hypothetical ETSTS scenarios that involved potential or confirmed lymph node metastasis. RESULTS: The survey was distributed to 349 MSTS members (open rate of 63%, completion rate 21%) and 3026 SSO members (open rate of 55%, completion rate 4.7%) and was completed by 214 respondents, of whom 73 (34.1%) and 141 (65.9%) were orthopedic oncology and surgical oncology fellowship-trained, respectively. The majority of respondents practiced in an academic setting (n = 171, 79.9%) and treat >10 extremity sarcoma cases annually (n = 138, 62.2%). In scenarios with confirmed nodal disease for clear cell and epithelioid sarcoma, surgical oncologists were inclined to perform lymphadenectomy, while orthopedic oncologists were inclined to offer targeted lymph node excision with adjuvant radiation (p < 0.001). There was heterogeneity of responses regarding the management of nodal disease regardless of training background. CONCLUSION: Self-reported management of nodal disease in ETSTS was variable among respondent groups with differences and similarities based on training background. These data highlight the variability of practice for nodal disease management and the need for consensus-based guidelines.


Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Oncología Quirúrgica , Humanos , Metástasis Linfática , Escisión del Ganglio Linfático , Sarcoma/cirugía , Sarcoma/patología , Extremidades/cirugía , Extremidades/patología , Neoplasias de los Tejidos Blandos/cirugía , Neoplasias de los Tejidos Blandos/patología , Encuestas y Cuestionarios
8.
Ann Surg Oncol ; 30(2): 926-940, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36115928

RESUMEN

INTRODUCTION: EORTC-62092 (STRASS) was a phase 3, randomized study that compared surgery alone versus surgery plus neoadjuvant radiotherapy (RT) for retroperitoneal sarcomas. RT was not associated with improved abdominal recurrence-free survival, the primary outcome measure, although on subanalysis, there may have been benefit for well-differentiated (WD) liposarcoma. This study investigated the real-world use and outcomes of RT (neoadjuvant and adjuvant) for the management of retroperitoneal liposarcoma. METHODS: We queried the National Cancer Database (NCDB) (2004-2017) for patients with nonmetastatic, primary retroperitoneal liposarcoma treated with resection with or without RT (n = 3911). Patients were stratified by treatment type and histology [WD (n = 2252), dedifferentiated (DD) (n = 1659)]. Propensity score (PS) matching was used before comparison of treatment groups. Overall survival (OS) was the primary outcome measure. RESULTS: Median follow-up time was 4.1 years, and median OS was 10.7 years. There was no association between RT and OS for either WDLPS or DDLPS cohorts. We performed a subgroup analysis of neoadjuvant RT only, similar to STRASS. For WDLPS after PS matching (n = 208), neoadjuvant RT was not associated with OS (hazard ratio [HR] 1.01, p = 0.0523) but was associated with longer postoperative hospital stay (p = 0.012). For DDLPS after PS matching (n = 290), neoadjuvant RT was not associated with OS (HR 1.02, p = 0.889). For both WD-LPS and DD-LPS, utilization of neoadjuvant RT was associated with treatment at high-volume (≥ 10 cases/year) and academic/network facilities. CONCLUSIONS: For primary retroperitoneal liposarcoma treated with surgical resection, radiotherapy was not associated with an overall survival benefit in this propensity-matched, adjusted analysis of the NCDB.


Asunto(s)
Liposarcoma , Neoplasias Retroperitoneales , Sarcoma , Humanos , Lipopolisacáridos , Liposarcoma/radioterapia , Liposarcoma/cirugía , Sarcoma/patología , Neoplasias Retroperitoneales/radioterapia , Neoplasias Retroperitoneales/cirugía , Radioterapia Adyuvante , Estudios Retrospectivos
11.
Ann Surg Oncol ; 30(1): 480-489, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36085392

RESUMEN

BACKGROUND: Patients with unplanned excision (UPE) of trunk and extremity soft tissue sarcoma (STS) present a significant management challenge for sarcoma specialists. Oncologic re-resection has been considered standard practice after UPE with positive or uncertain margins. A strategy of active surveillance or "watch and wait" has been suggested as a safe alternative to routine re-excision. In this context, the current study sought to evaluate short-term outcomes and morbidity after re-resection to better understand the risks and benefits of this treatment strategy. METHODS: A retrospective, single-institution study reviewed patients undergoing oncologic re-resection after UPE of an STS during a 5-year period (2015-2020), excluding those with evidence of gross residual disease. Short-term clinical outcomes were evaluated together with final pathologic findings. RESULTS: The review identified 67 patients undergoing re-resection after UPE of an STS. Of these 67 patients, 45 (67%) were treated with a combination of external beam radiation therapy (EBRT) and surgery. Plastic surgery was involved for reconstruction in 49 cases (73%). The rate of wound complications after re-resection was 45 % (n = 30), with 15 % (n = 10) of the patients experiencing a major wound complication. Radiation therapy and plastic surgery involvement were independently associated with wound complications. Notably, 45 patients (67%) had no evidence of residual disease in the re-resection specimen, whereas 13 patients (19 %) had microscopic disease, and 9 patients (13%) had indeterminate pathology. CONCLUSION: Given the morbidity of re-resection and limited identification of residual disease, treatment plans and discussions with patients should outline the expected pathologic findings and morbidity of surgery.


Asunto(s)
Sarcoma , Humanos , Estudios Retrospectivos , Sarcoma/cirugía
12.
Lancet Oncol ; 23(12): 1547-1557, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36343656

RESUMEN

BACKGROUND: The standard preoperative radiotherapy regimen of 50 Gy delivered in 25 fractions for 5 weeks for soft tissue sarcomas results in excellent local control, with major wound complications occurring in approximately 35% of patients. We aimed to investigate the safety of a moderately hypofractionated, shorter regimen of radiotherapy, which could be more convenient for patients. METHODS: This single-centre, open-label, single-arm, phase 2 trial (HYPORT-STS) was done at a single tertiary cancer care centre (MD Anderson Cancer Center, Houston, TX, USA). We administered preoperative radiotherapy to a dose of 42·75 Gy in 15 fractions of 2·85 Gy/day for 3 weeks (five fractions per week) to adults (aged ≥18 years) with non-metastatic soft tissue sarcomas of the extremities or superficial trunk and an Eastern Cooperative Oncology Group performance status of 0-3. The primary endpoint was a major wound complication occurring within 120 days of surgery. Major wound complications were defined as those requiring a secondary operation, or operations, under general or regional anaesthesia for wound treatment; readmission to the hospital for wound care; invasive procedures for wound care; deep wound packing to an area of wound measuring at least 2 cm in length; prolonged dressing changes; repeat surgery for revision of a split thickness skin graft; or wet dressings for longer than 4 weeks. We analysed our primary outcome and safety in all patients who enrolled. We monitored safety using a Bayesian, one-arm, time-to-event stopping rule simulator comparing the rate of major wound complications at 120 days post-surgery among study participants with the historical rate of 35%. This trial is registered with ClinicalTrials.gov, NCT03819985, recruitment is complete, and follow-up continues. FINDINGS: Between Dec 18, 2018, and Jan 6, 2021, we assessed 157 patients for eligibility, of whom 120 were enrolled and received hypofractionated preoperative radiotherapy. At no time did the stopping rule computation indicate that the trial should be stopped early for lack of safety. Median postoperative follow-up was 24 months (IQR 17-30). Of 120 patients, 37 (31%, 95% CI 24-40) developed a major wound complication at a median time of 37 days (IQR 25-59) after surgery. No patient had acute radiation toxicity (during radiotherapy or within 4 weeks of the radiotherapy end date) of grade 3 or worse (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) or an on-treatment serious adverse event. Four (3%) of 115 patients had late radiation toxicity (≥6 months post-surgery) of at least grade 3 (CTCAE or Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme): femur fractures (n=2), lymphoedema (n=1), and skin ulceration (n=1). There were no treatment-related deaths. INTERPRETATION: Moderately hypofractionated preoperative radiotherapy delivered to patients with soft tissue sarcomas was safe and could therefore be a more convenient alternative to conventionally fractionated radiotherapy. Patients can be counselled about these results and potentially offered this regimen, particularly if it facilitates care at a sarcoma specialty centre. Results on long-term oncological, late toxicity, and functional outcomes are awaited. FUNDING: The National Cancer Institute.


Asunto(s)
Traumatismos por Radiación , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Adolescente , Teorema de Bayes , Resultado del Tratamiento , Neoplasias de los Tejidos Blandos/radioterapia , Neoplasias de los Tejidos Blandos/cirugía , Sarcoma/radioterapia , Sarcoma/cirugía , Hipofraccionamiento de la Dosis de Radiación
13.
Clin Transl Med ; 12(7): e961, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35839307

RESUMEN

BACKGROUND: Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat. METHODS: In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance. RESULTS: Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult-associated EPS versus proximal, adult-associated EPS. CONCLUSIONS: Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.


Asunto(s)
Proteínas de Unión al ADN , Sarcoma , Adolescente , Niño , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/uso terapéutico , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/uso terapéutico , Genómica , Humanos , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Sarcoma/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/uso terapéutico , Adulto Joven
14.
Ann Surg Oncol ; 29(11): 7092-7100, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35501583

RESUMEN

BACKGROUND: Lymph node metastases (LNMs) are rare in patients with soft tissue sarcoma (STS), and there is limited evidence to guide clinical management. We describe our experience with sentinel lymph node biopsy (SLNB) and lymphadenectomy in STS patients. METHODS: A single-center, retrospective review was performed for patients with STS treated with SLNB and/or lymphadenectomy from 1994 to 2018. Clinicopathologic characteristics, multimodality treatment, regional/distant recurrence-free survival (RFS), and overall survival (OS) were examined. RESULTS: Eighty-six patients underwent SLNB (n = 34) and/or lymphadenectomy (n = 60) for STS. The most frequent histologic subtypes were epithelioid, clear cell, and undifferentiated pleomorphic sarcoma. Eight of 34 (23.5%) patients had a positive SLNB with 5-year OS of 71.4% compared with 71.9% for those with a negative SLNB. Eight of the 26 SLN-negative patients (30.8%) eventually developed nodal recurrence (n = 2) and/or (n = 6) distant metastasis with an estimated 5-year OS of 50%. Of patients undergoing lymphadenectomy, estimated 5-year OS was 44.6% and median RFS was 12 months. Eight (13.3%) had distant disease at time of lymphadenectomy, 20 (33.3%) developed distant recurrence after lymphadenectomy, and 6 (10%) developed regional-only recurrence. Patients with regional-only recurrence after lymphadenectomy had an estimated 5-year OS of 66.7% compared with 29.1% for those who recurred distantly. CONCLUSIONS: Patients with positive SLNB had similar survival to those with negative SLNB. Lymphadenectomy for isolated nodal disease is associated with poor RFS but reasonable 5-year OS when recurrence is regional-only. In STS, regional disease appears clinically distinct from distant metastatic disease and has better outcomes.


Asunto(s)
Sarcoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Neoplasias de los Tejidos Blandos , Humanos , Escisión del Ganglio Linfático , Metástasis Linfática , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos , Sarcoma/cirugía , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patología , Neoplasias de los Tejidos Blandos/cirugía
15.
Lab Invest ; 102(6): 658-666, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35228656

RESUMEN

Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models available, we generated additional cell lines to study these rare cancers. Patient-derived tumors were used to establish 4 new UPS models, including one radiation-associated UPS-UPS271.1, UPS511, UPS0103, and RIS620, one unclassified spindle cell sarcoma-USC060.1, and 3 new models of MPNST-MPNST007, MPNST3813E, and MPNST4970. This study examined the utility of the new cell lines as sarcoma models by assessing their tumorigenic potential and mutation status for known sarcoma-related genes. All the cell lines formed colonies and migrated in vitro. The in vivo tumorigenic potential of the cell lines and corresponding xenografts was determined by subcutaneous injection or xenograft re-passaging into immunocompromised mice. USC060.1 and UPS511 cells formed tumors in mice upon subcutaneous injection. UPS0103 and RIS620 tumor implants formed tumors in vivo, as did MPNST007 and MPNST3813E tumor implants. Targeted sequencing analysis of a panel of genes frequently mutated in sarcomas identified TP53, RB1, and ATRX mutations in a subset of the cell lines. These new cellular models provide the scientific community with powerful tools for detailed studies of tumorigenesis and for investigating novel therapies for UPS and MPNST.


Asunto(s)
Neurofibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Animales , Humanos , Ratones , Modelos Teóricos , Mutación , Neurofibrosarcoma/genética , Sarcoma/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/genética
16.
Int J Cancer ; 150(12): 2012-2024, 2022 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-35128664

RESUMEN

Palbociclib has been evaluated in early phase trials for well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) patients, with reported median progression-free survival (PFS) of 18 weeks. Here, we report on real-world use and surgical outcomes associated with palbociclib treatment. We retrospectively reviewed 61 consecutive patients with retroperitoneal WDLPS (n = 14) or DDLPS (n = 47) treated with palbociclib monotherapy between 1 March 2016 and 28 February 2021 at The University of Texas MD Anderson Cancer Center. At palbociclib initiation, median age was 64 (interquartile range [IQR] 56-72). In WDLPS and DDLPS cohorts, the median number of prior systemic treatments was 0 (IQR 0-0) and 2 (IQR 0-4), respectively. Median number of prior surgeries was 2 (WDLPS IQR 1-2.75) and 2 (DDLPS IQR 1-3). Median PFS was 9.2 (WDLPS IQR 3.9-21.9) and 2.6 months (DDLPS IQR 2.0-6.1), with median time on treatment of 7.4 months (WDLPS IQR 3.5-14.2) and 2.7 months (DDLPS IQR 2.0-5.7). Twelve patients ultimately underwent surgical resection. Resections were macroscopically complete (R0/R1) in half (n = 6/12), among whom only one patient experienced relapse after resection (median follow-up 7.5 months). All patients who underwent macroscopically incomplete resections progressed after surgery with median time to progression of 3.3 months (IQR 2.3-4.4). Surgery after palbociclib treatment was not associated with improved overall survival. Efficacy of palbociclib monotherapy for patients with advanced WDLPS and DDLPS is disappointing. While palbociclib may have been used to delay surgery, there was no clear benefit from treatment and few patients achieved prolonged tumor control.


Asunto(s)
Liposarcoma , Neoplasias de los Tejidos Blandos , Humanos , Liposarcoma/tratamiento farmacológico , Liposarcoma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Piperazinas , Piridinas , Neoplasias Retroperitoneales , Estudios Retrospectivos , Neoplasias de los Tejidos Blandos/patología
17.
Ann Surg Oncol ; 2022 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-35224688

RESUMEN

BACKGROUND: Sarculator is an online validated nomogram that predicts overall survival of patients with resected, primary extremity sarcomas. However, its ability to accurately predict outcomes in US patients with sarcoma is unknown. PATIENTS AND METHODS: Patients from the National Cancer Data Base (NCDB) (2006-2016) with resected stage I-III primary extremity or trunk sarcoma were included. Predicted overall survival (pOS) was calculated using the Sarculator algorithm, which includes patient age, tumor size (cm), grade (1-3), and histology, and compared with actual overall survival (aOS). Harrell's C-index was calculated to determine the discriminatory ability of Sarculator (0.7 = good, 0.8 = strong, 1.0 = perfect model), and calibration plots were created. RESULTS: In total, 9738 patients were included. Five-year pOS was 73.7% compared with aOS of 68.9%. The C-index for the entire cohort was 0.726. By stage, the C-index was 0.730 for stage I, 0.708 for stage II, and 0.679 for stage III. By histology, C-indices were highest for leiomyosarcoma (0.745), myxofibrosarcoma (0.722), and other histologies (0.721). By sociodemographic variables, Sarculator performed better for patients < 50 years (C-index 0.722), of other/unknown race (C-index 0.781), with private insurance (C-index 0.715), treated at a center other than a community cancer programs (C-index > 0.7), and with no comorbidities (C-index 0.716). Outcomes by zip code educational attainment and income were not markedly different (all C-indices > 0.7). CONCLUSIONS: Sarculator is overall a good predictor of aOS and useful tool for clinicians to aid in survival prognostication. However, clinicians should be aware of populations for whom Sarculator's predictions may be less accurate. Future work could focus on enhancing the Sarculator algorithm specifically for US patients by including demographic variables.

18.
Am J Cancer Res ; 11(8): 3980-3989, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34522462

RESUMEN

Insulin growth factor-1 (IGF-1) plays important roles in carcinogenesis. Previous studies have linked circulating IGF-1 and its main binding protein, insulin-like growth factor-binding protein-3 (IGFBP-3), to cancer risks. However, no study has been conducted in soft tissue sarcoma (STS). In this study, we investigated the relationship of genetically predicted circulating IGF-1 and IGFBP-3 with STS risks. Recent large genome-wide association studies (GWAS) have identified 413 single nucleotide polymorphisms (SNPs) associated with IGF-1 and 4 SNPs associated with IGFBP-3. We genotyped these SNPs in 821 patients and 851 healthy controls. We constructed weighted genetic risk scores (GRS) to predict circulating IGF-1 and IGFBP-3. We determined the associations of individual SNPs and GRS with the risks of STS using multivariate logistic regression analysis. We found high genetically predicted circulating IGF-1 and IGFBP-3 were both associated with increased STS risks. Dichotomized at the median values of IGF-1 and IGFBP-3 in controls, individuals with high level of IGF-1 exhibited a 27% increased risk of STS (odds ratio [OR]=1.27, 95% confidence interval [CI]=1.04-1.54, P=0.017), whereas the OR for high IGFBP-3 was 1.45 (95% CI=1.20-1.77, P<0.001). Interestingly, the significant association between IGFBP-3 and STS risk was only evident in women (OR=1.88, 95% CI=1.42-2.49, P<0.001), but not in men (OR=1.00, 95% CI=0.75-1.33, P=0.992). In stratified analyses by major STS subtypes, the strongest associations were observed in angiosarcoma for IGF-1, leiomyosarcoma for IGFBP-3, and gastrointestinal stromal tumors for IGFBP-3 in women. In conclusion, high circulating IGF-1 and IGFBP-3 levels were both associated with increased STS risks.

19.
Acta Neuropathol ; 142(3): 565-590, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34283254

RESUMEN

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that frequently harbor genetic alterations in polycomb repressor complex 2 (PRC2) components-SUZ12 and EED. Here, we show that PRC2 loss confers a dedifferentiated early neural-crest phenotype which is exclusive to PRC2-mutant MPNSTs and not a feature of neurofibromas. Neural crest phenotype in PRC2 mutant MPNSTs was validated via cross-species comparative analysis using spontaneous and transgenic MPNST models. Systematic chromatin state profiling of the MPNST cells showed extensive epigenomic reprogramming or chromatin states associated with PRC2 loss and identified gains of active enhancer states/super-enhancers on early neural crest regulators in PRC2-mutant conditions around genomic loci that harbored repressed/poised states in PRC2-WT MPNST cells. Consistently, inverse correlation between H3K27me3 loss and H3K27Ac gain was noted in MPNSTs. Epigenetic editing experiments established functional roles for enhancer gains on DLX5-a key regulator of neural crest phenotype. Consistently, blockade of enhancer activity by bromodomain inhibitors specifically suppressed this neural crest phenotype and tumor burden in PRC2-mutant PDXs. Together, these findings reveal accumulation of dedifferentiated neural crest like state in PRC2-mutant MPNSTs that can be targeted by enhancer blockade.


Asunto(s)
Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/genética , Neoplasias del Sistema Nervioso Periférico/tratamiento farmacológico , Neoplasias del Sistema Nervioso Periférico/genética , Complejo Represivo Polycomb 2/genética , Animales , Biomarcadores de Tumor , Proteínas de Ciclo Celular/antagonistas & inhibidores , Diferenciación Celular/genética , Línea Celular Tumoral , Perros , Elementos de Facilitación Genéticos/genética , Epigénesis Genética/genética , Proteínas de Homeodominio/genética , Humanos , Ratones , Ratones Transgénicos , Mutación , Neoplasias de la Vaina del Nervio/patología , Cresta Neural/patología , Neoplasias del Sistema Nervioso Periférico/patología , Especificidad de la Especie , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra
20.
JAMA Netw Open ; 4(3): e210945, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33734413

RESUMEN

Importance: Neurofibromatosis type 1 (NF1) is a complex genetic disorder that is associated with not only neurofibromas, but also an increased susceptibility to other neoplasms. Objective: To evaluate the prevalence of neoplasia and outcomes among patients with NF1. Design, Setting, and Participants: This cohort study was conducted among patients with NF1 at a single academic cancer center from 1985 to 2020 with median (range) follow-up of 2.9 years (36 days to 30.5 years). Of 2427 patients evaluated for NF1, 1607 patients who met the National Institutes of Health consensus criteria for NF1 were included. This group was compared with estimates from Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review 1975 to 2015 and SEER participants database unless otherwise specified. Data were analyzed from August 2018 to March 2020. Main Outcomes and Measures: Disease-specific survival (DSS) was measured from diagnosis date to date of neoplasm-specific death or censorship and calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Deaths from disease were considered a DSS end point; other deaths were considered censored observations. Secondary outcome measures were comparisons of (1) overall survival of patients with NF1 with neurofibroma neoplasms vs those without nonneurofibroma neoplasms, (2) neoplasm prevalence in the NF1 group vs general population estimates, and (3) age at diagnosis in the NF1 group vs general population estimates for the most common neoplasms in the NF1 group. Results: Among 1607 patients with NF1, the median (range) age at initial visit was 19 years (1 month to 83 years) and 840 (52.3%) were female patients. Among 666 patients who developed other neoplasms in addition to neurofibromas (41.4%), 295 patients (18.4%) developed glioma and 243 patients (15.1%) developed malignant peripheral nerve sheath tumor (MPNST), the most common neoplasms. Patients with NF1, compared with the general population, developed several neoplasms at a younger mean (SD) age (low-grade glioma: 12.98 [11.09] years vs 37.76 [24.53] years; P < .0001; high-grade glioma [HGG]: 27.31 [15.59] years vs 58.42 [19.09] years; P < .0001; MPNST: 33.88 [14.80] years vs 47.06 [20.76] years; P < .0001; breast cancer: 46.61 [9.94] years vs 61.71 [13.85] years; P < .0001). Patients with NF1 developed neoplasms more frequently compared with the general population (odds ratio, 9.5; 95% CI, 8.5-10.5; P < .0001). Among patients with NF1, significantly lower 5-year DSS rates were found among those with undifferentiated pleomorphic sarcoma (1 of 5 patients [20.0%]), HGG (8 of 34 patients [23.1%]), MPNST (72 of 228 patients [31.6%]), ovarian carcinoma (4 of 7 patients [57.1%]), and melanoma (8 of 12 patients [66.7%]) compared with those who had neoplasms classified as other (110 of 119 patients [92.4%]) (all P < .001) . Conclusions and Relevance: This cohort study found that among patients with NF1, those who developed undifferentiated pleomorphic sarcoma, HGG, MPNST, ovarian carcinoma, or melanoma had significantly lower DSS rates compared with those who developed other neoplasms. This study also found that patients with NF1 developed some neoplasms more frequently and at a younger age compared with individuals without NF1. HGGs and MPNST were noteworthy causes of death among patients NF1. This information may be useful for NF1 patient counseling and follow-up.


Asunto(s)
Neoplasias Primarias Múltiples/epidemiología , Neoplasias/epidemiología , Neurofibromatosis 1/epidemiología , Centros Médicos Académicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Tiempo , Adulto Joven
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