Comparing R-Bendamustine vs. R-CHOP Plus Maintenance Therapy as First-Line Systemic Treatment in Follicular Lymphoma: A Multicenter Retrospective GELTAMO Study.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and R-bendamustine (R-B) are the most common frontline treatment strategies for advanced-stage follicular lymphoma (FL). After R-CHOP induction therapy, using rituximab for maintenance therapy notably improves outcomes; however, whether this can be achieved by using the same approach after R-B therapy is still being determined. This retrospective analysis compared 476 FL patients from 17 GELTAMO centers who received R-based regimens followed by rituximab maintenance therapy for untreated advanced-stage FL. The complete response rate at the end of induction was higher with R-B and relapses were more frequent with R-CHOP. During induction, cytopenias were significantly more frequent with R-CHOP and so was the use of colony-stimulating factors. During maintenance therapy, R-B showed more neutropenia and infectious toxicity. After a median follow-up of 81 months (95% CI: 77-86), the 6-year rates of progression-free survival (PFS) were 79% (95% CI: 72-86) for R-bendamustine vs. 67% (95% CI: 61-73) for R-CHOP (p = 0.046), and 6-year overall survival (OS) values were 91% (95% CI: 86-96) for R-B vs. 91% (95% CI: 87-94) for R-CHOP (p = 0.49). In conclusion, R-B followed by rituximab maintenance therapy in patients with previously untreated FL resulted in significantly longer PFS than R-CHOP, with older patients also benefiting from this treatment without further toxicity. Adverse events during maintenance were more frequent with R-B without impacting mortality.

Circulating TNF-RII, IP-10 and HGF are associated with severity of COVID-19 in oncologic patients.

The COVID-19 patients showed hyperinflammatory response depending on the severity of the disease but little have been reported about this response in oncologic patients that also were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sixty-five circulating cytokines/chemokines were quantified in 15 oncologic patients, just after SARS-CoV-2 infection and fourteen days later, and their levels were compared in patients who required hospitalisation by COVID-19 versus non-hospitalised patients. A higher median age of 72 years (range 61-83) in oncologic patients after SARS-CoV-2 infection was associated with hospitalisation requirement by COVID-19 versus a median age of 49 years (20-75) observed in the non-hospitalised oncologic patients (p = 0.008). Moreover, oncologic patients at metastatic stage or with lung cancer were significantly associated with hospitalisation by COVID-19 (p = 0.044). None of these hospitalised patients required ICU treatment. Higher basal levels of tumour necrosis factor receptor II (TNF-RII), interferon-γ (IFNγ)-induced protein 10 (IP-10) and hepatocyte growth factor (HGF) in plasma were significantly observed in oncologic patients who required hospitalisation by COVID-19. Higher TNF-RII, IP-10 and HGF levels after the SARS-CoV-2 infection in oncologic patients could be used as biomarkers of COVID-19 severity associated with hospitalisation requirements.

Delays in diagnosis and surgery of sarcoma patients during the COVID-19 outbreak in Spain.

Background and objectives: Social distancing and quarantine implanted during the COVID-19 outbreak could have delayed the accession of oncologic patients to hospitals and treatments. This study analysed the management of sarcoma patients during this period in five Spanish hospitals. Design and methods: Clinical data from adult sarcoma patients, soft tissue and bone sarcomas, managed during the COVID-19 outbreak, from 15 March to 14 September 2020 (Covid cohort), were retrospectively collected and time for diagnosis, surgery and active treatments were compared with sarcoma patients managed during the same pre-pandemic period in 2018 (Control cohort). Results: A total of 126 and 182 new sarcoma patients were enrolled in the Covid and Control cohorts, respectively, who were mainly diagnosed as soft tissue sarcomas (81.0% and 80.8%) and at localized stage (80.2% and 79.1%). A diagnostic delay was observed in the Covid cohort with a median time for the diagnosis of 102.5 days (range 6-355) versus 83 days (range 5-328) in the Control cohort (p = 0.034). Moreover, a delay in surgery was observed in cases with localized disease from the Covid cohort with a median time of 96.0 days (range 11-265) versus 54.5 days (range 2-331) in the Control cohort (p = 0.034). However, a lower delay for neoadjuvant radiotherapy was observed in the Covid cohort with a median time from the diagnosis to the neoadjuvant radiotherapy of 47 days (range 27-105) versus 91 days (range 27-294) in the Control cohort (p = 0.039). No significant differences for adjuvant radiotherapy, neoadjuvant/adjuvant chemotherapy and neoadjuvant/adjuvant palliative chemotherapy were observed between both cohorts. Neither progression-free survival (PFS) nor overall survival (OS) was significantly different. Conclusion: Delays in diagnosis and surgery were retrospectively observed in sarcoma patients during the COVID-19 outbreak in Spain, while the time for neoadjuvant radiotherapy was reduced. However, no impact on the PFS and OS was observed.

Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Background and objectives: Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. Design and methods: As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. Results: A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Conclusion: Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

Gene expression in multiple sclerosis during pregnancy based on integrated bioinformatics analysis.

BACKGROUND: The modulation of the activity disease in patients with Multiple Sclerosis (MS) that occurs during pregnancy is a helpful model which could provide insight into central disease mechanisms and facilitate treatment. Therefore, the aim of the study was to identify differentially expressed genes in-silico to perform biological function pathway enrichment analysis and protein-protein interaction from pregnant women with MS. METHODS: Transcriptome data were obtained from the Gene Expression Omnibus (GEO) database. We selected the microarray dataset GSE17449. The gene expression dataset contains the data of mononuclear cells from four different groups sought, including seven healthy women (H), four healthy pregnant women (HP), eight women with multiple sclerosis (WMS), and nine women nine months pregnant with multiple sclerosis (PMS). The GSEA software was employed for enrichment analysis, and the REACTOME database was used for biological pathways. The protein-protein interaction (PPI) network was plotted with STRING. The databases used to identify the connection of DEGs with different signaling pathways were KEGG and WIKIPATHWAYS. RESULTS: We identified 42 differentially expressed genes in pregnant women with MS. The significant pathways included IL-10 signaling pathway, ErbB2 activates, the hemoglobin complex (HBD, HBB, HBA1, AHSP, and HBA2), IL-17 signaling pathway (LCN2 and MMP9), antigen processing and presentation, and Th17 cell differentiation (HLA-DQA1), Rap1 signaling pathway (ID1), NOD-Like receptor signaling pathway (CAMP and DEFA4), PD-L1 Signaling, Interferon gamma signaling (MMP9 and ARG1), Neutrophil degranulation (CAMP, DEFA4, ELANE, CEACAM8, S100P, CHI3L1, AZU1, OLFM4, CRISP3, LTF, ARG1, PGLYRP1, and TCN1). In the WIKIPATHWAYS set, significance was found Vitamin B12 metabolism (TCN1, HBB, and HBA2), and IL-18 signaling pathway (S100P). CONCLUSION: This study can be used to understand several essential target genes and pathways identified in the present study, which may serve as feasible targets for MS therapies.

Somatic Copy Number Alterations in Colorectal Cancer Lead to a Differentially Expressed ceRNA Network (ceRNet).

Colorectal cancer (CRC) represents the second deadliest malignancy worldwide. Around 75% of CRC patients exhibit high levels of chromosome instability that result in the accumulation of somatic copy number alterations. These alterations are associated with the amplification of oncogenes and deletion of tumor-ppressor genes and contribute to the tumoral phenotype in different malignancies. Even though this relationship is well known, much remains to be investigated regarding the effect of said alterations in long non-coding RNAs (lncRNAs) and, in turn, the impact these alterations have on the tumor phenotype. The present study aimed to evaluate the role of differentially expressed lncRNAs coded in regions with copy number alterations in colorectal cancer patient samples. We downloaded RNA-seq files of the Colorectal Adenocarcinoma Project from the The Cancer Genome Atlas (TCGA) repository (285 sequenced tumor tissues and 41 non-tumor tissues), evaluated differential expression, and mapped them over genome sequencing data with regions presenting copy number alterations. We obtained 78 differentially expressed (LFC > 1|< -1, padj < 0.05) lncRNAs, 410 miRNAs, and 5028 mRNAs and constructed a competing endogenous RNA (ceRNA) network, predicting significant lncRNA-miRNA-mRNA interactions. Said network consisted of 30 lncRNAs, 19 miRNAs, and 77 mRNAs. To understand the role that our ceRNA network played, we performed KEGG and GO analysis and found several oncogenic and anti-oncogenic processes enriched by the molecular players in our network. Finally, to evaluate the clinical relevance of the lncRNA expression, we performed survival analysis and found that C5orf64, HOTAIR, and RRN3P3 correlated with overall patient survival. Our results showed that lncRNAs coded in regions affected by SCNAs form a complex gene regulatory network in CCR.

Analysis of vaccine responses after anti-CD20 maintenance in B-cell lymphoma in the Balearic Islands. A single reference center experience.

Introduction: The use of maintenance approaches with anti-CD20 monoclonal antibodies has improved the outcomes of B-cell indolent lymphomas but may lead to significant peripheral B-cell depletion. This depletion can potentially hinder the serological response to neoantigens. Methods: Our objective was to analyze the effect of anti-CD20 maintenance therapy in a reliable model of response to neoantigens: SARS-CoV-2 vaccine responses and the incidence/severity ofCOVID-19 in a reference hospital. Results: In our series (n=118), the rate of vaccination failures was 31%. Through ROC curve analysis, we determined a cutoff for SARS-CoV-2 vaccine serologic response at 24 months from the last anti-CD20 dose. The risk of severe COVID-19 was notably higher within the first 24months following the last anti-CD20 dose (52%) compared to after this period (just 18%) (p=0.007). In our survival analysis, neither vaccine response nor hypogammaglobulinemia significantly affected OS. While COVID-19 led to a modest mortality rate of 2.5%, this figure was comparable to the OS reported in the general immunocompetent population. However, most patients with hypogammaglobulinemia received intravenous immunoglobulin therapy and all were vaccinated. In conclusion, anti-CD20 maintenance therapy impairs serological responses to SARS-CoV-2 vaccines. Discussion: We report for the first time that patients during maintenance therapy and up to 24 months after the last anti-CD20 dose are at a higher risk of vaccine failure and more severe cases of COVID-19. Nevertheless, with close monitoring, intravenous immunoglobulin supplementation or proper vaccination, the impact on survival due to the lack of serological response in this high-risk population can be mitigated, allowing for the benefits of anti-CD20 maintenance therapy, even in the presence of hypogammaglobulinemia.

Phase II trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/ CDKN2A.

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors demonstrated activity in terms of progression-free survival (PFS) in advanced dedifferentiated liposarcoma (DD-LPS), a sarcoma with CDK4 amplification. CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors. Preclinical investigators of this study found that CDK4 overexpression, while not of CDKN2A, was the most consistent predictive factor for palbociclib efficacy in sarcomas. Advanced adult-type soft-tissue sarcoma, excluding DD-LPS, or bone sarcoma patients, progressing after at least one systemic line, whose tumors overexpressed CDK4, but not CDKN2A at baseline biopsy, were accrued in this single-arm phase II trial (EudraCT number: 2016-004039-19). With the main endpoint of a 6-month PFS rate, 40% was considered promising in this population. Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles. A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening, archival material (141), and screening, baseline biopsy (95). There were 28 (29%) with favorable mRNA profiles from 95 screened patients at baseline. From 23 enrolled patients, 21 evaluable, the 6-month PFS rate was 29% (95% CI 9-48), and there were 6 patients out of 21 with a PFS longer than 6 months. The median PFS and overall survival were 4.2 (95% CI 3.6-4.8) and 12 (95% CI 8.7-15.4) months, respectively. Translational research showed a significant correlation between CDK4 mRNA and protein expression. Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.

An interpretable AI model for recurrence prediction after surgery in gastrointestinal stromal tumour: an observational cohort study.

Background: There are several models that predict the risk of recurrence following resection of localised, primary gastrointestinal stromal tumour (GIST). However, assessment of calibration is not always feasible and when performed, calibration of current GIST models appears to be suboptimal. We aimed to develop a prognostic model to predict the recurrence of GIST after surgery with both good discrimination and calibration by uncovering and harnessing the non-linear relationships among variables that predict recurrence. Methods: In this observational cohort study, the data of 395 adult patients who underwent complete resection (R0 or R1) of a localised, primary GIST in the pre-imatinib era at Memorial Sloan Kettering Cancer Center (NY, USA) (recruited 1982-2001) and a European consortium (Spanish Group for Research in Sarcomas, 80 sites) (recruited 1987-2011) were used to train an interpretable Artificial Intelligence (AI)-based model called Optimal Classification Trees (OCT). The OCT predicted the probability of recurrence after surgery by capturing non-linear relationships among predictors of recurrence. The data of an additional 596 patients from another European consortium (Polish Clinical GIST Registry, 7 sites) (recruited 1981-2013) who were also treated in the pre-imatinib era were used to externally validate the OCT predictions with regard to discrimination (Harrell's C-index and Brier score) and calibration (calibration curve, Brier score, and Hosmer-Lemeshow test). The calibration of the Memorial Sloan Kettering (MSK) GIST nomogram was used as a comparative gold standard. We also evaluated the clinical utility of the OCT and the MSK nomogram by performing a Decision Curve Analysis (DCA). Findings: The internal cohort included 395 patients (median [IQR] age, 63 [54-71] years; 214 men [54.2%]) and the external cohort included 556 patients (median [IQR] age, 60 [52-68] years; 308 men [55.4%]). The Harrell's C-index of the OCT in the external validation cohort was greater than that of the MSK nomogram (0.805 (95% CI: 0.803-0.808) vs 0.788 (95% CI: 0.786-0.791), respectively). In the external validation cohort, the slope and intercept of the calibration curve of the main OCT were 1.041 and 0.038, respectively. In comparison, the slope and intercept of the calibration curve for the MSK nomogram was 0.681 and 0.032, respectively. The MSK nomogram overestimated the recurrence risk throughout the entire calibration curve. Of note, the Brier score was lower for the OCT compared to the MSK nomogram (0.147 vs 0.564, respectively), and the Hosmer-Lemeshow test was insignificant (P = 0.087) for the OCT model but significant (P < 0.001) for the MSK nomogram. Both results confirmed the superior discrimination and calibration of the OCT over the MSK nomogram. A decision curve analysis showed that the AI-based OCT model allowed for superior decision making compared to the MSK nomogram for both patients with 25-50% recurrence risk as well as those with >50% risk of recurrence. Interpretation: We present the first prognostic models of recurrence risk in GIST that demonstrate excellent discrimination, calibration, and clinical utility on external validation. Additional studies for further validation are warranted. With further validation, these tools could potentially improve patient counseling and selection for adjuvant therapy. Funding: The NCI SPORE in Soft Tissue Sarcoma and NCI Cancer Center Support Grants.

Impact of SCHOLAR-1 Criteria on Chimeric Antigen Receptor T Cell Therapy Efficacy in Aggressive B Lymphoma: A Real-World GELTAMO/GETH Study.

In the pre-chimeric antigen receptor T cell (CAR-T) therapy era, the SCHOLAR-1 study identified a group of patients with refractory aggressive B cell lymphoma (ABCL) with particularly poor prognoses. We recently published our real-world data from Spain, focused on this SCHOLAR-1 refractory group, and compared patients who underwent CAR-T therapy with the previous standard of care. In this study, we found that the efficacy of CAR-T therapy in refractory patients, in terms of progression-free survival (PFS) and overall survival (OS), was superior to that of the treatments available in the pre-CAR-T era. The main objective of these new analyses was to analyze treatment efficacy in terms of response rates and survival for patients with ABCL with or without the SCHOLAR-1 criteria. In addition, we analyzed the prognostic impact of each SCHOLAR-1 criterion independently. Our study aimed to assess the prognostic impact of SCHOLAR-1 criteria on ABCL patients treated with CAR-T therapy in Spain. This multicenter, retrospective, observational study. We included all adult patients treated with commercially available CAR-T cell products and diagnosed with ABCL different from primary mediastinal large B cell lymphoma between February 2019 and July 2022. Patients meeting any SCHOLAR-1 criteria (progressive disease as the best response to any line of therapy, stable disease as the best response to ≥4 cycles of first-line therapy or ≥2 cycles of later-line therapy, or relapse at <12 months after autologous stem cell transplantation [auto-SCT]) in the line of treatment before CAR-T therapy (SCHOLAR-1 group) were compared with those not meeting any of these criteria (non-SCHOLAR-1 group). To analyze the prognostic impact of individual SCHOLAR-1 criteria, all the patients who met any of the SCHOLAR-1 criteria at any time were included to assess whether these criteria have the same prognostic impact in the CAR-T era. In addition, patients were grouped according to whether they were refractory to the first line of treatment, refractory to the last line of treatment, or relapsed early after auto-SCT. The PFS and OS were calculated from the time of appearance of the SCHOLAR-1 refractoriness criteria. Of 329 patients treated with CAR-T (169 with axi-cel and 160 with tisa-cel), 52 were in the non-SCHOLAR-1 group and 277 were in the SCHOLAR-1 group. We found significantly better outcomes in the non-SCHOLAR-1 patients compared with the SCHOLAR-1 patients (median PFS of 12.2 and 3.3 months, respectively; P = .009). In addition, axi-cel showed better results in terms of efficacy than tisa-cel for both the non-SCHOLAR-1 group (hazard ratio [HR] for PFS, 2.7 [95% confidence interval (CI), 1.1 to 6.7; P = .028]; HR for OS, 7.1 [95% CI, 1.5 to 34.6; P = .015]) and SCHOLAR-1 group (HR for PFS, 1.8 [95% CI, 1.3 to 2.5; P < .001]; HR for OS, 1.8 [95% CI, 1.2 to 2.6; P = .002]), but also significantly more toxicity. Finally, separately analyzing the prognostic impact of each SCHOLAR-1 criterion revealed that refractoriness to the last line of treatment was the variable with the most significant impact on survival. In conclusion, SCHOLAR-1 refractoriness criteria notably influence the efficacy of CAR-T therapy. In our experience, axi-cel showed better efficacy than tisa-cel for both SCHOLAR-1 and non-SCHOLAR-1 patients. Refractoriness to the last line of treatment was the variable with the most significant impact on survival in the CAR-T therapy era.

RECIST 1.1 Target Lesion Categorical Response in Metastatic Renal Cell Carcinoma: A Comparison of Conventional versus Volumetric Assessment.

Purpose To investigate Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) approximations of target lesion tumor burden by comparing categorical treatment response according to conventional RECIST versus actual tumor volume measurements of RECIST target lesions. Materials and Methods This is a retrospective cohort study of individuals with metastatic renal cell carcinoma enrolled in a clinical trial (from 2003 to 2017) and includes individuals who underwent baseline and at least one follow-up chest, abdominal, and pelvic CT study and with at least one target lesion. Target lesion volume was assessed by (a) Vmodel, a spherical model of conventional RECIST 1.1, which was extrapolated from RECIST diameter, and (b) Vactual, manually contoured volume. Volumetric responses were determined by the sum of target lesion volumes (Vmodel-sum TL and Vactual-sum TL, respectively). Categorical volumetric thresholds were extrapolated from RECIST. McNemar tests were used to compare categorical volume responses. Results Target lesions were assessed at baseline (638 participants), week 9 (593 participants), and week 17 (508 participants). Vmodel-sum TL classified more participants as having progressive disease (PD), compared with Vactual-sum TL at week 9 (52 vs 31 participants) and week 17 (57 vs 39 participants), with significant overall response discordance (P < .001). At week 9, 25 (48%) of 52 participants labeled with PD by Vmodel-sum TL were classified as having stable disease by Vactual-sum TL. Conclusion A model of RECIST 1.1 based on a single diameter measurement more frequently classified PD compared with response assessment by actual measured tumor volume. Keywords: Urinary, Kidney, Metastases, Oncology, Tumor Response, Volume Analysis, Outcomes Analysis ClinicalTrials.gov registration no. NCT01865747 © RSNA, 2023 Supplemental material is available for this article.

Real-World Evidence on the Clinical Characteristics and Management of Patients with Chronic Lymphocytic Leukemia in Spain Using Natural Language Processing: The SRealCLL Study.

The SRealCLL study aimed to obtain real-world evidence on the clinical characteristics and treatment patterns of patients with chronic lymphocytic leukemia (CLL) using natural language processing (NLP). Electronic health records (EHRs) from seven Spanish hospitals (January 2016-December 2018) were analyzed using EHRead® technology, based on NLP and machine learning. A total of 534 CLL patients were assessed. No treatment was detected in 270 (50.6%) patients (watch-and-wait, W&W). First-line (1L) treatment was identified in 230 (43.1%) patients and relapsed/refractory (2L) treatment was identified in 58 (10.9%). The median age ranged from 71 to 75 years, with a uniform male predominance (54.8-63.8%). The main comorbidities included hypertension (W&W: 35.6%; 1L: 38.3%; 2L: 39.7%), diabetes mellitus (W&W: 24.4%; 1L: 24.3%; 2L: 31%), cardiac arrhythmia (W&W: 16.7%; 1L: 17.8%; 2L: 17.2%), heart failure (W&W 16.3%, 1L 17.4%, 2L 17.2%), and dyslipidemia (W&W: 13.7%; 1L: 18.7%; 2L: 19.0%). The most common antineoplastic treatment was ibrutinib in 1L (64.8%) and 2L (62.1%), followed by bendamustine + rituximab (12.6%), obinutuzumab + chlorambucil (5.2%), rituximab + chlorambucil (4.8%), and idelalisib + rituximab (3.9%) in 1L and venetoclax (15.5%), idelalisib + rituximab (6.9%), bendamustine + rituximab (3.5%), and venetoclax + rituximab (3.5%) in 2L. This study expands the information available on patients with CLL in Spain, describing the diversity in patient characteristics and therapeutic approaches in clinical practice.

REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial.

BACKGROUND: Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. METHODS: Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. RESULTS: From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. CONCLUSIONS: Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02638766.

The utility of selective partial neurectomy of the musculocutaneous nerve in children with bilateral spastic elbow.

PURPOSE: This study aims to determine the utility of selective partial neurectomy of the musculocutaneous nerve (MCN) in pediatric patients with bilateral spastic elbow. METHODS: A prospective, cross-sectional, case series study was performed in nine pediatric patients (four females and five males) with bilateral spastic elbow, all with a 11.4-year-old average age, where 18 selective partial neurectomies of the MCN were carried out. They were evaluated with goniometry of both spastic elbows at resting position and active amplitude, and staging spasticity employing the Modified Ashworth Scale (MAS) in the preoperative and postoperative period. The results are reported 1 year after surgery. RESULTS: The etiology of the spasticity was secondary to cerebral palsy in eight patients (88.8%) and in one patient (11.11%) secondary to traumatic brain injury. A clinical improvement was observed in goniometry comparing the preoperative and postoperative resting position, a mean preoperative of 44.38 degrees (SD ± 7.61) versus 98.05 degrees (SD ± 24.44), respectively, and preoperative active amplitude a mean of 86.55 degrees (SD ± 15.97) versus the mean postoperative of 47.33 (SD ± 17.86). A relevant decrease on the MAS after surgical intervention was observed, resulting from an average preoperative state according to MAS of 3.78 (SD ± 0.42) to a postoperative state according to MAS of 1.44 (SD ± 0.51), these changes being statistically significant (p ≤ 0.001). No postoperative complications were observed. CONCLUSIONS: Selective partial neurectomy of the MCN has shown good results in patients with bilateral spastic elbow in whom antispastic drugs and physical therapy have failed, and has prove permanent effects.

Pathogenic variant profile in DNA damage response genes correlates with metastatic breast cancer progression-free survival in a Mexican-mestizo population.

Introduction: Metastatic breast cancer causes the most breast cancer-related deaths around the world, especially in countries where breast cancer is detected late into its development. Genetic testing for cancer susceptibility started with the BRCA 1 and 2 genes. Still, recent research has shown that variations in other members of the DNA damage response (DDR) are also associated with elevated cancer risk, opening new opportunities for enhanced genetic testing strategies. Methods: We sequenced BRCA1/2 and twelve other DDR genes from a Mexican-mestizo population of 40 metastatic breast cancer patients through semiconductor sequencing. Results: Overall, we found 22 variants -9 of them reported for the first time- and a strikingly high proportion of variations in ARID1A. The presence of at least one variant in the ARID1A, BRCA1, BRCA2, or FANCA genes was associated with worse progression-free survival and overall survival in our patient cohort. Discussion: Our results reflected the unique characteristics of the Mexican-mestizo population as the proportion of variants we found differed from that of other global populations. Based on these findings, we suggest routine screening for variants in ARID1A along with BRCA1/2 in breast cancer patients from the Mexican-mestizo population.

Effectiveness and Safety of Trabectedin and Radiotherapy for Patients With Myxoid Liposarcoma: A Nonrandomized Clinical Trial.

Importance: Preclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring. Objective: To explore the effectiveness and safety of trabectedin combined with RT. Design, Setting, and Participants: This international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall. Interventions: Trabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment. Main Outcomes and Measures: The primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response. Results: A total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated. Conclusions and Relevance: Although the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.

Cell-Free DNA Dynamic Concentration and Other Variables Are Predictors of Early Progression after Chimeric Antigen Receptor T Cell Therapy in Patients with Diffuse Large B Cell Lymphoma.

We propose a novel biomarker that can identify patients at high risk of early progression after chimeric antigen receptor (CAR) T cell therapy. Calculation of cell-free DNA (cfDNA) with a pre-apheresis (PA) and pre-lymphodepletion (PL) sample allows monitoring of tumor dynamics (∆cfDNA). In the present study, ∆cfDNA and other biomarkers and clinical variables were evaluated in 58 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL). ∆cfDNA (>11 ng/mL plasma; P =.003), C-reactive protein (CRP) PL (>1.06 mg/dL; P = .004), lactate dehydrogenase (LDH) PL (>304; P = .006), disease status PL (progressive disease; P = .035) and sex (male; P = .016) were highly correlated with 1 month progression. After adjusting for ∆cfDNA, CRP PL, and LDH PL, disease status PL, and sex, ∆cfDNA remained associated with 1-month progression after CAR T cell infusion.

Impact of pre- and/or post-autologous stem cell transplantation exposure to brentuximab vedotin on survival outcomes in patients with high-risk Hodgkin lymphoma.

The AETHERA trial demonstrated that brentuximab vedotin (BV) consolidation after autologous stem cell transplantation (ASCT) in patients with Hodgkin lymphoma (HL) at high risk of relapse/progression increases progression-free survival (PFS). Patients previously exposed to BV were excluded from that trial. However, BV alone or in combination with chemotherapy is frequently used as front-line treatment and/or pre-ASCT salvage therapy. We analyzed data from 156 patients with high-risk HL who underwent ASCT with (BV-CON, n = 62) or without (non-BV, n = 94) BV consolidation. Fifty-seven patients received BV-based salvage regimens before ASCT. The 3-year overall survival and PFS for all patients were 91.6% and 70.0%, respectively. Multivariate analysis showed that BV-CON was associated with better PFS (HR 0.39, p = 0.01), whereas positive PET at transplant leaded to worse PFS (HR 2.71, p = 0.001). BV-CON improved PFS in PET-positive patients (72.2% vs. 43.0%, p = 0.05), with a beneficial trend observed in PET negative (88.8% vs. 75.2%, p = 0.09). BV-CON patients with or without BV exposure pre-ASCT had a significantly better PFS than non-BV with or without BV pretransplant treatment (HR 0.36, p = 0.004). The efficacy of real-life BV consolidation therapy was similar to that in the AETHERA trial. This therapeutic strategy improves survival independently of BV exposure prior to ASCT.

Evaluation of 4 prognostic indices in follicular lymphoma treated in first line with immunochemotherapy.

Several clinical risk models have been proposed to predict the outcome of follicular lymphoma (FL). The development of next-generation sequencing technologies has allowed the integration of somatic gene mutations into clinical scores to build genotyped-based risk models, such as the m7-Follicular Lymphoma International Prognostic Index (FLIPI). We explored 4 clinical or clinicogenetic-risk models in patients with symptomatic FL who received frontline immunochemotherapy. Of 191 patients with FL grades 1 to 3a, 109 were successfully genotyped. The treatment consisted of rituximab (R) plus cyclophosphamide, vincristine, and prednisone (R-CVP)/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (72.5%) or R-bendamustine (R-B) (27.5%). The proportion of cases classified as high risk for FLIPI, FLIPI-2, PRIMA-prognostic index, or m7-FLIPI were 39.3%, 14%, 30.3%, and 22%, respectively. No case with low-intermediate FLIPI was upgraded in the m7-FLIPI, but 18 of the 42 high-risk patients with FLIPI were downgraded to low-risk m7-FLIPI. The sensitivity and specificity for the prediction of POD24 were highest for FLIPI. The discrimination between progression-free survival (PFS) and overall survival (OS) was the best for FLIPI (c-index: 0.644 and 0.727, respectively). When analyzed only in patients treated with R-B, m7-FLIPI showed a higher discrimination between PFS and OS. Thus, the FLIPI remains the clinical risk score with higher discrimination in patients with advanced FL treated with immunochemotherapy; however, the performance of the m7-FLIPI should be further investigated in patients treated with R-B.