Early treatment discontinuation in patients with deficient mismatch repair or microsatellite instability high metastatic colorectal cancer receiving immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy.

BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer.

Background: Immune checkpoint inhibitors (ICIs) are the guideline endorsed first choice for patients with deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) mCRC, however a significant proportion experience primary or secondary resistance. BRAF V600E mutated (BRAFm) and dMMR/MSI-H mCRC can be treated with BRAF + EGFR inhibitors but specific data on the efficacy after progression to ICIs are missing.

Methods: We collected consecutive patients with BRAFm dMMR/MSI-H mCRC treated from 2017 to 2024 with a combination of BRAFi+EGFRi+/-MEKi, after disease progression on ICIs.

Nanobody-liposomes as novel cancer vaccine platform to efficiently stimulate T cell immunity.

Cancer vaccines can be utilized in combination with checkpoint inhibitors to optimally stimulate the anti-tumor immune response. Uptake of vaccine antigen by antigen presenting cells (APCs) is a prerequisite for T cell priming, but often relies on non-specific mechanisms. Here, we have developed a novel vaccination strategy consisting of cancer antigen-containing liposomes conjugated with CD169- or DC-SIGN-specific nanobodies (single domain antibodies) to achieve specific uptake by APCs.

Vaccination with DC-SIGN-Targeting αGC Liposomes Leads to Tumor Control, Irrespective of Suboptimally Activated T-Cells.

Cancer vaccines have emerged as a potent strategy to improve cancer immunity, with or without the combination of checkpoint blockade. In our investigation, liposomal formulations containing synthetic long peptides and α-Galactosylceramide, along with a DC-SIGN-targeting ligand, Lewis Y (Le), were studied for their anti-tumor potential. The formulated liposomes boosted with anti-CD40 adjuvant demonstrated robust invariant natural killer (iNKT), CD4, and CD8 T-cell activation in vivo.

Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

Background: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.

Patients And Methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents.

The Prognostic Nutritional Index in patients with microsatellite instability-high metastatic gastric or gastroesophageal cancers receiving immune checkpoint inhibitors.

Background: Microsatellite instability high (MSI-H) and/or mismatch repair deficient (dMMR) status is the strongest predictive factor for immune checkpoint inhibitors (ICIs) benefit in patients with metastatic gastroesophageal cancer (mGC). Primary resistance to ICIs is a relevant issue, but prognostic and predictive factors are lacking.

Materials And Methods: In this multinational, retrospective cohort of patients with MSI-H/dMMR mGC treated with ICIs without chemotherapy we collected baseline laboratory values to establish the prognostic nutritional index (PNI).

Negative hyperselection of elderly patients with RAS and BRAF wild-type metastatic colorectal cancer receiving initial panitumumab plus FOLFOX or 5-FU/LV.

Background: Upfront anti-EGFR therapy represents the standard of care for patients with left-sided, MSS/pMMR, RAS and BRAF wild-type mCRC. Molecular 'hyperselection' may optimize EGFR inhibition by detecting additional resistance alterations.

Materials And Methods: We used comprehensive genomic profiling on archival samples of elderly patients enrolled in the PANDA trial to detect: HER2 amplification/mutations; MET amplification; NTRK/ROS1/ALK/RET rearrangements; PIK3CA exon 20 mutations; PTEN alterations; AKT1 mutations; MAP2K1 mutations.

Long-term outcomes and persistent toxicities following BRAF/MEK inhibitor therapy for advanced melanoma.

Background: Recent studies have shown that approximately 20% of patients have 4-5 year progression free survival (PFS) on BRAF/MEK inhibitors. The long-term safety and efficacy in these patients with more durable responses have not been studied.

Methods: This retrospective multicenter cohort study assessed response, progression, and adverse events in patients from eight institutions in four countries with >4-year PFS following BRAF/MEK inhibitors.

Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors.

Purpose: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI.

Experimental Design: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3' RNA sequencing was performed from primary tumors.

COVID-19 and (Im)migrant Carers in Italy: The Production of Carer Precarity.

This article explores the impact of COVID-19 restrictions on foreign health workers in Italy. Focusing on caregivers in Lombardia, we explore what we call carer precarity, an emergent form of precarity resulting from pandemic restrictions exacerbating existing socio-legal vulnerabilities. The duality of the carer role-complete household and societal reliance in addition to simultaneous socio-legal marginalization-shapes their precarity.

Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes.

Patients And Methods: We screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers.

Constrained to be (im)mobile? Refugees' and Asylum seekers' practices to integrate in restrictive socio-economic urban contexts in Northern Italy.

This article comparatively examines forms of (im)mobility among refugees and asylum seekers (RAS) in coping with dispersal process, restrictive migration policies and local socio-economic characteristics in three cities of Northern Italy. Drawing on qualitative data, it sheds light on the everyday forms of (im)mobility of RAS to resist structural barriers limiting their opportunities to access jobs and welfare services. The Results show that people's capacity to overcome barriers depends upon individual characteristics and informal networks, and is shaped by particularities of local contexts.

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer.

Background: Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.

Cerebrospinal fluid and arterial acid-base equilibria in spontaneously breathing third-trimester pregnant women.

Background: Acid-base status in full-term pregnant women is characterised by hypocapnic alkalosis. Whether this respiratory alkalosis is primary or consequent to changes in CSF electrolytes is not clear.

Methods: We enrolled third-trimester pregnant women (pregnant group) and healthy, non-pregnant women of childbearing age (controls) undergoing spinal anaesthesia for Caesarean delivery and elective surgery, respectively.

Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies.

Prognostic impact of performance status on the outcomes of immune checkpoint inhibition strategies in patients with dMMR/MSI-H metastatic colorectal cancer.

Background: Immune checkpoint inhibitors yielded unprecedented outcomes in patients with mismatch repair deficient/ microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), but clinical decision-making in this rapidly evolving treatment landscape is challenging. Since performance status (PS) represents a well-established prognostic factor in clinical practice, we investigated whether worse PS, overall or related to either patients' frailty or high tumour burden, could affect the outcomes in this whole patients' population and according to immune checkpoint inhibitor treatment type.

Methods: We conducted a global study at Tertiary Cancer Centres and collected data of patients with dMMR/MSI-H mCRC treated with anti- programmed-death (ligand)-1 (PD(L)-1) monotherapy or anti-PD-1/anti- cytotoxic T-lymphocyte antigen 4 combination.

Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial.

Background: Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer.

Negative Ultraselection of Patients With / Wild-Type, Microsatellite-Stable Metastatic Colorectal Cancer Receiving Anti-EGFR-Based Therapy.

Purpose: Several uncommon genomic alterations beyond and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including exon 20// mutations, / amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations.

ALK Inhibitors in Patients With ALK Fusion-Positive GI Cancers: An International Data Set and a Molecular Case Series.

Purpose: In GI cancers, anaplastic lymphoma kinase () 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 rearrangement treated with at least one line of ALKi.

Cancer-related fatigue and depression: a monocentric, prospective, cross-sectional study in advanced solid tumors.

Background: Cancer-related fatigue (CRF) is common in patients with advanced solid tumors and several risk factors are described. The possible role of depression is reported by clinicians despite the association with CRF being unclear.

Material And Methods: In this monocentric, cross-sectional, prospective study we recruited patients with advanced solid tumors who were hospitalized at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan.

Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers.

Background: Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.

Methods: We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set).

Variant allele frequency in baseline circulating tumour DNA to measure tumour burden and to stratify outcomes in patients with RAS wild-type metastatic colorectal cancer: a translational objective of the Valentino study.

Introduction: In patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in comparison with CEA and RECIST-defined sum of target lesions.

Methods: In this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel.

Targeted protein degraders from an oncologist point of view: The Holy Grail of cancer therapy?

In the era of precision medicine, monoclonal antibodies and small molecule inhibitors are the mainstays of the biological therapy in patients with solid tumors. However, resistance to treatment and the "undruggability" of certain key oncogenic proteins emerged as major limitations and jeopardize the clinical benefit of modern therapeutic approaches. Targeted protein degraders are novel molecules entering the early phase of clinical development that exploit the intracellular ubiquitine-proteasome system to promote a specific degradation of target proteins.