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Abstract Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a ‘control group’ consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor.

We observed the afterglow of GRB 130427A with the Reionization and Transients Infrared Camera (RATIR) instrument on the 1.5 m Harold L. Johnson telescope of the Observatorio Astronómico Nacional in Sierra San Pedro Mártir. Our homogenous griZY JH photometry extends from the night of the burst to three years later. We fit a model for the afterglow. There is a significant positive residual that matches the behavior of SN 1998bw in the griZ filters; we suggest that this is a photometric signature of the supernova SN 2013cq associated with the Gamma-ray burst. The peak absolute magnitude of the supernova is . [ABSTRACT FROM AUTHOR]

We present a sample of 45 Damped Lyα system (DLA; ) counterparts (33 detections, 12 upper limits) which host gamma-ray bursts (GRB-DLAs) in order to investigate star formation and metallicity within galaxies hosting DLAs. Our sample spans and is nearly three times larger than any previously detected DLA counterparts survey based on quasar line-of-sight searches (QSO-DLAs). We report star formation rates (SFRs) from rest-frame UV photometry and spectral energy distribution modeling. We find that DLA counterpart SFRs are not correlated with either redshift or H i column density. Thanks to the combination of Hubble Space Telescope and ground-based observations, we also investigate DLA host star formation efficiency. Our GRB-DLA counterpart sample spans both higher efficiency and low efficiency star formation regions compared to the local Kennicutt–Schmidt relation, local star formation laws, and cosmological simulations. We also compare the depletion times of our DLA hosts sample to other objects in the local universe; our sample appears to deviate from the star formation efficiencies measured in local spiral and dwarf galaxies. Furthermore, we find similar efficiencies as local inner disks, SMC, and Lyman-break galaxy outskirts. Finally, our enrichment time measurements show a spread of systems with under- and over-abundance of metals, which may suggest that these systems had episodic star formation and a metal enrichment/depletion as a result of strong stellar feedback and/or metal inflow/outflow. [ABSTRACT FROM AUTHOR]

We present optical and near-infrared (NIR) light curves and optical spectra of SN 2013dx, associated with the nearby (redshift 0.145) gamma-ray burst GRB 130702A. The prompt isotropic gamma-ray energy released from GRB 130702A is measured to be erg (1 keV to 10 MeV in the rest frame), placing it intermediate between low-luminosity GRBs like GRB 980425/SN 1998bw and the broader cosmological population. We compare the observed light curves of SN 2013dx to a SN 1998bw template, finding that SN 2013dx evolves ∼20% faster (steeper rise time), with a comparable peak luminosity. Spectroscopically, SN 2013dx resembles other broad-lined SNe Ic, both associated with (SN 2006aj and SN 1998bw) and lacking (SN 1997ef, SN 2007I, and SN 2010ah) gamma-ray emission, with photospheric velocities around peak of ∼ 21,000 km s−1. We construct a quasi-bolometric () light curve for SN 2013dx, only the fifth GRB-associated SN with extensive NIR coverage and the third with a bolometric light curve extending beyond . Together with the measured photospheric velocity, we derive basic explosion parameters using simple analytic models. We infer a 56Ni mass of , an ejecta mass of , and a kinetic energy of erg (statistical uncertainties only), consistent with previous GRB-associated supernovae. When considering the ensemble population of GRB-associated supernovae, we find no correlation between the mass of synthesized 56Ni and high-energy properties, despite clear predictions from numerical simulations that should correlate with the degree of asymmetry. On the other hand, clearly correlates with the kinetic energy of the supernova ejecta across a wide range of core-collapse events. [ABSTRACT FROM AUTHOR]

We present our extensive observational campaign on the Swift-discovered GRB 141121A, almost 10 years after its launch. Our observations cover radio through X-rays and extend for more than 30 days after discovery. The prompt phase of GRB 141121A lasted 1410 s and, at the derived redshift of z = 1.469, the isotropic energy is Eγ,iso = 8.0 × 1052 erg. Due to the long prompt duration, GRB 141121A falls into the recently discovered class of ultra-long GRBs (UL-GRBs). Peculiar features of this burst are (1) a flat early-time optical light curve and (2) a radio-to-X-ray rebrightening around three days after the burst. The latter is followed by a steep optical-to-X-ray decay and a much shallower radio fading. We analyze GRB 141121A in the context of the standard forward–reverse shock (FS, RS) scenario and we disentangle the FS and RS contributions. Finally, we comment on the puzzling early-time (t ≲ 3 days) behavior of GRB 141121A, and suggest that its interpretation may require a two-component jet model. Overall, our analysis confirms that the class of UL-GRBs represents our best opportunity to firmly establish the prominent emission mechanisms in action during powerful gamma-ray burst explosions, and future missions (like SVOM, XTiDE, or ISS-Lobster) will provide many more of such objects. [ABSTRACT FROM AUTHOR]

The successful 2020 launch and 2021 landing of the National Aeronautics and Space Administration’s (NASA) Perseverance Mars rover initiated the first phase of the NASA and European Space Agency (ESA) Mars Sample Return (MSR) campaign. The goal of the MSR campaign is to collect scientifically interesting samples from the Martian surface and return them to Earth for further study in terrestrial laboratories. The MSR campaign consists of three major spacecraft components to accomplish this objective: the Perseverance Mars rover, the Sample Retrieval Lander (SRL) and the Earth Return Orbiter (ERO). Onboard the ERO spacecraft is the Capture, Containment and Return System (CCRS). CCRS will capture, process and return to Earth the samples that have been collected after they are launched into Mars orbit by the Mars Ascent Vehicle (MAV), which is delivered to Mars onboard the SRL. To facilitate the processing of the orbiting sample (OS) via the CCRS, we have designed and developed a vision system to determine the OS capture orientation. The vision system is composed of two cameras sensitive to the visible portion of the electromagnetic spectrum and two illumination modules constructed from broadband light emitting diodes (LED). Vision system laboratory tests and physics-based optical simulations predict CCRS ground processing will be able to correctly identify the OS post-capture orientation using only a single vision system image that is transmitted to Earth from Mars orbit.

Introduction: Tumour BRCA1 /2 sequencing has progressively increased along with the expanding indications for poly(ADP-ribose) polymerase inhibitors. In our study, we investigated the feasibility and outcomes of a workflow for the identification of germline carriers based on tumour sequencing results., Methods: Between April 2020 and December 2022, BRCA1/2 tumour testing results from 2020 patients were reviewed. Analysed tumours included: 323 ovarian, 104 breast, 314 pancreas-biliary, 87 prostate, 374 gastrointestinal, 309 lung, and 509 less common histologies. Testing was performed through small (only BRCA1/2 , 16%) or comprehensive (>50 genes) next-generation sequencing panels (84%). Patients with pathogenic/likely pathogenic variants were referred for genetic counselling and germline testing., Results: Tumour BRCA1/2 pathogenic variants were identified in 145 patients (7%). The pathogenic variant frequency ranged between 23% (75/323 ovarian) and 3.5% (11/314 pancreas-biliary). The highest frequency was observed in high-grade ovarian carcinomas (27%, 64/235). By 30 June 2023, 79 out of 145 patients (54%) underwent subsequent genetic counselling and germline testing. In these patients, mostly affected with ovarian carcinoma (67%, 53/79), 48 were confirmed germline pathogenic variants (61%)., Conclusions: In our tumour-to-germline testing approach, we observed the BRCA1/2 pathogenic variant frequency reported in other large unselected ovarian cancer cohorts, thus confirming its effectiveness in identifying putative germline carriers irrespective of eligibility for germline testing. As the range of tumours subjected to genetic testing broadens, this approach is expected to also be effective in other tumour settings for enhancing the identification of carriers, reducing the burden on genetic services, and avoiding unnecessary concerns related to germline testing., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SD: research funding paid directly to my Institution from Roche, Incyte, Nerviano Medical Science srl, Pfizer Inc. MN: Travel expenses from AstraZeneca, speaker honorarium from Accademia della Medicina and Incyte; honoraria from Sandoz, Medpoint SRL, Incyte, AstraZeneca and Servier for editorial collaboration. Consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia, Servier, Astrazeneca and Taiho. FN: honoraria from AstraZeneca. LA: consultant honorarium from Roche Italia. All the other authors declare no competing interests.

Background: Metastatic Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors characterized by high morbidity and limited systemic treatment options, mainly based on radiometabolic treatments or chemotherapy. Based on the preclinical rationale that PGGLs carcinogenesis relies on angiogenesis, treatment with tyrosine kinase inhibitors (TKI) may represent another viable therapeutic option., Methods: We conducted a prospective phase II study in patients with metastatic or unresectable PGGLs. Patients received sunitinib (50 mg daily for 4 weeks, followed by a 2-week rest period) until progressive disease (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was 12-month progression-free survival (PFS) rate; secondary endpoints were safety overall response rate (ORR) according to RECIST 1.1 criteria and overall survival (OS). EudraCT Number: 2011-002632-99., Results: Fifty patients were included. At a median follow-up of 71.7 months (IQR 35.4-100.1), the 1 year-PFS rate was 53.4 % (95 %CI 41.1-69.3) and median PFS was 14.1 months (95 % CI 8.9-25.7). ORR was 15.6 %, the median OS was 49.4 months (95 %CI 21.2-NA), and grade 3 or higher treatment-related adverse events were reported in 34 % patients. No significant correlation was found between specific genetic alterations or genomic clusters and sunitinib efficacy., Conclusion: Sunitinib is an active drug in patients with advanced PGGLs, capable of inducing prolonged disease control with a manageable toxicity profile., Competing Interests: Declaration of Competing Interest All other authors declared no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a 'control group' consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor., (© 2024. The Author(s).)

Background: Retreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in RAS/BRAF genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening., Methods: Patients with RAS/BRAF V600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. The next-generation sequencing (NGS) panel Oncomine™ was employed for ctDNA testing., Results: A total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). RAS/BRAF V600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for KRAS , NRAS , and BRAF mutant clones: 0.52%, 0.62%, and 0.12%, respectively; p = 0.01), with KRAS Q61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status ( p = 0.12). Among the 133 patients with RAS/BRAF V600E wt tumors according to LB, 40 (30%) harbored a mutation in at least another gene potentially implied in anti-EGFR resistance, mainly with subclonal expression (median VAF, 0.56%). In detail, alterations in PIK3CA , FBXW7 , GNAS , MAP2K , ERBB2 , BRAF (class I and II non-BRAFV600E), SMAD , EGFR , AKT1 , and CTNNB1 occurred in 13%, 8%, 7%, 3%, 2%, 2%, 1%, 1%, 1%, and 1% cases, respectively. Co-mutations were detected in 13 (33%) out of 40 patients., Conclusions: This is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAF V600E wt ctDNA., Competing Interests: SL: consulting or an advisory role—Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, BMS, Servier, and MSD; research funding—Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and BMS; speakers’ fees from Roche, Lilly, BMS, Servier, Merck Serono, Pierre-Fabre, GlaxoSmithKline, and Amgen. FP: honoraria—Merck-Serono, Amgen, Bayer, Servier, Takeda, Pierre-Fabre, MSD, BMS, and Astellas; research grants for non-profit studies—AstraZeneca, BMS, Agenus, Amgen. CC: honoraria—Amgen, Bayer, Merck, Roche, and Servier; consulting or advisory role—Amgen, Bayer, MSD, and Roche; speakers’ bureau—Servier; research funding—Bayer, Merck, and Servier; travel, accommodations, and expenses—Roche and Servier. DR: honoraria—Takeda Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Germani, Vetere, Giordano, Ciracì, Capone, Tamborini, Conca, Busico, Pietrantonio, Piva, Boccaccino, Simionato, Bortolot, Manca, Lonardi, Conca, Borelli, Carullo, Del Re, Fontanini, Rossini and Cremolini.)

Glioblastoma, isocitrate dehydrogenase-wildtype (GB), is the most common and aggressive primary brain malignancy with poor outcome. Immune checkpoint inhibitors (ICIs) have been tested in GB and, despite disappointing results, the identification of a small subgroup of responders underlies the need to improve our understanding of the tumour microenvironment (TME) immunity. This study aimed to determine whether the expression of selected immune checkpoints on tissue-resident memory T cells (Trm) may predict patient outcome. We conducted a single cohort observational study. Tumour samples were collected from 45 patients with histologically confirmed GB (WHO grade 4) and processed to obtain single-cell suspensions. Patients were assessed for the correlation of Trm phenotype with overall survival (OS) or progression-free survival (PFS) using multiparametric flow cytometry and uni/multivariate analyses. Levels of Trm expressing programmed cell death protein 1 (PD1) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) were found to be linked to clinical outcome. Low frequency of Trm expressing PD1 or TIM3 or both markers defined subgroups as independent positive prognostic factors for patient survival. On multivariate analysis, low CD8+CD103+PD1+TIM3+ Trm and Karnofsky performance status (KPS) ≥70 were confirmed to be the most predictive independent factors associated with longer OS (hazard ratios-HR [95%CI]: 0.14 [0.04-0.52] p < 0.001, 0.39 [0.16-0.96] p = 0.04, respectively). The CD8+CD103+ Trm subgroups were also age-related predictors for survival in GB., (© 2023 The Authors. Immunology published by John Wiley & Sons Ltd.)

Background: Immunotherapy (IO) single agent or combined with chemotherapy (CT-IO) is the standard treatment for advanced non-small-cell lung cancer (aNSCLC) without driver alterations. IO efficacy in patients with novel driver alterations is not well reported., Materials and Methods: Data of aNSCLC patients treated with IO or CT-IO in any line from January 2016 to September 2022 were retrospectively collected. Patients harboring novel driver alterations (m-cohort), including MET exon 14 skipping, BRAF (V600E or atypical), RET rearrangements, HER2 point mutations/exon 20 insertions or uncommon EGFR mutations/EGFR exon 20 insertions, and wild type patients (wt-cohort) were eligible. Clinico-pathological data were extracted from Institutional databases and compared through chi square or Fisher's exact test. Survivals were estimated through Kaplan-Meier method and compared by log-rank test., Results: m-cohort and wt-cohort included 84 and 444 patients, respectively. Progression free survival (PFS) was 5.53 vs. 4.57 months (P= .846) and overall survival (OS) was 25.1 vs. 9.37 months, (P < .0001) for m-cohort compared to wt-cohort. Within the m-cohort, BRAF atypical mutations had the better outcomes (Overall Response Rate [ORR], PFS), targeted agents timing did not affect response to IO and CT-IO had better ORR and disease control rate (DCR) compared to IO single agent (P = .0160 and P = .0152). In the PD-L1≥50% group, first line IO single agent resulted in inferior ORR (P = .027) and PFS (P = .022) in m-cohort compared to wt-cohort., Conclusion: IO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required., Competing Interests: Disclosure Diego Signorelli declares personal fees from AstraZeneca, Merck Sharp and Dohme, Boehringer Ingelheim, BMS, Roche and Sanofy. Arsela Prelaj declares personal fees from AstraZeneca, Italfarmaco, F. Hoffmann-La Roche, BMS. Roberto Ferrara declares advisory role from Merck Sharp and Dohme. Claudia Proto declares personal fees from Italfarmaco, AstraZeneca, BMS and Merck Sharp and Dohme. Giuseppe Lo Russo provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Merck Sharp and Dohme, Takeda, Amgen, Eli Lilly, B.M.S., F. Hoffmann-La Roche, Italfarmaco, Novartis, Sanofi, Pfizer, G.S.K. and AstraZeneca. Marina Chiara Garassino declares personal financial interests with the following organizations: AstraZeneca, Merck Sharp and Dohm, International GmbH, BMS, Boehringer Ingelheim Italia S.P.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, F. Hoffmann-La Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Ose Immuno Therapeutics, Blueprint, Jansenn, Sanofi; she also declares Institutional financial interests with the following organizations: Eli Lilly, Merck Sharp and Dohm, Pfizer (MISP); AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.P.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, Glaxo Smith Kline GSK, Spectrum pharmaceuticals. Paolo Marchetti provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: F. Hoffmann-La Roche, Merck Sharp and Dohme, BMS, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novartis and Pfizer. Filippo de Braud provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Ignyta, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. Sara Manglaviti: advisory board for Italpharma; travel accommodation by MSD and Sanofi outside the submitted work. Mario Occhipinti: advosry board for BMS and personal fee by MSD. Laura Mazzeo: travel accomodation by Sanofi. Marta Brambilla: travel accomodation by Lilli and Leo Pharma, Teresa Beninato: travel accomodation by Lilli, MSD, BMS and Sanofi. The other authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: During the last few years it has been shown that an anaplastic T cell lymphoma can develop as a rare and late sequelae of implant-based breast reconstruction. This malignancy was recognized in the 2017 by WHO and named breast implant associated anaplastic large T cell lymphoma (BIA-ALCL). BIA-ALCL usually presents as abundant effusion around the implant, thus, in addition to cytology smears, its diagnosis also requires immunohistochemistry, T cells clonality and cytometry. Due to the increasing attention of clinicians, it is likely that the number of the BIA-ALCL suspected cases will grow in the future, implying the necessity of a reliable and cost-effective diagnostic procedure., Methods: To achieve this goal, we retrospectively analyzed the results of laboratory investigations performed at our Institute (Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Italy) on 44 effusions obtained from 31 women suspected for BIA-ALCL., Results: Through cytology, eight out of 44 effusions showed the presence of BIA-ALCL cells. Lymphoma cells were than confirmed in seven samples by immunohistochemistry and/or T cell clonality and/or cytometry. Overall, cytology showed 100% sensitivity, 97% specificity and positive and negative predictive values of 87.5% and 100% respectively. Further analyses were particularly useful in effusions showing small percentages of BIA-ALCL cells. Moreover, an extended cytometric profile that can be applied when fast confirmation of the cytologic result is required was also identified., Conclusions: Our results evidenced a central role of cytopathology in the management of BIA-ALCL suspected effusions and suggested that further laboratory investigations might be applied only in cases showing atypical/activated lymphoid cells through cytology.

BRAF V600 mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these aberrantly activated cellular pathways are inhibited by BRAFi whose potent antitumor effect and therapeutic potential are dampened by the development of resistance. Here, by using primary melanoma cell lines, generated from lymph node lesions of metastatic patients, we show that the combination of two FDA-approved drugs, the histone deacetylate inhibitor (HDCAi) romidepsin and the immunomodulatory agent IFN-α2b, reduces melanoma proliferation, long-term survival and invasiveness and overcomes acquired resistance to the BRAFi vemurafenib (VEM). Targeted resequencing revealed that each VEM-resistant melanoma cell line and the parental counterpart are characterized by a distinctive and similar genetic fingerprint, shaping the differential and specific antitumor modulation of MAPK/AKT pathways by combined drug treatment. By using RNA-sequencing and functional in vitro assays, we further report that romidepsin-IFN-α2b treatment restores epigenetically silenced immune signals, modulates MITF and AXL expression and induces both apoptosis and necroptosis in sensitive and VEM-resistant primary melanoma cells. Moreover, the immunogenic potential of drug-treated VEM-resistant melanoma cells results significantly enhanced, given the increased phagocytosis rate of these cells by dendritic cells, which in turn exhibit also a selective down-modulation of the immune checkpoint TIM-3. Overall, our results provide evidence that combined epigenetic-immune drugs can overcome VEM resistance of primary melanoma cells by oncogenic and immune pathways reprogramming, and pave the way for rapidly exploiting this combination to improve BRAFi-resistant metastatic melanoma treatment, also via reinforcement of immune checkpoint inhibitor therapy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

In pseudomyxoma peritonei (PMP), KRAS and GNAS mutations are frequent. We hypothesized that these mutations may contribute to the suppression of antitumor immunity: KRAS may induce GMCSF expression, while GNAS may enhance the expression of cyclic adenosine monophosphate and A2AR signaling. This study aimed to explore possible mechanisms facilitated by KRAS and GNAS mutations for escaping immune surveillance. Additionally, we looked for new potential therapeutic and prognostic targets in this rare disease which is poorly characterized at the molecular level. GM-CSF, A2AR, CD73, CD39, and PD-L1 expression was investigated by immunohistochemistry in 40 PMPs characterized for GNAS and KRAS mutational status. Immune cell populations were studied by immunohistochemistry and nanostring nCounter ® . Following the criteria of a prognostic nomogram reported for PMP, we stratified the patients into two different risk groups, with 28 "low-risk" and 12 "high-risk" patients. We observed the expression of GM-CSF (74%); CD39 (37%); CD73 (53%); A2AR (74%); and PD-L1 (16%) which was unrelated to GNAS or KRAS status. The tumor microenvironment showed the presence of CD4+ T cells (86%); CD8+ T cells (27%); CD20+ B (67%); CD15+ cells (86%); and CD163+ M2 macrophages (67%), while CD56+ NK cells were absent. CD163 expression (27%) in PMP tumor cells was associated with poor prognosis. GNAS mutation and A2AR expression were not associated with a specific immune transcriptional signature. However, the expression assay revealed 21 genes associated with prognosis. The "high-risk" patients exhibited worse progression-free survival (HR = 2.3, CI 95%: 1.1-5.1, p = 0.034) and significant downregulation of MET , IL8 , PPARG , DTX4 , HMGA1, ZIC2 , WNT5B, and CCRL2 . In conclusion, we documented the presence of immunosuppressive factors such as GM-CSF, A2AR, and PD-L1 in PMP. These factors were not associated with GNAS and KRAS status and could be explored as therapeutic molecular targets. Additionally, a set of potential prognostic biomarkers, including CD163 expression in tumor cells, deserve further investigation.

Purpose: The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments., Patients and Methods: Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors., Results: Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types., Conclusion: Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice.

Tumour DNA sequencing is essential for precision medicine since it guides therapeutic decisions but also fosters the identification of patients who may benefit from germline testing. Notwithstanding, the tumour-to-germline testing workflow presents a few caveats. The low sensitivity for indels at loci with sequences of identical bases (homopolymers) of ion semiconductor-based sequencing techniques represents a well-known limitation, but the prevalence of indels overlooked by these techniques in high-risk populations has not been investigated. In our study, we addressed this issue at the homopolymeric regions of BRCA1/2 in a retrospectively selected cohort of 157 patients affected with high-grade ovarian cancer and negative at tumour testing by ION Torrent sequencing. Variant allele frequency (VAF) of indels at each of the 29 investigated homopolymers was systematically revised with the IGV software. Thresholds to discriminate putative germline variants were defined by scaling the VAF to a normal distribution and calculating the outliers that exceeded the mean + 3 median-adjusted deviations of a control population. Sanger sequencing of the outliers confirmed the occurrence of only one of the five putative indels in both tumour and blood from a patient with a family history of breast cancer. Our results indicated that the prevalence of homopolymeric indels overlooked by ion semiconductor techniques is seemingly low. A careful evaluation of clinical and family history data would further help minimise this technique-bound limitation, highlighting cases in which a deeper look at these regions would be recommended., (© 2023. The Author(s).)

Background: Pan-TRK inhibitors Entrectinib and Larotrectinib have been recently approved as tumor-agnostic therapies in NTRK1-2-3 rearranged patients and there is therefore an urgent need to identify reliable and accessible biomarkers for capturing NTRK fusions in the real-world practice., Objective: We aim to assess the analytical validity of the recently released pan-TRK assay (Ventana), running a head-to-head comparison between immunohistochemistry and Archer FusionPlex Lung Panel (ArcherDX) that is designed to detect key fusions in 13 genes, also including NTRK1-3., Methods: Pan-TRK IHC and NGS analysis were conducted on a retrospective/prospective cohort of 124 cancer patients (carcinomas, 93 cases; soft tissue sarcomas, 19; primary central nervous system tumours, 10; and neuroblastomas, 2). FISH data were available in most of the IHC/NGS discordant cases., Results: A comparison between IHC and NGS results was carried out in 117 cases: among 30 pan-TRK positive cases, NTRK rearrangement by NGS was found in 11 (37%), while one of the 87 (1.1%) pan-TRK negative cases (a case of NSCLC) showed a TPM3-NRTK1 rearrangement by NGS. Accordingly, sensitivity and specificity of IHC in predicting NTRK status were 91.7% and 81.9%, respectively, while negative (NPV) and positive predictive value (PPV) were 98.8% and 36.7%, respectively., Conclusions: These data lead to suggest that IHC with VENTANA pan-TRK antibody can be a reliable screening tool for the identification of patients potentially bearing NTRK rearranged tumours.

Purpose: This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O 6 -methylguanine-DNA methyltransferase (MGMT)-silenced metastatic colorectal cancer (mCRC)., Patients and Methods: Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus MGMT methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule., Results: Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported., Conclusion: The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC., Competing Interests: Federica MoranoHonoraria: ServierTravel, Accommodations, Expenses: Sanofi, Servier Sara LonardiConsulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, MSDSpeakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, AmgenResearch Funding: Amgen, Merck Serono, Bayer (Inst), Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst) Lisa SalvatoreHonoraria: Roche, Merck Serono, Servier, Bayer, Amgen, Sanofi, AstraZeneca, Pierre Fabre, MSDConsulting or Advisory Role: Merck Serono, Servier, Bayer, Roche, Amgen, AstraZeneca, Sanofi, Pierre Fabre, MSDTravel, Accommodations, Expenses: Sanofi, Merck Serono, Bayer, Roche, Servier, Celgene Chiara CremoliniHonoraria: Roche, Amgen, Bayer, Servier, MSD, MerckConsulting or Advisory Role: Roche, Bayer, Amgen, MSDSpeakers' Bureau: ServierResearch Funding: Merck, Bayer, Roche, Servier Patrizia RaccaHonoraria: Merck Serono, Roche, Amgen, Servier Monica NigerConsulting or Advisory Role: Incyte, Basilea Pharmaceutical, EMD Serono, MSD/AstraZenecaTravel, Accommodations, Expenses: Celgene Francesca CortiTravel, Accommodations, Expenses: Advanced Accelerator Applications Alberto ZaniboniConsulting or Advisory Role: Amgen, Servier, Bayer, Merck Serono, MerckSpeakers' Bureau: servier, Astellas Pharma (Inst) Celeste CagnazzoSpeakers' Bureau: Boehringer Ingelheim, Novartis Massimo Di MaioHonoraria: Pfizer, Takeda, AstraZeneca, Janssen, Eisai, Novartis, Roche, Astellas Pharma, MSD OncologyConsulting or Advisory Role: AstraZeneca, Pfizer, Takeda, Janssen, Eisai, Novartis, Roche, MSD Oncology, AmgenResearch Funding: Tesaro (Inst), GlaxoSmithKline (Inst) Maria Di BartolomeoHonoraria: Lilly, MSD Oncology, ServierConsulting or Advisory Role: Lilly, MSD OncologyResearch Funding: LillyTravel, Accommodations, Expenses: Roche, Sanofi Filippo De BraudHonoraria: Roche, Pfizer, BMS, Merck, MSD, Servier, Sanofi, Amgen Astellas BioPharma, IncyteConsulting or Advisory Role: Roche, Incyte, EMD SERONO, Bristol Myers Squibb, Nerviano Medical Sciences, Sanofi, Novartis Italy, nms medical science, MenariniResearch Funding: Novartis (Inst), Roche (Inst), Merck Serono (Inst), Pfizer (Inst), Servier (Inst), Philogen (Inst), Loxo (Inst), Tesaro (Inst), Nerviano Medical Sciences (Inst), Kymab (Inst), Bristol Myers Squibb/Medarex, Merck KGaA, Ignyta, MedImmune, Exelixis, Bayer Health, Daiichi Sankyo Europe GmbH, Incyte, Basilea Pharmaceutical, Janssen Oncology Filippo PietrantonioHonoraria: Servier, Bayer, AstraZeneca/MedImmune, Lilly, Sanofi, MSD Oncology, AmgenConsulting or Advisory Role: Amgen, Servier, MSD Oncology, MerckResearch Funding: Bristol Myers Squibb (Inst), Astrazeneca (Inst)No other potential conflicts of interest were reported.

Tumour testing of the BRCA1/2 genes is routinely performed in patients with different cancer histological subtypes. To accurately identify patients with tumour-detected germline pathogenic variants (PVs) is a relevant issue currently under investigation. This study aims at evaluating the performance of the tumour-to-germline diagnostic flowchart model defined at our Institutional Molecular Tumour Board (MTB). Results from tumour BRCA sequencing of 641 consecutive unselected cancer patients were discussed during weekly MTB meetings with the early involvement of clinical geneticists for appropriate referral to genetic counselling. The overall tumour detection rate of BRCA1/2 PVs was 8.7% (56/641), ranging from 24.4% (31/127) in high-grade ovarian cancer to 3.9% (12/304) in tumours not associated with germline BRCA1/2 PVs. Thirty-seven patients with PVs (66%) were evaluated by a clinical geneticist, and in 24 of them (64.9%), germline testing confirmed the presence of the PV in blood. Nine of these patients (37.5%) were not eligible for germline testing according to the criteria in use at our institution. Cascade testing was subsequently performed on 18 relatives. The tumour-to-germline diagnostic pipeline, developed in the framework of our institutional MTB, compared with guideline-based germline testing following genetic counselling, proved to be effective in identifying a higher number of germline BRCA PVs carriers., Competing Interests: FB: Consultant Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini. Speaker: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, ACCMED, Nadirex, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum. Principal Investigator for Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, DAICHI SANKIO Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA MN: Travel expenses from Celgene, speaker honorarium from Accademia della Medicina and consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte and MSD Italia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Azzollini, Vingiani, Agnelli, Tamborini, Perrone, Conca, Capone, Busico, Peissel, Rosina, Ducceschi, Mantiero, Lopez, Raspagliesi, Niger, Duca, Damian, Proto, de Braud, Pruneri and Manoukian.)

Purpose: In GI cancers, anaplastic lymphoma kinase ( ALK ) rearrangements are extremely less frequent than in non-small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce., Materials and Methods: We assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis., Results: Primary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response)., Conclusion: Treatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion-positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed., Competing Interests: Marzia Del ReConsulting or Advisory Role: Sanofi, Celgene, Janssen-Cilag, Ipsen, Roche Molecular DiagnosticsSpeakers' Bureau: Sanofi, Pfizer, Novartis, Janssen-Cilag, Ipsen, AstraZeneca, Astellas Pharma, Roche, MSD Oncology Paolo MancaPatents, Royalties, Other Intellectual Property: I have a patent for a method for the identification of gene panels optimal for TMB estimation (Inst) Andrew HendifarConsulting or Advisory Role: Novartis, Ipsen, Perthera, Celgene, AbbVie, EisaiResearch Funding: Ipsen, NGM Biopharmaceuticals (Inst)Travel, Accommodations, Expenses: HalozymeOther Relationship: FibroGen Alexander DrilonHonoraria: Pfizer, Loxo/Bayer/Lilly, IASLCConsulting or Advisory Role: Ignyta, Loxo, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Repare Therapeutics, Melendi, Archer, Nuvalent Inc, Janssen, Amgen, Merus, Axis Pharma, Medscape, Liberum, Med Learning, PeerView, EPG Health, JNCCN/Harborside, Ology, Clinical Care Options, touchIME, Entos, Treeline, Prelude Therapeutics, Applied Pharmaceutical Science IncSpeakers' Bureau: Helsinn Therapeutics, Beigene, Remedica Ltd, TP Therapeutics, Verastem, Ignyta/Genentech/Roche, AstraZeneca, Liberum, Loxo/Bayer/Lilly, Lungevity, NIH, PER, OncLive/MJH Life Sciences, Clinical Care Options/NCCN, Lung Cancer Canada, AIOT, Chugai Pharma, Chugai Pharma, Sirio Libanes Hospital, Answers in CME, Faculty RTP, RV MoreResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology, Merus, Boehringer Ingelheim Guilherme HaradaSpeakers' Bureau: MSD, AstraZeneca, Pfizer Anne Hansen ReeHonoraria: MSD Oncology, BMSiResearch Funding: BMSi (Inst) Samuel KlempnerStock and Other Ownership Interests: TP Therapeutics, Nuvalent IncHonoraria: NateraConsulting or Advisory Role: Lilly, Astellas Pharma, Bristol Myers Squibb, Pieris Pharmaceuticals, Merck, Daiichi Sankyo/UCB Japan, Sanofi/Aventis, MersanaResearch Funding: Leap Therapeutics (Inst), BeiGene (Inst), Silverback Therapeutics (Inst)Other Relationship: NCCN Gunhild Mari MælandsmoPatents, Royalties, Other Intellectual Property: Patent application submitted for a nine-protein/gene panel predicting response to anti VEGF therapies in combination with chemotherapy (Inst) Hege G. RussnesHonoraria: AstraZeneca (Inst), Pfizer (Inst), InCyte (Inst), Merck (Inst), Roche (Inst)Research Funding: Foundation Medicine (Inst) James M. ClearyHonoraria: Blueprint Medicines, Syros PharmaceuticalsConsulting or Advisory Role: Bristol Myers SquibbResearch Funding: Merck, Tesaro, AstraZeneca, Esperas Pharma, AbbVie (Inst), Merus (Inst), Roche/Genentech (Inst), BMS (Inst)Travel, Accommodations, Expenses: Roche, Agios, Bristol Myers Squibb Andrea Sartore-BianchiConsulting or Advisory Role: Amgen, Bayer, Sanofi, Servier, Novartis Maria Di BartolomeoHonoraria: Lilly, MSD Oncology, Servier, BMSiConsulting or Advisory Role: Lilly, MSD OncologyResearch Funding: LillyTravel, Accommodations, Expenses: Roche, Sanofi Filippo PietrantonioHonoraria: Servier, Bayer, AstraZeneca/MedImmune, Lilly, Sanofi, MSD Oncology, AmgenConsulting or Advisory Role: Amgen, Servier, MSD Oncology, MerckResearch Funding: Bristol Myers Squibb (Inst), Astrazeneca (Inst)No other potential conflicts of interest were reported.

Aim: Diagnostic laboratories are progressively introducing next-generation sequencing (NGS) technologies in the routine workflow to meet the increasing clinical need for comprehensive molecular characterization in cancer patients for diagnosis and precision medicine, including fusion-transcripts detection. Nevertheless, the low quality of messenger RNA (mRNA) extracted from formalin-fixed paraffin-embedded (FFPE) samples may affect the transition from traditional single-gene testing approaches [like fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or polymerase chain reaction (PCR)] to NGS. The present study is aimed at assessing the overall accuracy of RNA fusion transcripts detection by NGS analysis in FFPE samples in real-world diagnostics., Methods: Herein, NGS data from 190 soft tissue tumors (STTs) and carcinoma cases, discussed in the context of the institutional Molecular Tumor Board, are reported and analyzed by FusionPlex © Solid tumor kit through the manufacturer's pipeline and by two well-known fast and accurate open-source tools [Arriba (ARR) and spliced transcripts alignment to reference (STAR)-fusion (SFU)]., Results: The combination of FusionPlex © Solid tumor with ArcherDX ® Analysis suite (ADx) analysis package has been proven to be sensitive and specific in STT samples, while partial loss of sensitivity has been found in carcinoma specimens., Conclusions: Albeit ARR and SFU showed lower sensitivity, the use of additional fusion-detection tools can contribute to reinforcing or extending the output obtained by ADx, particularly in the case of low-quality input data. Overall, our results sustain the clinical use of NGS for the detection of fusion transcripts in FFPE material., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2022.)

Purpose: The activity of androgen-deprivation therapy (ADT) in androgen receptor-positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC., Methods: This was a single-institution phase II trial. A two-stage Simon's design was applied. The primary end point was confirmed objective response rate. Secondary end points were disease control rate, safety, progression-free survival, and overall survival. Patients were eligible when the following criteria were met: histologic diagnosis of AR-overexpressing SGC, measurable disease according to RECIST 1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and luteinizing hormone-releasing hormone agonist until progression or unacceptable toxicities., Results: From 2015 to 2019, 24 AR+ patients with SGC (23 men; median age 65.8 years) were treated within the study. The overall response rate was 21% (5 partial responses), with a disease control rate of 62.5%. The median duration of response was 5.82 months. Median progression-free survival was 3.65 months (95% CI, 1.94 to 5.89), and median overall survival was 22.47 months (95% CI, 6.74 to not reached). Objective response to previous ADT did not correlate with the activity of abiraterone. Adverse events (AEs) were recorded in 22 cases (92%) with grade 3 AEs in six patients (25%): fatigue (two), flushing (one), supraventricular tachycardia (one), and two non-drug-related AEs. No drug-related grade 4 or 5 AEs were recorded., Conclusion: Abiraterone plus luteinizing hormone-releasing hormone agonist is active and safe as a second-line option in AR-expressing, castration-resistant SGC., Competing Interests: Laura D. LocatiHonoraria: McCann Health, BiogenConsulting or Advisory Role: Bristol Myers Squibb Foundation, Eisai, Lilly, Ipsen, MSD, Merck SeronoResearch Funding: EisaiTravel, Accommodations, Expenses: Eisai, BMS, Merck Serono, MSD Carlo ResteghiniHonoraria: Sun Pharma Paolo BossiHonoraria: Bristol Myers Squibb, Merck, Regeneron, GlaxoSmithKline, MSD OncologyConsulting or Advisory Role: Merck Serono, Bristol Myers Squibb, Sanofi/Regeneron, Angelini Pharma, MSD Oncology, Sun Pharma, GlaxoSmithKlineResearch Funding: Amgen, Merck Serono, Roche, MSD Oncology, GlaxoSmithKline, Regeneron Lisa LicitraConsulting or Advisory Role: Eisai, Boehringer Ingelheim, AstraZeneca, SOBI, Novartis, Bayer, MSD, Merck Serono, Roche, Bristol Myers Squibb, Incyte, Doxapharma, GlaxoSmithKline, Nanobiotix, Debiopharm Group, Amgen, Ipsen, RocheResearch Funding: AstraZeneca, Novartis, Roche, MSD, Eisai, Merck Serono, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Exelixis, IRX Therapeutics, Medpace, Pfizer, Debiopharm Group, RocheTravel, Accommodations, Expenses: Merck Serono, Bristol Myers Squibb, MSD, Eisai, AstraZenecaNo other potential conflicts of interest were reported.

Background: A recent phase II randomized Japanese study reported better survival with regorafenib followed at progression by cetuximab ± irinotecan compared with the reverse standard sequence in chemo-refractory and anti-EGFR-naïve, RAS wild-type (wt) mCRC patients. Nowadays the use of anti-EGFR antibodies is more frequently anticipated to the first-line of therapy especially in patients with left-sided RAS/BRAF wt tumours. However, retrospective analyses and phase II single-arm trials showed promising activity of re-using anti-EGFRs in metastatic colorectal cancer (mCRC) patients who previously achieved benefit from a first-line anti-EGFR-based treatment. Post-hoc analyses of these trials revealed that the detection of RAS mutations in circulating tumour DNA (ct-DNA) at the time of re-treatment may be useful to identify resistant patients., Patients and Methods: PARERE (NCT04787341) is a prospective, open label, multicentre phase II study in which 214 RAS/BRAF wt chemo-refractory mCRC patients with previous benefit from first-line anti-EGFR-based treatment and RAS/BRAF wt ct-DNA in the liquid biopsy collected at the time of inclusion will be randomized in a 1:1 ratio to receive panitumumab followed after progression by regorafenib versus the reverse sequence. Primary endpoint is overall survival. Secondary endpoints are 1st-progression free-survival (PFS), 2nd-PFS, time to failure strategy, objective response rate, and safety., Aim of the Study: The aim of this study is to validate the role of anti-EGFR retreatment and its proper placement in the therapeutic route of mCRC patients selected according to the analysis of ct-DNA in liquid biopsy. Results are expected at the end of 2023., (Copyright © 2021. Published by Elsevier Inc.)

To match the high capacity of metallic anodes, all-solid-state batteries require high energy density, long-lasting composite cathodes such as Ni-Mn-Co (NMC)-based lithium oxides mixed with a solid-state electrolyte (SSE). However in practice, cathode capacity typically fades due to NMC cracking and increasing NMC/SSE interface debonding because of NMC pulverization, which is only partially mitigated by the application of a high cell pressure during cycling. Using smart processing protocols, we report a single-crystal particulate LiNi 0.83 Mn 0.06 Co 0.11 O 2 and Li 6 PS 5 Cl SSE composite cathode with outstanding discharge capacity of 210 mA h g -1 at 30 °C. A first cycle coulombic efficiency of >85, and >99% thereafter, was achieved despite a 5.5% volume change during cycling. A near-practical discharge capacity at a high areal capacity of 8.7 mA h cm -2 was obtained using an asymmetric anode/cathode cycling pressure of only 2.5 MPa/0.2 MPa.

Introduction: Preclinical models recently unveiled the vulnerability of LKB1/KRAS comutated NSCLC to metabolic stress-based treatments. Because miR-17 is a potential epigenetic regulator of LKB1, we hypothesized that wild-type LKB1 (LKB1 WT ) NSCLC with high miR-17 expression may be sensitive to an energetic stress condition, and eligible for metabolic frailties-based therapeutic intervention., Methods: We took advantage of NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion and of patient-derived xenografts (PDXs) with high (LKB1 WT /miR-17 high) or low (LKB1 WT /miR-17 low) miR-17 expression. We evaluated LKB1 pathway impairment and apoptotic response to metformin. We retrospectively evaluated LKB1 and miR-17 expression levels in tissue specimens of patients with NSCLC and PDXs. In addition, a lung cancer series from The Cancer Genome Atlas data set was analyzed for miR-17 expression and potential correlation with clinical features., Results: We identified miR-17 as an epigenetic regulator of LKB1 in NSCLC and confirmed targeting of miR-17 to LKB1 3' untranslated region by luciferase reporter assay. We found that miR-17 overexpression functionally impairs the LKB1/AMPK pathway. Metformin treatment prompted apoptosis on miR-17 overexpression only in LKB1 WT cell lines, and in LKB1 WT /miR-17 high PDXs. A retrospective analysis in patients with NSCLC revealed an inverse correlation between miR-17 and LKB1 expression and highlighted a prognostic role of miR-17 expression in LKB1 WT patients, which was further confirmed by The Cancer Genome Atlas data analysis., Conclusions: We identified miR-17 as a mediator of LKB1 expression in NSCLC tumors. This study proposes a miR-17 expression score potentially exploitable to discriminate LKB1 WT patients with NSCLC with impaired LKB1 expression and poor outcome, eligible for energy-stress-based treatments., (Copyright © 2021 International Association for the Study of Lung Cancer. All rights reserved.)