Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis.

Sentinel Lymph Node Biopsy for Extremity and Truncal Soft Tissue Sarcomas: A Systematic Review of the Literature.

BACKGROUND: Regional lymph node metastasis (RLNM) occurs infrequently in patients with soft tissue sarcoma (STS), although certain STS subtypes have a higher propensity for RLNM. The identification of RLNM has significant implications for staging and prognosis; however, the precise impact of node-positive disease on patient survival remains a topic of controversy. Although the benefits of sentinel lymph node biopsy (SLNB) are well documented in patients with melanoma and breast cancer, whether this procedure offers a benefit in STS is controversial. METHODS: A systematic literature search was performed and articles reviewed to determine if SLNB in patients with extremity/truncal STS impacts disease-free or overall survival. RESULTS: Six studies were included. Rates of sentinel lymph node positivity were heterogeneous (range 4.3-50%). The impact of SLNB on patient outcomes remains unclear. The overall quality of available evidence was low, as assessed by the Grading of Recommendations, Assessment, Development, and Evaluation system. CONCLUSIONS: The literature addressing the impact of nodal basin evaluation on the staging and management of patients with extremity/truncal STS is confounded by heterogeneous patient cohorts and clinical practices. Multicenter prospective studies are warranted to determine the true incidence of RLNM and whether SLNB could benefit patients with clinically occult RLNM at diagnosis.

Percutaneous Cryoablation Provides Disease Control for Extra-Abdominal Desmoid-Type Fibromatosis Comparable with Surgical Resection.

PURPOSE: The aim of this study was to determine outcomes and prognostic factors for patients with primary and locally recurrent extra-abdominal desmoid tumors who underwent percutaneous cryoablation, and to compare with patients treated with surgery. METHODS: Group characteristics were compared using Fisher's exact test, and propensity score matching was performed using the nearest-neighbor approach. Kaplan-Meier and log-rank analyses were used to evaluate the variation in first local recurrence and disease control, while multivariate Cox regression was used to identify factors associated with first local recurrence. All statistical tests were two-sided and a p-value of 0.05 was considered statistically significant. RESULTS: Twenty-two cryoablation patients were matched with 33 surgical patients (n = 55). Median follow-up after cryoablation was 16.3 months versus 14.9 months after surgery. Two-year local recurrence-free survival (LRFS) was 59% after cryoablation and 71% after surgery, and median LRFS was 26.6 months after cryoablation but was not reached after surgery. Two-year disease control for all patients was 85%, however median disease control was not reached in either the cryoablation or surgery groups. There was no significant difference in LRFS or disease control between matched cryoablation and surgical patients. No local recurrences occurred after the first cryoablation in patients with zero or one of the following risk factors: tumor size > 5 cm, age ≤ 25 years, or locally recurrent disease. All patients with two or more of these risk factors recurred locally after the first cryoablation. CONCLUSION: Percutaneous cryoablation of primary and locally recurrent extra-abdominal desmoid tumors provides freedom from first local recurrence and long-term disease control comparable with surgery.

Histologic Subtype Defines the Risk and Kinetics of Recurrence and Death for Primary Extremity/Truncal Liposarcoma.

OBJECTIVE: We sought to define the prognostic significance of histologic subtype for extremity/truncal liposarcoma (LPS). BACKGROUND: LPS, the most common sarcoma, is comprised of 5 histologic subtypes. Despite their distinct behaviors, LPS outcomes are frequently reported as a single entity. METHODS: We analyzed data on all patients from a single-institution prospective database treated from July 1982 to September 2017 for primary, nonmetastatic, extremity or truncal LPS of known subtype. Clinicopathologic variables were tested using competing risk analyses for association with disease-specific death (DSD), distant recurrence (DR), and local recurrence (LR). RESULTS: Among 1001 patients, median follow-up in survivors was 5.4 years. Tumor size and subtype were independently associated with DSD and DR. Size, subtype, and R1 resection were independently associated with LR. DR was most frequent among pleomorphic and round cell LPS; the former recurred early (43% by 3 years), and the latter over a longer period (23%, 3 years; 37%, 10 years). LR was most common in dedifferentiated LPS, in which it occurred early (24%, 3 years; 33%, 5 years), followed by pleomorphic LPS (18%, 3 years; 25%, 10 years). CONCLUSIONS: Histologic subtype is the factor most strongly associated with DSD, DR, and LR in extremity/truncal LPS. Both risk and timing of adverse outcomes vary by subtype. These data may guide selective use of systemic therapy for patients with round cell and pleomorphic LPS, which carry a high risk of DR, and radiotherapy for LPS subtypes at high risk of LR when treated with surgery alone.

Outcome of 1000 Patients With Gastrointestinal Stromal Tumor (GIST) Treated by Surgery in the Pre- and Post-imatinib Eras.

OBJECTIVE: To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. BACKGROUND: Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. METHODS: We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). RESULTS: OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00-7.40, P < 0.0001) and OS (HR 3.37, 95% CI 1.60-7.13, P = 0.001)]. CONCLUSIONS: Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.

Pseudoaneurysm within a desmoid tumor in an extremity: report of 2 cases.

Desmoid tumor is considered a benign neoplasm, yet substantial morbidity can result from local invasion of structures adjacent to the tumor or from complications related to its treatment. We report two patients with extremity desmoid tumor who were each found at MRI to have an unsuspected pseudoaneurysm within their tumor after prior treatments (surgery and systemic therapy in one, surgery alone in the other). Such a pseudoaneurysm probably results from weakening of an arterial wall by adjacent desmoid tumor, as well as from local trauma. Due to the potential risk for life-threatening rupture of a pseudoaneurysm, one patient underwent surgical repair and the other, coil embolization. To our knowledge the presence of pseudoaneurysm has been reported within a few cases of abdominal desmoid tumor but not within an extremity desmoid tumor. This diagnosis has not been reported to have been made at MRI, either.

Association of MRI T2 Signal Intensity With Desmoid Tumor Progression During Active Observation: A Retrospective Cohort Study.

OBJECTIVE: The aim of this study was to identify predictors of desmoid progression during observation. SUMMARY OF BACKGROUND DATA: Untreated desmoids can grow, remain stable, or regress, but reliable predictors of behavior have not been identified. METHODS: Primary or recurrent desmoid patients were identified retrospectively from an institutional database. In those managed with active observation who underwent serial magnetic resonance imaging (MRIs) with T2-weighted sequences, baseline tumor size was recorded, and 2 radiologists independently estimated the percentage of tumor volume showing hyperintense T2 signal at baseline. Associations of clinical or radiographic characteristics with progression-free survival (PFS; by RECIST) were evaluated by Cox regression and Kaplan-Meier statistics. RESULTS: Among 160 patients with desmoids, 72 were managed with observation, and 37 of these had serial MRI available for review. Among these 37 patients, median age was 35 years and median tumor size was 4.7 cm; all tumors were extra-abdominal (41% in abdominal wall). Although PFS was not associated with size, site, or age, it was strongly associated with hyperintense T2 signal in ≥90% versus <90% of baseline tumor volume (as defined by the "test" radiologist; hazard ratio = 11.3, P = 0.003). For patients in the ≥90% group (n = 20), 1-year PFS was 55%, compared with 94% in the <90% group (n = 17). The percentage of baseline tumor volume with hyperintense T2 signal defined by a validation radiologist correlated with results of the test radiologist (ρ = 0.75). CONCLUSION: The percent tumor volume characterized by hyperintense T2 signal is associated with desmoid progression during observation and may help distinguish patients who would benefit from early intervention from those who may be reliably observed.

Yield of Colonoscopy in Identification of Newly Diagnosed Desmoid-Type Fibromatosis with Underlying Familial Adenomatous Polyposis.

BACKGROUND: Desmoid-type fibromatosis can arise in patients with familial adenomatous polyposis (FAP), therefore patients with desmoids often undergo colonoscopy to rule out FAP. Because finding FAP is uncommon, we sought to define subsets of desmoid patients in whom colonoscopy frequently identified FAP. METHODS: Patients with desmoid-type fibromatosis were identified from surgery and pathology databases at a single institution, and information on colonoscopy and FAP diagnosis was collected retrospectively. CTNNB1 mutation status was defined by Sanger sequencing and digital polymerase chain reaction of archived specimens. RESULTS: Among 626 patients with desmoids, 26 were diagnosed with FAP. In 20 patients, FAP diagnosis predated the desmoid diagnosis. Among patients without prior FAP diagnosis, 161 underwent colonoscopy, which identified only six cases of FAP (diagnostic yield 3.7%). Yields were substantially higher among patients with four characteristics: age < 40 years (11% yield), intra-abdominal or retroperitoneal tumors (5.4%), multifocal disease (29%), and family history (8%) (all p < 0.001). All cases of FAP were detected in patients younger than 40 years of age and with at least one of the other three characteristics. CTNNB1 mutation status was available in 82 patients with known FAP status. None of the 61 patients with CTNNB1 mutations were diagnosed with FAP, while 7 of the 21 patients with no CTNNB1 mutation detected (24%) were FAP patients. CONCLUSIONS: Patients with desmoid-type fibromatosis and undiagnosed FAP generally have multiple risk factors, which may be used to selectively recommend colonoscopic screening. Routine CTNNB1 sequencing may also rule out FAP and allow for deferral of colonoscopy.

The association of renal cell carcinoma with gastrointestinal stromal tumors.

BACKGROUND AND OBJECTIVES: Prior small studies have reported a possible association between renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). In the largest known series, our objective was to describe the prevalence of RCC among patients with GISTs over 26 years at Memorial Sloan Kettering Cancer Center (MSKCC). METHODS: We retrospectively reviewed MSKCC's prospectively maintained sarcoma and RCC databases and identified all patients with both RCC and GIST between 1980 and 2016. Demographic and clinicopathological characteristics were obtained. RESULTS: A total of 9/405 (2.2%) GIST patients were identified with RCC, with a mean follow-up of 9.2 (range 3.8-28.4) years. Five out of nine (55.6%) patients had RCC and GIST diagnosis within 6 months of each other. Mean RCC tumor size was 3.0 (range 1.8-8) cm and 8/9 (88.9%) patients were RCC stage 1. A total of 4/9 (44.4%) patients had papillary RCC (pRCC) histology, 5/9 (55.6%) had additional alternative malignancies, and 4/9 (44.4%) had primary small bowel GIST. CONCLUSIONS: Our series suggests a possible association of RCC with GISTs. In addition, we found a high frequency of pRCC histology, alternative malignancies, and small bowel GISTs in co-occurring RCC-GIST patients. Further investigation to identify genetic mutations, in this population, would assist in surveillance and treatment.

Histology-based Classification Predicts Pattern of Recurrence and Improves Risk Stratification in Primary Retroperitoneal Sarcoma.

OBJECTIVE: To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma. BACKGROUND: The histologic diversity and rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome. METHODS: From a single-institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR). RESULTS: Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (<10%), but early distant recurrence was common (36% at 5 years). Nomograms were developed to predict DSD, LR, and DR. CONCLUSIONS: Histologic type/subtype is the most important independent predictor of DSD, LR, and DR in primary retroperitoneal sarcoma. Histology predicts the pattern and incidence of LR and DR and will aid in more accurate patient counseling and selection of patients for adjuvant therapy trials.

The importance of surgical margins in retroperitoneal sarcoma.

Surgery is the "gold-standard" treatment for retroperitoneal sarcomas, but local recurrence is common, and can cause disease-related death. Complete gross resection is associated with improved survival, but debate exists as to whether resection of adjacent organs to improve margins or prescription of neoadjuvant radiation leads to better outcomes. This review summarizes data addressing prognostic value of margin, extent of surgery necessary to optimize treatment of retroperitoneal sarcomas, and role of histology in optimizing therapy.

Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis.

CTNNB1 mutations or APC abnormalities have been observed in ∼85% of desmoids examined by Sanger sequencing and are associated with Wnt/ß-catenin activation. We sought to identify molecular aberrations in "wild-type" tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild-type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A-derived gene expression profiles, wild-type and mutated tumors clustered together. Whole-exome sequencing of eight of the wild-type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild-type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low-frequency CTNNB1 mutation or APC loss in wild-type desmoids was validated in the remaining eight wild-type desmoids; directed miSeq identified low-frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild-type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild-type tumors (determined by next-generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/ß-catenin activation as the common pathway governing desmoid initiation.

A Phase Ib/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib for the Neoadjuvant Treatment of Soft Tissue Sarcomas.

LESSONS LEARNED: Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations. BACKGROUND: For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS. METHODS: Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m(2) gemcitabine on days 1 and 8, 75 mg/m(2) docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response. RESULTS: The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥ 90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed. CONCLUSION: GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.

Outcomes of Systemic Therapy for Patients with Metastatic Angiosarcoma.

BACKGROUND: Angiosarcomas (AS) are rare tumors of vascular origin with a variable behavior and overall poor prognosis. We sought to assess the outcomes of patients treated for metastatic disease. METHODS: We performed a retrospective analysis of 119 patients treated for metastatic AS. Outcomes and efficacy measurements of the first and subsequent lines of treatment were analyzed. RESULTS: Median age was 61 years, and the most frequent primary sites were chest wall/breast (31%), viscera (22%) and head/neck (20%). Seventy-three (61%) and 46 (39%) patients received ≥ 2 and ≥ 3 lines of therapy, respectively. The most commonly used agents included taxanes and anthracyclines. Median overall survival was 12.1 months. Median times to tumor progression were 3.5 months for first line, 3.7 months for second line and 2.7 months for third line. Among 48 patients evaluable per RECIST, the overall response rate to first line was 30% and <10% in subsequent lines. Doxorubicin, liposomal doxorubicin and taxanes resulted in similar response rates and survival, and there was no apparent benefit for combination chemotherapy. CONCLUSION: Despite reasonable response rates in the first-line setting, benefit from systemic therapy is short-lived in metastatic AS, and outcomes are poor. Doxorubicin, liposomal doxorubicin and taxanes are reasonable and appropriate choices for monotherapy.

Soft tissue tumors of the trunk: management of local disease in the breast and chest and abdominal walls.

Soft tissue sarcomas of the trunk are rare lesions, generally managed using an algorithm similar to that employed for extremity sarcomas. This review summarizes the standard treatment of truncal sarcomas and considers how these recommendations differ for each of the various common histologic subtypes observed on the trunk: desmoid, dermatofibrosarcoma protuberans (DFSP), and angiosarcoma.

PDGFRß Signaling Cooperates with ß-Catenin to Modulate c-Abl and Biologic Behavior of Desmoid-Type Fibromatosis.

PURPOSE: This study sought to identify ß-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRß), affect these targets to alter natural history or treatment response in patients. EXPERIMENTAL DESIGN: In vitro experiments utilized primary desmoid cell lines to examine regulation of ß-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies. RESULTS: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a ß-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRß signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRß and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRß/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment. CONCLUSIONS: The ß-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.

Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

PURPOSE: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. PATIENTS AND METHODS: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. RESULTS: Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. CONCLUSIONS: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649.

Current Management of Desmoid Tumors: A Review.

Importance: Desmoid tumor (DT) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Previously, surgery was the standard primary treatment modality; however, within the past decade, a paradigm shift toward less-invasive management has been introduced and an effort to harmonize the strategy among clinicians has been made. To update the 2020 global evidence-based consensus guideline on the management of patients with DT, the Desmoid Tumor Working Group convened a 1-day consensus meeting in Milan, Italy, on June 30, 2023, under the auspices of the European Reference Network on Rare Adult Solid Cancers and Sarcoma Patient Advocacy Global Network, the Desmoid Foundation Italy, and the Desmoid Tumor Research Foundation. The meeting brought together over 90 adult and pediatric sarcoma experts from different disciplines as well as patients and patient advocates from around the world. Observations: The 2023 update of the global evidence-based consensus guideline focused on the positioning of local therapies alongside surgery and radiotherapy in the treatment algorithm as well as the positioning of the newest class of medical agents, such as γ-secretase inhibitors. Literature searches of MEDLINE and Embase databases were performed for English-language randomized clinical trials (RCTs) of systemic therapies to obtain data to support the consensus recommendations. Of the 18 full-text articles retrieved, only 4 articles met the inclusion criteria. The 2023 consensus guideline is informed by a number of new aspects, including data for local ablative therapies such as cryotherapy; other indications for surgery; and the γ-secretase inhibitor nirogacestat, the first representative of the newest class of medical agents and first approved drug for DT. Management of DT is complex and should be carried out exclusively in designated DT referral centers equipped with a multidisciplinary tumor board. Selection of the appropriate strategy should consider DT-related symptoms, associated risks, tumor location, disease morbidities, available treatment options, and preferences of individual patients. Conclusions and Relevance: The therapeutic armamentarium of DT therapy is continually expanding. It is imperative to carefully select the management strategy for each patient with DT to optimize tumor control and enhance quality of life.

A prognostic nomogram for prediction of recurrence in desmoid fibromatosis.

OBJECTIVE: To construct a postoperative nomogram to estimate the risk of local recurrence for patients with desmoid tumors. BACKGROUND: The standard management of desmoid tumors is resection, but many recur locally. Other options include observation or novel chemotherapeutics, but little guidance exists on selecting treatment. METHODS: Patients undergoing resection during 1982-2011 for primary or locally recurrent desmoids were identified from a single-institution prospective database. Cox regression analysis was used to assess risk factors and to create a recurrence nomogram, which was validated using an international, multi-institutional data set. RESULTS: Desmoids were treated surgically in 495 patients (median follow-up of 60 months). Of 439 patients undergoing complete gross resection, 100 (23%) had recurrence. Five-year local recurrence-free survival was 69%. Eight patients died of disease, all after R2 resection. Adjuvant radiation was not associated with improved local recurrence-free survival. In multivariate analysis, factors associated with recurrence were extremity location, young age, and large tumor size, but not margin. Abdominal wall tumors had the best outcome (5-year local recurrence-free survival rate of 91%). Age, site, and size were used to construct a nomogram with concordance index of 0.703 in internal validation and 0.659 in external validation. Integration of additional variables (R1 margin, sex, depth, and primary vs recurrent presentation) did not importantly improve concordance (internal concordance index of 0.707). CONCLUSIONS: A postoperative nomogram including only size, site, and age predicts local recurrence and can aid in counseling patients. Systemic therapies may be appropriate for young patients with large, extremity desmoids, but surgery alone is curative for most abdominal wall lesions.