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. Methods: We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models. Results: Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two's effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, 'aggregated' burden scores were developed to distinguish 'protective' (endocrine and musculoskeletal) and 'harmful' (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS. Conclusions: Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response

APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research

Introduction: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). Methods and objectives: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. Conclusion: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project

Cancers of unknown primary origin: current perspectives and future therapeutic strategies

It is widely accepted that systemic neoplastic spread is a late event in tumour progression. However, sometimes, rapidly invasive cancers are diagnosed because of appearance of metastatic lesions in absence of a clearly detectable primary mass. This kind of disease is referred to as cancer of unknown primary (CUP) origin and accounts for 3-5% of all cancer diagnosis. There is poor consensus on the extent of diagnostic and pathologic evaluations required for these enigmatic cases which still lack effective treatment. Although technology to predict the primary tumour site of origin is improving rapidly, the key issue is concerning the biology which drives early occult metastatic spreading. This review provides the state of the art about clinical and therapeutic management of this malignant syndrome; main interest is addressed to the most recent improvements in CUP molecular biology and pathology, which will lead to successful tailored therapeutic options

Profili di espressione genica dei tumori colorettali con instabilità microsatellitare: focus sui geni immuno-correlati

Negli ultimi anni, i miglioramenti nell’ambito dello screening, della diagnosi e della gestione terapeutica personalizzata hanno determinato un netto miglioramento della prognosi dei pazienti con carcinoma colorettale (CRC). Complessivamente, nel trattamento del tumore del colon-retto metastatico sono molteplici le opzioni di cura oggi disponibili, comprendenti trattamenti locoregionali (chirurgia, radioterapia, ablazione) integrati con terapie sistemiche; la scelta della strategia ottimale deve essere condivisa fin da subito da un team multidisciplinare e individualizzata sul singolo paziente in base alle caratteristiche cliniche e tumorali. La ricerca oncologica è quindi molto impegnata nell’individuazione di fattori prognostici e predittivi, sia dal punto di vista clinico che patologico-molecolare. Nello specifico, per quanto riguarda i tumori del colon-retto, essi possono essere raggruppati sulla base di talune specifiche caratteristiche molecolari che ne determinano diversa sensibilità ai vari trattamenti oltre che diversa prognosi. L‘instabilità dei microsatelliti (MSI-H), in particolare, alterazione dovuta a difetti nel sistema del mismatch repair (MMR), è al momento oggetto di estremo interesse scientifico, data l’evidenza di una sua correlazione con una maggiore sensibilità ai trattamenti immunologici. Le forme MSI-H risultano essere circa il 15% nello stadio II-III e il 4-5% nello stadio IV. I tumori colorettali MSI-H hanno caratteristiche peculiari e specifiche da un punto di vista clinico, istologico e molecolare: sono più frequentemente localizzati nel colon di destra e diagnosticati in giovane età ed ad uno stadio più precoce rispetto alle altre forme stabili; sono più spesso caratterizzati da un istotipo mucinoso e da una peculiare elevata infiltrazione linfocitaria intra-tumorale correlata ad una spiccata risposta immunitaria anti-tumorale, oltre che dall’elevata frequenza della mutazione V600E del gene BRAF. L’instabilità dei microsatelliti ha anche importanti correlazioni prognostiche e predittive. Considerati gli stadi precoci di malattia, questi tumori hanno buona prognosi e verosimilmente non traggono beneficio da un trattamento adiuvante con le sole fluoropirimidine, mentre nello stadio di malattia metastatica hanno una prognosi più sfavorevole con una minore chemiosensibilità rispetto ai tumori stabili e una probabile resistenza al trattamento con alcuni farmaci a bersaglio molecolare, nello specifico gli anti-EGFR. Tuttavia, nello stadio avanzato, è molto promettente l’utilizzo di farmaci immunoterapici o checkpoint-inibitori. La loro efficacia, già dimostrata in alcuni studi di fase I-II, ha il suo razionale biologico nella presenza di un elevato carico mutazionale dei tumori MSI-H con conseguente presenza di numerosi neo-antigeni che determinano attivazione di una risposta immunitaria anti-tumorale ed una elevata infiltrazione linfocitaria. Lo studio di fase II multicentrico CheckMate-142 ha valutato, in due coorti separate di pazienti con CRC metastatico (mCRC) MSI-H/dMMR pretrattato con chemioterapia, l’efficacia del farmaco immunoterapico nivolumab (anticorpo monoclonale anti-PD-1) e della combinazione di nivolumab e ipilimumab (anti-CTLA4), mentre lo studio di fase II KEYNOTE-164 ha valutato, in pazienti con caratteristiche simili, l’efficacia di pembrolizumab (anti-PD-1). I risultati emersi da questi studi sono molto incoraggianti riguardo l’efficacia dell’immunoterapia in questo sottogruppo di pazienti. Tuttavia, ad una analisi più attenta, si può notare come solo circa la metà dei pazienti trattati con gli anti-PD1 e il 70% di quelli trattati con la combinazione dei due immunoterapici tragga un beneficio realmente significativo dalla terapia somministrata. Questo porta a pensare che i CRC MSI-H/dMMR possano costituire, in realtà, un gruppo eterogeneo di tumori che si differenziano per il diverso microambiente immunitario associato. Quest’ultima ipotesi è sostenuta anche da osservazioni sul melanoma, un altro tumore con elevato carico mutazionale e buona risposta all’immunoterapia, che hanno riconosciuto la presenza di due fenotipi differenti: un fenotipo tumorale “infiammato”, con spiccata attivazione immunitaria e un fenotipo “non infiammato”, che invece non la presenta, i quali sembrano correlare rispettivamente in modo positivo e negativo con la risposta all’immunoterapia. Sulla base di tali considerazioni l’intento del nostro studio è stato quello di valutare il profilo immunitario dei tumori colorettali MSI-H/dMMR attraverso l’analisi dell’espressione dell’mRNA relativo a geni immuno-correlati utilizzando la piattaforma genica nanoString. Il risultato dell’analisi ha confermato come i tumori CRC MSI-H/dMMR costituiscono un gruppo eterogeneo di neoplasie dal punto di vista del microambiente immunitario. Dalla valutazione quantitativa complessiva dei geni maggiormente significativi in termini di differenza di espressione tra i vari campioni (o deregolazione) è stato possibile costruire un classificatore in grado di distinguere in modo dicotomico i CRC dMMR/MSI-H in due gruppi: i tumori cosiddetti COLD, che mostrano una significativa down-regolazione dei geni correlati al sistema immunitario, e i tumori cosiddetti NOT COLD, che, al contrario, mostrano una up-regolazione completa o parziale di questi geni. I tumori COLD rispetto ai NOT COLD si differenziano inoltre per caratteristiche cliniche, presentandosi più frequentemente negli stadi più avanzati di malattia e a livello del colon sinistro, di espressione genica, mostrando una netta deregolazione di numerosi geni immuno-correlati, nella densità delle popolazioni cellulari associate, in particolare presentando un numero minore di linfociti infiltranti il tumore (TILs), cellule citotossiche, macrofagi, cellule T, mastociti, cellule T CD8+ e cellule B, e, infine, nella prognosi, essendo la sopravvivenza globale inferiore, considerando sia la totalità dei pazienti, sia i pazienti con malattia metastatica. Le differenze nell’espressione dei geni relativi alle funzioni del sistema immunitario e quelle clinico-patologiche riscontrate tra questi due gruppi suggeriscono che, benché parte dello stesso sottogruppo molecolare, essi possano non beneficiare allo stesso modo dell’immunoterapia. Queste considerazioni, che dovranno essere ulteriormente confermate e validate, ci indicano la possibilità, in futuro, di selezionare tra i pazienti con CRC MSI-H/dMMR, quelli che potranno verosimilmente beneficiare del trattamento immunoterapico e quelli in cui questi tipi di farmaci non rappresentano la strategia ottimale. Un'ulteriore prospettiva futura potrebbe essere quella di valutare l’applicazione di questo classificatore nei tumori colorettali stabili e nei tumori non colorettali, al fine di individuare potenziali pazienti responsivi all’immunoterapia anche in questi gruppi

Molecular Imaging of Pulmonary Nodules

OBJECTIVE: Lung nodules can be benign or malignant, reflecting many possible causes, ranging from inflammatory and infectious processes to neoplasms. Incidental detection on chest x-ray or thoracic CT often requires further evaluation by imaging or invasive procedures. CONCLUSION: Currently, 18F-FDG PET/CT offers both anatomic and metabolic characterization of lung nodules. Fluorine-18-thymidine, 11C-methionine, 68Ga-DOTA-somatostatin analogs, and 18F-dihydroxyphenylalanine may offer additional molecular information useful for diagnosis and treatment planning

Impact of first trimester fasting glycemic levels on expression of proteoglycans in pregnancy

Aim: The aim of this study was to assess the influence of glucose metabolism on the expression of glycosaminoglycans (GAGs) and proteoglycans (PGs) in pregnant women. Material and Methods: Seventy-six women in the first trimester of pregnancy (10–13 weeks) attending the Gynecologic and Obstetric Clinic, University of Sassari, were enrolled and gave early morning urine samples. Groups I, II and III included women with serum glucose values of 65–89 mg/dL, 90–99 mg/dL and 100–125 mg/dL, respectively. Urine GAGs/PGs distribution was determined by electrophoresis on cellulose acetate strips. Urinary N-Acetyl-β-glucosaminidase was estimated kinetically. Results: Analysis of urinary GAGs/PGs electrophoretic profiles showed a significant increase in heparan sulfate (HS) excretion (P = 0.017) as well as a reduced chondroitin sulfate (CS) excretion (P = 0.048) in the group II pregnant women compared with the group I, and higher values of the HS/CS ratio in groups II and III compared to group I. Furthermore, we observed a positive correlation among fasting blood glucose levels and the relative content of HS, the HS/CS and urinary trypsin inhibitor/CS ratios, and the N-Acetyl-β- glucosaminidase levels. Conclusions: The assessment of risk factors for gestational diabetes mellitus should also take into account fasting blood glucose values of 90–99 mg/dL, as the findings of our study indicated an alteration in the metabolism of GAGs during the early stages of pregnancy.</br

F-FDG-PET/CT imaging in cardiac tumors: illustrative clinical cases and review of the literature

Cardiac tumors are a very rare condition. Mostly, they are benign tumors (75%), with myxomas being the most frequent. The remaining 25% are malignant; either primary malignant sarcoma or secondary metastases. Given the small number of cases reported and the lack of prospective and randomized clinical trials, the level of evidence for the optimal multimodal treatment of primary cardiac sarcomas is very low and the optimal imaging diagnostic workup is not well established. In particular, 18 F-FDG-PET/CT is not yet included in routine diagnosis of cardiac masses. Here, we report four illustrative clinical cases and a review of the literature on the current available data on the role of 18 F-fluorodeoxyglucose PET/CT imaging in cardiac tumors

P16 immunostaining and HPV testing in histological specimens from the uterine cervix

Background: The cellular tumor suppressor protein p16INK4a (p16) has been identified as a biomarker for transforming human papilloma virus (HPV) infections. P16 is a cyclin-dependent kinase inhibitor that regulates the cell cycle and cell proliferation by inhibiting cell cycle G1 progression. Purpose of the study: To confirm the role of p16 as biomarker for transforming HPV infections and possible clinical applications in histological samples from the uterine cervix. Materials and Methods: The subject of this study included 56 biopsies of the cervical canal collected from January 2012 to September 2012 in the Institute of Pathology of the University of Sassari. The search for HPV immunohistochemistry was performed with the monoclonal antibody DAKO 1:25, while for the detection of p16 was used CINtecTM p16 (INK4a) histology kit. Results: In 56 biopsies performed in women aged between 23 and 69 years, the authors highlighted, by histological analysis, 24 cases of low-grade squamous intraepithelial lesion (LSIL) - cervical intraepithelial neoplasia (CIN1) and 31 cases of high-grade squamous intraepithelial lesion (HSIL) - CIN2/3); 15 CIN2, 14 CIN3, and two cervical squamous cell carcinoma in situ (SCIS). One case was an infiltrating squamous cell carcinoma (ISC). In 24 CIN1, there was a 16.67% positivity for p16 and an equal percentage occurred for HPV. In 15 cases of CIN2 the percentage of positivity for p16 was considerably increased (73.33%), unlike the search for HPV which had a positivity rate of 20%. Finally, in 14 cases of CIN3, and in three carcinomas, the positivity for p16 was equal to 100%, however the search for HPV positivity was between 0% and 7.14%. Conclusions: These results demonstrated that p16 was a highly sensitive marker of cervical dysplasia. The authors have shown that p16 overexpression increased with the severity of cytological abnormalities and that had a greater ability to identify the viral infection compared to the classical immunohistochemical staining for HPV

Fifteen-year follow-up of relapsed indolent non-Hodgkin lymphoma patients vaccinated with tumor-loaded dendritic cells

We previously published the results of a pilot study showing that vaccination with tumor-loaded dendritic cells (DCs) induced both T and B cell response and produced clinical benefit in the absence of toxicity in patients with relapsed, indolent non-Hodgkin lymphoma (iNHL). The purpose of the present short report is to provide a 15-year follow-up of our study and to expand the biomarker analysis previously performed. The long-term follow-up highlighted the absence of particular or delayed toxicity and the benefit of active immunization with DCs loaded with autologous, heat-shocked and UV-C treated tumor cells in relapsed iNHL (5-year and 10-year progression-free survival (PFS) rates: 55.6% and 33.3%, respectively; 10-year overall survival (OS) rate: 83.3%). Female patients experienced a better PFS (p=0.016) and a trend towards a better OS (p=0.185) compared with male patients. Of note, we observed a non-negligible fraction of patients (22%) who experienced a long-lasting complete response. In a targeted gene expression profiling of pre-treatment tumor biopsies in 11 patients with available formalin-fixed, paraffin-embedded tissue, we observed that KIT, ATG12, TNFRSF10C, PBK, ITGA2, GATA3, CLU, NCAM1, SYT17 and LTK were differentially expressed in patients with responder versus non-responder tumors. The characterization of peripheral monocytic cells in a subgroup of 14 patients with available baseline blood samples showed a higher frequency of the subset of CD14++CD16+ cells (intermediate monocytes) in patients with responding tumors. Since in patients with relapsed iNHL the available therapeutic options are often incapable of inducing a long-lasting complete remission and can be sometimes characterized by intolerable toxicity, we think that the encouraging results of our long-term follow-up analysis represent a stimulus to further investigate the role of active vaccination in this specific setting and in earlier lines of therapy and to explore novel combinatorial strategies encompassing other innovative immunotherapy agents, such as immune-checkpoint inhibitors