Association of Lateral Pelvic Lymph Nodes with Disease Recurrence and Organ Preservation in Patients with Distal Rectal Adenocarcinoma Treated with Total Neoadjuvant Therapy.

OBJECTIVE: Assess the significance of enlarged lateral lymph nodes (LLN) for disease recurrence, metastasis, and organ preservation in patients with rectal cancer. BACKGROUND: Optimal treatment of rectal adenocarcinoma involving LLN is subject to debate. METHODS: A post hoc analysis of the OPRA trial, a multicenter study of patients with rectal cancer treated with total neoadjuvant therapy (TNT) followed by total mesorectal excision or watch-and-wait management. We analyzed the association of visible LLN (LLN+), LLN≥7 mm (short axis) on baseline MRI, and LLN≥4 mm on restaging MRI with recurrence, metastasis, and rectum preservation. RESULTS: At baseline, 57 out of 324 (18%) patients had LLN+. In 30 (53%) of 57 patients with LLN+ on baseline MRI, the LLN disappeared after TNT. Disease recurrence in LLN was rare (3.5% of patients with LLN+ and 0.4% of patients with LLN-). All patients with recurrence in LLN also had distant metastasis. The rate of organ preservation was significantly lower in patients with LLN≥4 mm on restaging MRI (P=0.013). We found no significant differences in rates of local recurrence or metastasis between patients with LLN+ vs. LLN- and in patients with LLN≥7 vs.<7 mm on baseline MRI. LLN dissection was performed in 3 patients; 2 of them died of distant metastasis. CONCLUSIONS: LLN involvement is not associated with disease recurrence or metastasis, but persistence of LLN≥4 mm after TNT is negatively associated with rectum preservation in patients with locally advanced rectal cancer treated with TNT. Dissection of lateral nodes likely benefits few patients.

MRI Predicts Residual Disease and Outcomes in Watch-and-Wait Patients with Rectal Cancer.

Background MRI plays a crucial role in restaging locally advanced rectal cancer treated with total neoadjuvant therapy (TNT); however, prospective studies have not evaluated its ability to accurately select patients for nonoperative management. Purpose To evaluate the ability of restaging MRI to predict oncologic outcomes and identify imaging features associated with residual disease (RD) after TNT. Materials and Methods This was a secondary analysis of the Organ Preservation in Rectal Adenocarcinoma (OPRA) trial, which randomized participants from April 2014 to March 2020 with stages II or III rectal adenocarcinoma to undergo either induction or consolidation TNT. Participants enrolled in the OPRA trial who underwent restaging MRI were eligible for inclusion in the present study. Radiologists classified participants as having clinical complete response (cCR), near-complete clinical response (nCR), or incomplete clinical response (iCR) based on restaging MRI at a mean of 8 weeks ± 4 (SD) after treatment. Oncologic outcomes according to MRI response category were assessed using Kaplan-Meier curves. Logistic regression analysis was performed to identify imaging characteristics associated with RD. Results A total of 277 participants (median age, 58 years [IQR, 17 years]; 179 male) who were randomized in the OPRA trial had restaging MRI forms completed. The median follow-up duration was 4.1 years. Participants with cCR had higher rates of organ preservation compared with those with nCR (65.3% vs 41.6%, log-rank P < .001). Five-year disease-free survival for participants with cCR, nCR, and iCR was 81.8%, 67.6%, and 49.6%, respectively (log-rank P < .001). The MRI response category also predicted overall survival (log-rank P < .001), distant recurrence-free survival (log-rank P = .005), and local regrowth (log-rank P = .02). Among the 266 participants with at least 2 years of follow-up, 129 (48.5%) had RD. At multivariable analysis, the presence of restricted diffusion (odds ratio, 2.50; 95% CI: 1.22, 5.24) and abnormal nodal morphologic features (odds ratio, 5.04; 95% CI: 1.43, 23.9) remained independently associated with RD. Conclusion The MRI response category was predictive of organ preservation and survival. Restricted diffusion and abnormal nodal morphologic features on restaging MRI scans were associated with increased likelihood of residual tumor. ClinicalTrials.gov identifier: NCT02008656 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Milot in this issue.

Baseline MRI predictors of successful organ preservation in the Organ Preservation in Rectal Adenocarcinoma (OPRA) trial.

BACKGROUND: Prospective randomized trials have not yet identified baseline features predictive of organ preservation in locally advanced rectal cancers treated with total neoadjuvant therapy and a selective watch-and-wait strategy. METHODS: This was a secondary analysis of the OPRA trial, which randomized patients with stage II-III rectal adenocarcinoma to receive either induction or consolidation total neoadjuvant therapy. Patients were recommended for total mesorectal excision, or watch and wait based on clinical response at 8 ± 4 weeks after completing treatment. Standardized baseline clinical and radiological variables were collected prospectively. Survival outcomes, including total mesorectal excision-free survival, disease-free survival, and overall survival, were assessed by intention-to-treat analysis. Cox proportional hazards models were used to evaluate associations between baseline variables and survival outcomes. RESULTS: Of the 324 patients randomized for the OPRA trial, 38 (11.7%) had cT4 tumours, 230 (71.0%) cN-positive disease, 101 (32.5%) mesorectal fascia involvement, and 64 (19.8%) extramural venous invasion. Several baseline features were independently associated with recommendation for total mesorectal excision on multivariable analysis: nodal disease (HR 1.66, 95% c.i. 1.12 to 2.48), extramural venous invasion (HR 1.57, 1.07 to 2.29), mesorectal fascia involvement (HR 1.45, 1.01 to 2.09), and tumour length (HR 1.11, 1.00 to 1.22). Of these, nodal disease (HR 2.02, 1.15 to 3.53) and mesorectal fascia involvement (HR 2.02, 1.26 to 3.26) also predicted worse disease-free survival. Age (HR 1.03, 1.00 to 1.06) was associated with overall survival. CONCLUSION: Baseline MRI features, including nodal disease, extramural venous invasion, mesorectal fascia involvement, and tumour length, independently predict the likelihood of organ preservation after completion of total neoadjuvant therapy. Mesorectal fascia involvement and nodal disease are associated with disease-free survival.

Endoscopic Predictors of Residual Tumor After Total Neoadjuvant Therapy: A Post Hoc Analysis From the Organ Preservation in Rectal Adenocarcinoma Trial.

BACKGROUND: Restaging endoscopy plays a critical role in selecting patients with locally advanced rectal cancer who respond to neoadjuvant therapy for nonoperative management. OBJECTIVE: This study evaluated the restaging endoscopic features that best predict the presence of residual tumor in the bowel wall. DESIGN: This was a post hoc analysis of a prospective randomized trial. SETTINGS: The Organ Preservation in Rectal Adenocarcinoma Trial randomly assigned patients across 18 institutions with stage II/III rectal adenocarcinoma to receive either induction or consolidation total neoadjuvant therapy. Surgeons completed a restaging tumor assessment form, which stratified patients across 3 tiers of clinical response. PATIENTS: Patients enrolled in the Organ Preservation in Rectal Adenocarcinoma Trial with a completed tumor assessment form were included. MAIN OUTCOME MEASURES: The main outcome was residual tumor, which was defined as either an incomplete clinical response or local tumor regrowth within 2 years of restaging. Independent predictors of residual tumor were identified using backward-selected multivariable logistic regression analysis. Subgroup analyses for complete and near complete clinical responders were performed. RESULTS: Surgeons completed restaging forms for 263 patients at a median of 7.7 weeks after neoadjuvant therapy; 128 patients (48.7%) had a residual tumor. On multivariable regression analysis, several characteristics of a near complete response, including ulcer (OR 6.66; 95% CI, 2.54-19.9), irregular mucosa (OR 3.66; 95% CI, 1.61-8.68), and nodularity (OR 2.96; 95% CI, 1.36-6.58), remained independent predictors of residual tumor. A flat scar was associated with lower odds of harboring residual disease (OR 0.32; 95% CI, 0.11-0.93) for patients categorized as clinical complete responders. LIMITATIONS: Limitations include analysis of endoscopic features at a single time point and ambiguities in tumor assessment form response criteria. CONCLUSIONS: Patients with ulcer, nodularity, or irregular mucosa, on restaging endoscopy have higher odds of residual tumor. Recognizing negative prognostic implications of these features will help surgeons better select candidates for nonoperative management and suggests that patients with high-risk characteristics would benefit from close interval surveillance. See Video Abstract . PREDICTORES ENDOSCPICOS DE TUMOR RESIDUAL DESPUS DE TERAPIA NEOADYUVANTE TOTAL UN ANLISIS POST HOC DEL ENSAYO DE PRESERVACIN DE RGANOS EN ADENOCARCINOMA RECTAL: ANTECEDENTES:La reestadificación por endoscopia juega un papel crítico en la selección de pacientes con cáncer de recto localmente avanzado que responden a la terapia neoadyuvante para el manejo no quirúrgico.OBJETIVO:Este estudio evaluó las características endoscópicas de reestadificación que mejor predicen la presencia de tumor residual en la pared intestinal.DISEÑO:Este fue un análisis post hoc de un ensayo prospectivo aleatorizado.ESCENARIO:El ensayo Organ Preservation in Rectal Adenocarcinoma aleatorizó a pacientes de 18 instituciones con adenocarcinoma de recto en estadio II/III para recibir terapia neoadyuvante total de inducción o consolidación. Los cirujanos completaron un formulario de reestadificación de evaluación del tumor, que estratificó a los pacientes en tres niveles de respuesta clínica.PACIENTES:Se incluyeron pacientes inscritos en el ensayo de preservación de órganos en adenocarcinoma rectal con un formulario de evaluación del tumor completado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue presencia de tumor residual, que se definió como una respuesta clínica incompleta o un nuevo crecimiento local del tumor dentro de los dos años posteriores a la reestadificación. Los predictores independientes de tumor residual se identificaron mediante un análisis de regresión logística multivariable seleccionado hacia atrás. Se realizaron análisis de subgrupos para pacientes con respuesta clínica completa y casi completa.RESULTADOS:Los cirujanos completaron formularios de reestadificación para 263 pacientes en una mediana de 7.7 semanas después de la terapia neoadyuvante; 128 (48.7%) tenían tumor residual. En el análisis de regresión multivariable, varias características de una respuesta casi completa, incluyendo úlcera (OR 6.66; IC 95% 2.54-19.9), mucosa irregular (OR 3.66; IC 95% 1.61-8.68) y nodularidad (OR 2.96; IC 95% 1.36 -6.58) siguieron siendo predictores independientes de tumor residual. Una cicatriz plana se asoció con menores probabilidades de albergar enfermedad residual (OR 0.32; IC del 95 %: 0.11-0.93) para los pacientes clasificados como respondedores clínicos completos.LIMITACIONES:Las limitaciones de este estudio incluyen el análisis de las características endoscópicas en un solo momento y las ambigüedades en los criterios de respuesta.en la forma de evaluación del tumorCONCLUSIONES:Los pacientes con úlcera, nodularidad o mucosa irregular en la endoscopia de reestadificación tienen mayores probabilidades de tumor residual. El reconocer las implicaciones pronósticas negativas de estas características ayudará a los cirujanos a seleccionar mejor a los candidatos para el tratamiento no quirúrgico y sugiere que los pacientes con características de alto riesgo se beneficiarían de una vigilancia a intervalos estrechos. (Traducción-Dr. Jorge Silva Velazco ).

Depth normalization of small RNA sequencing: using data and biology to select a suitable method.

Deep sequencing has become one of the most popular tools for transcriptome profiling in biomedical studies. While an abundance of computational methods exists for 'normalizing' sequencing data to remove unwanted between-sample variations due to experimental handling, there is no consensus on which normalization is the most suitable for a given data set. To address this problem, we developed 'DANA'-an approach for assessing the performance of normalization methods for microRNA sequencing data based on biology-motivated and data-driven metrics. Our approach takes advantage of well-known biological features of microRNAs for their expression pattern and chromosomal clustering to simultaneously assess (i) how effectively normalization removes handling artifacts and (ii) how aptly normalization preserves biological signals. With DANA, we confirm that the performance of eight commonly used normalization methods vary widely across different data sets and provide guidance for selecting a suitable method for the data at hand. Hence, it should be adopted as a routine preprocessing step (preceding normalization) for microRNA sequencing data analysis. DANA is implemented in R and publicly available at https://github.com/LXQin/DANA.

Performance evaluation of transcriptomics data normalization for survival risk prediction.

One pivotal feature of transcriptomics data is the unwanted variations caused by disparate experimental handling, known as handling effects. Various data normalization methods were developed to alleviate the adverse impact of handling effects in the setting of differential expression analysis. However, little research has been done to evaluate their performance in the setting of survival outcome prediction, an important analysis goal for transcriptomics data in biomedical research. Leveraging a unique pair of datasets for the same set of tumor samples-one with handling effects and the other without, we developed a benchmarking tool for conducting such an evaluation in microRNA microarrays. We applied this tool to evaluate the performance of three popular normalization methods-quantile normalization, median normalization and variance stabilizing normalization-in survival prediction using various approaches for model building and designs for sample assignment. We showed that handling effects can have a strong impact on survival prediction and that quantile normalization, a most popular method in current practice, tends to underperform median normalization and variance stabilizing normalization. We demonstrated with a small example the reason for quantile normalization's poor performance in this setting. Our finding highlights the importance of putting normalization evaluation in the context of the downstream analysis setting and the potential of improving the development of survival predictors by applying median normalization. We make available our benchmarking tool for performing such evaluation on additional normalization methods in connection with prediction modeling approaches.

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.

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.

A Phase II Trial of Sorafenib and Dacarbazine for Leiomyosarcoma, Synovial Sarcoma, and Malignant Peripheral Nerve Sheath Tumors.

BACKGROUND: Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. MATERIALS AND METHODS: Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m2 intravenously (later reduced to 850 mg/m2). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. RESULTS: The study included 37 patients (19 female); median age was 55 years (range 26-87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression-free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m2, only 3 of the final 12 (25%) patients required dose reduction. CONCLUSION: This phase II study met its primary endpoint with an 18-week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. IMPLICATIONS FOR PRACTICE: Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease-control rates; however, it also increases the potential for significant toxicity.

A Phase I Study of Binimetinib (MEK162) Combined with Pexidartinib (PLX3397) in Patients with Advanced Gastrointestinal Stromal Tumor.

LESSONS LEARNED: The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs).Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies.Additional trials are needed to further explore combined KIT and MEK inhibition in treatment-naïve and TKI-refractory patients with advanced GIST. BACKGROUND: Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models. METHODS: This was an investigator-initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned. RESULTS: Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose-limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment-emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression-free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1-mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment. CONCLUSION: Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib-refractory patients.

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.

A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor.

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541 .

Targeted exome sequencing profiles genetic alterations in leiomyosarcoma.

Leiomyosarcoma (LMS) belongs to the class of genetically complex sarcomas and shows numerous, often non-recurrent chromosomal imbalances and aberrations. We investigated a group of LMS using NGS platform to identify recurrent genetic abnormalities and possible therapeutic targets. Targeted exome sequencing of 230 cancer-associated genes was performed on 35 primary soft tissue and visceral (extra-uterine) LMS. Sequence data were analyzed to identify single nucleotide variants, small insertions/deletions (indels), and copy number alterations. Key alterations were further investigated using FISH assay. The study group included patients with median age of 64 years and median tumor size of 7 cm. The primary sites included retroperitoneal/intra-abdominal, extremity, truncal, and visceral. Thirty-one tumors were high grade LMS, while four were low grade. Losses of chromosomal regions involving key tumor suppressor genes PTEN (10q), RB1 (13q), CDH1 (16q), and TP53 (17p) were the most frequent genetic events. Gains mainly involved chromosome regions 17p11.2 (MYOCD) and 15q25-26 (IGF1R). The most frequent mutations were identified in the TP53 gene in 13 of 35 (37%) cases. FISH analysis showed amplification of the myocardin (MYOCD) gene in 5 of 25 (20%) cases analyzed. None of the four low grade LMS showed losses or mutations of PTEN or TP53 genes. Genetic complexity is the hallmark of LMS with losses of important tumor suppressor genes being a common feature. MYOCD, a key gene associated with smooth muscle differentiation, is amplified in a subset of both retroperitoneal and extremity LMS. Further studies are necessary to investigate the significance of gains/amplifications in the development of these tumors.

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.

Optimal Percent Myxoid Component to Predict Outcome in High-Grade Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma.

BACKGROUND: Myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS) are aggressive, genetically complex sarcomas. The minimum myxoid component used as a criterion for myxofibrosarcoma varies widely, so we determined the optimal myxoid component cutpoints for stratifying outcomes of UPS and myxofibrosarcoma. We also analyzed clinicopathologic factors associated with outcome. METHODS: Review of a prospective, single-institution database identified 197 patients with primary, high-grade extremity/truncal myxofibrosarcoma or UPS resected during 1992-2013. Histology was reviewed and percent myxoid component determined for each tumor. Disease-specific survival (DSS) and distant recurrence-free survival (DRFS) were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. RESULTS: Median follow-up for survivors was 6.4 years. In minimum p value analysis of myxoid component, the best cutpoint for both DSS and DRFS was 5% (adjusted p ≤ 0.001), followed by 70%. Therefore, sarcomas with <5% myxoid component (n = 69) were classified as UPS and those with ≥5% myxoid component (n = 128) as myxofibrosarcoma. Five-year DRFS was 24% for UPS, 51% for 5-69% myxoid component myxofibrosarcoma, and 65% for ≥70% myxoid component myxofibrosarcoma. Myxoid component, tumor size, and age were independently associated with DSS; myxoid component and tumor size were associated with DRFS. Only tumor site was associated with local recurrence. CONCLUSIONS: Percent myxoid component and tumor size are the two most important predictors of DSS and DRFS in high-grade myxofibrosarcoma and UPS. A 5% myxoid component cutpoint is an improved criterion for classifying myxofibrosarcoma. Myxoid component-based classification improves stratification of patient outcome and will aid in selection of patients for systemic therapy and clinical trials.

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.

Comparison of Perioperative Radiation Therapy and Surgery Versus Surgery Alone in 204 Patients With Primary Retroperitoneal Sarcoma: A Retrospective 2-Institution Study.

OBJECTIVE: To compare outcomes of patients with retroperitoneal or pelvic sarcoma treated with perioperative radiation therapy (RT) versus those treated without perioperative RT. BACKGROUND: RT for retroperitoneal or pelvic sarcoma is controversial, and few studies have compared outcomes with and without RT. METHODS: Prospectively maintained databases were reviewed to retrospectively compare patients with primary retroperitoneal or pelvic sarcoma treated during 2003-2011. Multivariate Cox regression models were used to assess associations with the primary endpoints: local recurrence-free survival (LRFS) and disease-specific survival. RESULTS: At 1 institution, 172 patients were treated with surgery alone, whereas at another institution 32 patients were treated with surgery and perioperative proton beam RT or intensity-modulated RT with or without intraoperative RT. The groups were similar in age, tumor size, grade, and margin status (all P > 0.08). The RT group had a higher percentage of pelvic tumors (P = 0.03) and a different distribution of histologies (P = 0.04). Perioperative morbidity was higher in the RT group (44% vs 16% of patients; P = 0.004). After a median follow-up of 39 months, 5-year LRFS was 91% (95% confidence interval, 79%-100%) in the RT group and 65% (57%-74%) in the surgery-only group (P = 0.02). On multivariate analysis, RT was associated with better LRFS (hazard ratio, 0.26; P = 0.03). Five-year disease-specific survival was 93% (95% confidence interval, 82%-100%) in the RT group and 85% (78%-92%) in the surgery-only group (P = 0.3). CONCLUSIONS: The addition of advanced-modality RT to surgery for primary retroperitoneal or pelvic sarcoma was associated with improved LRFS, although this did not translate into significantly better disease-specific survival. This treatment strategy warrants further investigation in a randomized trial.

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.

Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial.

BACKGROUND: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. METHODS: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. FINDINGS: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). INTERPRETATION: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. FUNDING: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.