Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model.

Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease

‘Whether you are gay or straight, I don’t like to see effeminate dancing’: effeminophobia in performance-level ballroom dance

This article discusses recent responses to performances of same-sex male ballroom dancing in order to consider the subtle difference which can exist between homophobia and effeminophobia. Given that the world of performance-level ballroom dancing is a gay-friendly environment, in which many participants are openly gay identified, this article will argue that a discourse of effeminophobia, rather than homophobia, underpins the world of performance-level ballroom dance. Performance-level ballroom dance is often read as camp not only because it represents exaggerated gender roles but because its official technique requires that the male dancer synthesise codes of masculinity and femininity in his dancing. What protects the gender-dissident male ballroom dancer from being read as effeminate is that he is paired with a female body performing excessive femininity. Without the foil of the hyper-feminine female partner, the same-sex couple draws attention to the fact that the male ballroom dancer is not dancing as a man but in accordance with ballroom’s queer construction of masculinity. Given that performance-level dance has struggled for so many years to be viewed as masculine sport, practitioners may, quite understandably, be anxious about any representation which suggests that ballroom dance may be an effeminate activity

Relationship between RET fusion partner and treatment outcomes in patients (pts) with non-small cell lung cancer (NSCLC) from the phase I/II ARROW study and real-world data (RWD)

Background: The ARROW study is assessing the anti-tumour activity of pralsetinib, a highly-selective RET inhibitor in advanced solid tumours, including RET fusion+ NSCLC. Prolonged overall survival (OS) was reported with RET inhibitor therapy in NSCLC pts with CCDC6 vs KIF5B RET fusions (Tan AC, et al. JTO 2020). We examined the relationship between RET fusion partner and treatment outcomes in pts with RET fusion+ NSCLC from ARROW and RWD. Methods: In phase 2 of ARROW, 233 pts with RET fusion+ NSCLC (KIF5B n=164, CCDC6 n=41, Other n=28) received 400mg/day pralsetinib until progression, intolerance or withdrawal. Primary endpoints: overall response rate (ORR) and safety. In Q4 2021, 67 pts with RET fusion+ NSCLC (KIF5B n=46, CCDC6 n=8, Other n=13) met eligibility criteria from the nationwide (US-based) de-identified Flatiron Health-FMI NSCLC clinico-genomic database. Cox regression analyses are reported. Results: Baseline characteristics by RET fusion partner were balanced across subgroups within ARROW. ORR was similar with KIF5B and CCDC6, but lower with Other RET fusions (Table); the same trend was seen in treatment-naïve and prior treatment subgroups. Disease control rate (DCR) was high in all pts, but lowest in the Other RET fusions subgroup. Median duration of response (DOR) and progression-free survival (PFS) were higher with CCDC6 vs KIF5B RET fusions irrespective of prior treatment. OS data are immature. In the RWD cohort, median OS was numerically longer in CCDC6 and Other RET fusions vs KIF5B RET-driven disease (52.8 and 38.5 vs 19.1 months); when adjusted for covariates including RET inhibitor usage (KIF5B n=12, CCDC6 n=5, Other n=5), OS HRs for CCDC6 and Other RET fusions vs KIF5B were 0.49 (95% CI: 0.08–3.11) and 0.41 (95% CI: 0.13–1.30), respectively. Conclusions: Pralsetinib is active in RET fusion+ NSCLC, regardless of fusion partner or prior treatment. CCDC6 RET-driven disease may have a better prognosis vs KIF5B

Prognostic Impact of KRAS Mutation Subtypes in 677 Patients with Metastatic Lung Adenocarcinomas

BackgroundWe previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared with patients with KRAS wild-type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer.MethodsWe reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6-year time period. We evaluated the associations among KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient dataset.ResultsAmong 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p = 0.99), smoking status (p = 0.33), or when comparing specific amino acid substitutions (p = 0.20). In our dataset, patients with KRAS codon 13 mutant tumors (n = 53) had shorter overall survival compared with patients with codon 12 mutant tumors (n = 624) (1.1 versus 1.3 years, respectively; p = 0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex, and smoking status (hazard ratio: 1.52, 95% confidence interval: 1.11–2.08; p = 0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 versus 1.1 years, respectively; p = 0.41).ConclusionsAmong individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are no apparent differences in outcome based on KRAS mutation subtype

The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma

BACKGROUND: Paediatric high grade glioma (pHGG) is a distinct biological entity to histologically similar tumours arising in older adults, and has differing copy number profiles and driver genetic alterations. As functionally important intragenic copy number aberrations (iCNA) and fusion genes begin to be identified in adult HGG, the same has not yet been done in the childhood setting. We applied an iCNA algorithm to our previously published dataset of DNA copy number profiling in pHGG with a view to identify novel intragenic breakpoints. RESULTS: We report a series of 288 iCNA events in pHGG, with the presence of intragenic breakpoints itself a negative prognostic factor. We identified an increased number of iCNA in older children compared to infants, and increased iCNA in H3F3A K27M mutant tumours compared to G34R/V and wild-type. We observed numerous gene disruptions by iCNA due to both deletions and amplifications, targeting known HGG-associated genes such as RB1 and NF1, putative tumour suppressors such as FAF1 and KIDINS220, and novel candidates such as PTPRE and KCND2. We further identified two novel fusion genes in pHGG - CSGALNACT2:RET and the complex fusion DHX57:TMEM178:MAP4K3. The latter was sequence-validated and appears to be an activating event in pHGG. CONCLUSIONS: These data expand upon our understanding of the genomic events driving these tumours and represent novel targets for therapeutic intervention in these poor prognosis cancers of childhood.We are grateful for support from the Rosetrees Trust, the Brain Tumour Charity and Fundacao para a Ciencia e Tecnologia, Portugal (PhD Studentship SFRH/BD/33473/2008). DC, AM, LB and CJ acknowledge NHS funding to the Biomedical Research Centre

Simultaneous detection of lung fusions using a multiplex RT-PCR next generation sequencing-based approach:A multi-institutional research study

Contains fulltext : 195300.pdf (publisher's version ) (Open Access

ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1-mutant lung cancer

Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity