Germline pathogenic variants of cancer predisposition genes in a multicentre Italian cohort of pancreatic cancer patients.

BACKGROUND AND AIM: Germline BRCA1-2 test is routinely recommended in Pancreatic Cancer (PC) patients, due to its clinical-epidemiological relevance. Data on the prevalence of germline pathogenic variants (gPV) in other cancer predisposition and DNA Damage Repair (DDR) system-related genes in unselected PC cases are sparce in Italy. We assessed this prevalence in a multicentre cohort, to derive recommendations for PC patients. METHODS: Clinical data of 1200 consecutive PC patients, of any age and stage, tested with a multigene germline panel were collected. A descriptive analysis of gPV frequency and clinical variables was performed both in 1092 patients tested for an 18 genes core-panel (CP-18 cohort) and in 869 patients screened only for CDKN2A. RESULTS: 11.5 % (126/1092) of CP-18 cohort patients harbored a gPV in ≥ 1 gene. Highest gPV frequencies were detected in ATM (3.1 %), BRCA2 (2.9 %), BRCA1 (1.6 %), CHEK2 (1.1 %). Patients harboring any CP-18 gene and BRCA1-2 gPV were younger and with a higher rate of personal (PH) or family history (FH) of cancer when compared to no gPV patients. The risk of having a gPV was ≥ 7 % in all subgroups of patients, including those aged > 73, with tumor stage I-III and negative FH/PH. CDKN2A gPV were detected in 2.6 % (23/869) of patients. CONCLUSIONS: A remarkable prevalence of gPV in cancer predisposition and DDR genes is reported in this large multicentre cohort of consecutive and unselected PC patients. Therefore, we recommend multigene germline testing (at least including BRCA1-2, ATM, CDKN2A, PALB2) for all PC patients, irrespective of age, stage, PH/FH.

Streamlining the diagnostic pathway for Lynch syndrome in colorectal cancer patients: a 10-year experience in a single Italian Cancer Center.

BACKGROUND: Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAF V600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT). METHODS: Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients. RESULTS: Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times. CONCLUSION: Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.

BRAFV600E immunohistochemistry can reliably substitute BRAF molecular testing in the Lynch syndrome screening algorithm in colorectal cancer.

AIMS: The Lynch syndrome (LS) screening algorithm requires BRAF testing as a fundamental step to distinguish sporadic from LS-associated colorectal carcinomas (CRC). BRAF testing by immunohistochemistry (IHC) has shown variable results in the literature. Our aim was to analyse concordance between BRAFV600E IHC and BRAF molecular analysis in a large, mono-institutional CRC whole-slide, case series with laboratory validation. METHODS AND RESULTS: MisMatch repair (MMR) protein (hMLH1, hPMS2, hMSH2, and hMSH6) and BRAFV600E IHC were performed on all unselected cases of surgically resected CRCs (2018-2023). An in-house validation study for BRAFV600E IHC was performed in order to obtain optimal IHC stains. BRAFVV600E IHC was considered negative (score 0), positive (scores 2-3), and equivocal (score 1). Interobserver differences in BRAFV600E IHC scoring were noted in the first 150 cases prospectively collected. Nine-hundred and ninety CRCs cases (830 proficient (p)MMR/160 deficient (d)MMR) were included and all cases performed BRAFV600E IHC (BRAFV600E IHC-positive 13.5% of all series; 66.3% dMMR cases; 3.4% pMMR cases), while 333 also went to BRAF mutation analysis. Optimal agreement in IHC scoring between pathologists (P < 0.0001) was seen; concordance between BRAFV600E IHC and BRAF molecular analysis was extremely high (sensitivity 99.1%, specificity 99.5%; PPV 99.1%, and NPV 99.5%). Discordant cases were reevaluated; 1 score 3 + IHC/wildtype case was an interpretation error and one score 0 IHC/mutated case was related to heterogenous BRAFV600E IHC expression. Among the 12 IHC-equivocal score 1+ cases (which require BRAF molecular analysis), three were BRAF-mutated and nine BRAF-wildtype. CONCLUSION: BRAFV600E IHC can be used as a reliable surrogate of molecular testing after stringent in-house validation.

Prevalence and type of MMR expression heterogeneity in colorectal adenocarcinoma: therapeutic implications and reporting.

Mismatch repair (MMR) immunohistochemical (IHC) evaluation has entered pathology routine practice as the first-line screening method to identify patients with MMR deficient (MMRd)/microsatellite instability (MSI) colorectal cancer (CRC), and its misdiagnosis may significantly impact the personalization of CRC patient care. To determine the prevalence of MMR protein intratumor heterogeneity in real-world practice, we collected a series of 8282 CRCs tested for MMR proteins in the setting of Lynch syndrome universal screening. Four heterogenous cases were also investigated for tumor infiltrating lymphocytes count, MSI status, and consensus molecular subtypes by Nanostring nCounter® Platform. Overall, 1056 (12.8%) CRCs showed a MMR altered status, with 46 cases showing a heterogeneous MMR profile (0.56% of the total, and 4.36% of all MMRd cases). To conclude, the authors make some critical remarks regarding the approach to MMR heterogeneity in clinical practice and routine diagnostics.

Synchronous and metachronous primary colorectal cancers with concordant and discordant mismatch repair status.

Multiple primary colorectal carcinomas (CRCs) synchronous, when detected approximately at the same time, or metachronous, when a significant amount of time has elapsed between diagnoses can show both mismatch repair (MMR) status concordance and discordance between primary tumors. The aim was to evaluate the MMR status of a monoinstitutional, retrospective cohort of synchronous and metachronous CRCs, with a focus on the frequency of cases with discordant MMR status, and explore the MMR status of metastatic nodal deposits. All synchronous and metachronous CRCs diagnosed in our institution between 2011 and 2023 were collected. Clinicopathologic characteristics were evaluated, including MMR status of all CRCs, BRAF mutation, and MLH1 promoter methylation analyses. MMR status discordant cases were further analyzed, and MMR testing was performed on nodal metastases. Of 3671 patients, 107 (2.9%) had multiple CRCs (94 synchronous and 13 metachronous; total number of CRCs 220). Sixty CRCs were MMR deficient (dMMR) (27.3%), and most were right-sided and high-grade and showed special histologic features (P < .00001). Ninety-three patients showed intertumoral MMR concordance: 70 (65.4%) with MMR-proficient (pMMR) CRCs, and 23 (21.5%) were dMMR. Fourteen patients (13.1%) showed intertumoral MMR discordance (at least one dMMR and one pMMR), and in 5 patients, nodal metastases were present: 2 patients harbored metastases only from their pMMR cancer, 2 only from their dMMR cancer, and in 1 patient both pMMR and dMMR metastases were present. In conclusion, all multiple primary CRCs should be analyzed for MMR status as discordant MMR is possible as well as discordant metastatic nodal deposits, and this may be important for patient management.

Impact of formalin fixation on mismatch repair protein evaluation by immunohistochemistry.

Mismatch repair/microsatellite instability (MMR/MSI) status in colorectal cancer (CRC) has become fundamental as a diagnostic, prognostic, and predictive factor. MMR immunohistochemistry (IHC) is considered a simple and reliable approach; however, its effectiveness depends on pre-analytic factors. Aim of this study was to investigate the impact of different fixation times/protocols on MMR protein IHC quality. Left over tissue from surgically resected CRC samples (cold ischemia time < 30 min) where fixed as follows: standard formalin fixation (24-48 h); hypo-fixation (<20 h); hyper-fixation (>90 h); cold (4°C) fixation (24-48 h); standard fixation for small sample size (0.5×0.5 cm). Samples for each group were collected from 30 resected CRC and the following parameters were evaluated on 600 immunohistochemical stains: intensity of expression; patchiness of staining; presence of central artefact. Forty-six immunoreactions were inadequate (score 0 intensity), the majority regarding MLH1 or PMS2 in the hypo-fixation group (47.8%), followed by the hyper-fixation group (28.1%); cold formalin fixation showed the least inadequate cases. Patchiness and central artefact were more frequent in hypo-fixation and standard fixation group compared to the others. MLH1 (closely followed by PMS2) performed worse with regard to immunostaining intensity (p=0.0002) in the standard and in the hypo-fixation group (p< 0.00001). Using a small sample size improved patchiness/central artefacts. This is the first study specifically created to evaluate the impact of fixation on MMR protein IHC, showing that both formalin hypo- and hyper-fixation can cause problems; 24-h formalin fixation as well as cold (4°C) formalin fixation are recommended for successful IHC MMR evaluation.

The role of immunotherapy in microsatellites stable metastatic colorectal cancer: state of the art and future perspectives.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, despite several advances has been achieved in last decades. Few prognostic and predictive biomarkers guide therapeutic choice in metastatic CRC (mCRC), among which DNA mismatch repair deficiency and/or microsatellite instability (dMMR/MSI) holds a crucial role. Tumors characterized by dMMR/MSI benefit from immune checkpoint inhibitors. However, most of the mCRC patients (around 95%) are microsatellite stable (MSS), thereby intrinsically resistant to immunotherapy. This represents a clear unmet need for more effective treatments in this population of patients. In this review, we aim to analyze immune-resistance mechanisms and therapeutic strategies to overcome them, such as combinations of immunotherapy and chemotherapy, radiotherapy or target therapies specifically in MSS mCRC. We also explored both available and potential biomarkers that may better select MSS mCRC patients for immunotherapy. Lastly, we provide a brief overview on future perspectives in this field, such as the gut microbiome and its potential role as immunomodulator.

The observational clinical registry (cohort design) of the European Reference Network on Rare Adult Solid Cancers: The protocol for the rare head and neck cancers.

INTRODUCTION: Care for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374). STUDY DESIGN: Registry-based cohort study including only people with rare head and neck cancers. OBJECTIVES: to help describe the natural history of rare head and neck cancers;to evaluate factors that influence prognosis;to assess treatment effectiveness;to measure indicators of quality of care. METHODS: Settings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won't select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients' and cancers' variables and indicators describing the quality of care. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/confounders and confounding by indication (selective prescribing) will be present. RESULTS: The registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed.

ctDNA to Guide Treatment of Colorectal Cancer: Ready for Standard of Care?

OPINION STATEMENT: Circulating tumor DNA (ctDNA) has already shown clinically relevant results in early-stage colon cancer patient management. Its prognostic value is by far much stronger than that of the available clinico-pathological biomarkers, therefore, has the potential to personalize the treatment after radical surgery through intensifying or de-intensifying the adjuvant therapy. Further developments and improvements should be pursued by (a) optimizing ctDNA assays and (b) validating its clinical utility in the different stages of this disease. Two main avenues of ctDNA testing are being pursued: tumor-informed vs tumor-agnostic assays. Two main clinical trial designs are under study: ctDNA-based strategy and ctDNA-by-treatment interaction. The former needs large sample sizes to address the main questions of the studies; thus, the target delta benefit may be the main challenge in these trial designs. The latter may be challenged by unavoidable contamination bias. To date, several clinical trials are ongoing worldwide. We believe that this large number of trials may provide an excellent common database for the demonstration of surrogacy of ctDNA for the classical 3-year disease-free survival endpoint. This would mark a huge methodological improvement to speed up new drug testing and development in the adjuvant treatment of this disease.

Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (CDKN2A+) and without (CDKN2A-) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A-. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed. RESULTS: In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A- patients provided evidence for HMBS, EPCAM, and MRE11 as potential new candidate genes and confirmed ATM, BRCA2, and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A- patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A. CONCLUSION: These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A- patients.

Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients.

Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all <70 y), CDKN2A (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A,BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH.

Beyond BRCA: The Emerging Significance of DNA Damage Response and Personalized Treatment in Pancreatic and Prostate Cancer Patients.

The BRCA1/2 germline and/or somatic pathogenic variants (PVs) are key players in the hereditary predisposition and therapeutic response for breast, ovarian and, more recently, pancreatic and prostate cancers. Aberrations in other genes involved in homologous recombination and DNA damage response (DDR) pathways are being investigated as promising targets in ongoing clinical trials. However, DDR genes are not routinely tested worldwide. Due to heterogeneity in cohort selection and dissimilar sequencing approaches across studies, neither the burden of PVs in DDR genes nor the prevalence of PVs in genes in common among pancreatic and prostate cancer can be easily quantified. We aim to contextualize these genes, altered in both pancreatic and prostate cancers, in the DDR process, to summarize their hereditary and somatic burden in different studies and harness their deficiency for cancer treatments in the context of currently ongoing clinical trials. We conclude that the inclusion of DDR genes, other than BRCA1/2, shared by both cancers considerably increases the detection rate of potentially actionable variants, which are triplicated in pancreatic and almost doubled in prostate cancer. Thus, DDR alterations are suitable targets for drug development and to improve the outcome in both pancreatic and prostate cancer patients. Importantly, this will increase the detection of germline pathogenic variants, thereby patient referral to genetic counseling.

Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer.

Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15-20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.

Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine.

Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one of the most frequent hereditary syndromes; it is mainly associated with colorectal cancer (CRC). Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies, initially with contradictory results; however, longer follow-up confirmed a reduced CRC incidence and mortality. The CAPP2 study recruited 861 Lynch syndrome participants randomly assigned to 600 mg of aspirin versus placebo. Like sporadic CRCs, a significant CRC risk reduction was seen after an extended follow-up, with a median treatment time that was relatively short (2 years). The ongoing CAPP3 will address whether lower doses are equally effective. Based on pharmacology and clinical data on sporadic CRCs, the preventive effect should also be obtained with low-dose aspirin. The leading international guidelines suggest discussing with Lynch syndrome carriers the possibility of using low-dose aspirin for CRC prevention. We aim systematically promote this intervention with all Lynch syndrome carriers.

Long-Term Follow-up of the Italian Flexible Sigmoidoscopy Screening Trial.

BACKGROUND: Recent reports showed that the protective effect of flexible sigmoidoscopy (FS) screening was maintained up to17 years, although differences were reported by sex. OBJECTIVE: To assess long-term reduction of colorectal cancer (CRC) incidence and mortality after a single FS screening. DESIGN: Parallel randomized controlled trial. (ISRCTN registry number: 27814061). SETTING: 6 centers in Italy. PARTICIPANTS: Persons aged 55 to 64 years expressing interest in having FS screening if invited, recruited from 1995 to 1999 and followed until 2012 (incidence) and 2014 to 2016 (mortality). INTERVENTION: Eligible persons were randomly assigned (1:1 ratio) to either the once-only FS screening group or control (usual care) group. MEASUREMENTS: Incidence and mortality rate ratios (RRs) and rate differences. RESULTS: A total of 34 272 persons (17 136 in each group) were included in the analysis; 9911 participants had screening in the intervention group. Median follow-up was 15.4 years for incidence and 18.8 years for mortality. Incidence of CRC was reduced by 19% (RR, 0.81 [95% CI, 0.71 to 0.93]) in the intention-to-treat (ITT) analysis, comparing the intervention with the control group, and by 33% (RR, 0.67 [CI, 0.56 to 0.81]) in the per protocol (PP) analysis, comparing participants screened in the intervention group with the control persons. Colorectal cancer mortality was reduced by 22% (RR, 0.78 [CI, 0.61 to 0.98]) in the ITT analysis and by 39% (RR, 0.61 [CI, 0.44 to 0.84]) in the PP analysis. Incidence of CRC was statistically significantly reduced among both men and women. Colorectal cancer mortality was statistically significantly reduced among men (ITT RR, 0.73 [CI, 0.54 to 0.97]) but not among women (ITT RR, 0.90 [CI, 0.59 to 1.37]). LIMITATION: Self-selection of volunteers from the general population sample targeted for recruitment may limit generalizability. CONCLUSION: The strong protective effect of a single FS screening for CRC incidence and mortality was maintained up to 15 and 19 years, respectively. PRIMARY FUNDING SOURCE: Italian Association for Cancer Research, Italian National Research Council, Istituto Oncologico Romagnolo, Fondo "E. Tempia," University of Milan, and Local Health Unit ASL-Torino.

"Present and future of immunotherapy in Neuroendocrine Tumors".

Immunotherapy, so promising in many neoplasms, still does not have a precise role in the treatment of neuroendocrine neoplasms (NENs). In this article, we provide an overview on the current knowledge about immunotherapy with immune checkpoint inhibitors (ICIs) applied to NENs, evaluating future perspectives in this setting of tumors.Evidence so far available for ICIs in gastroenteropancreatic (GEP)-NENs is definitively not as robust as for other tumors such as Small Cell Lung Cancer or Merkel Cell Carcinoma. In fact, with regard to the well-differentiated forms of NENs (NETs), the results obtained nowadays have been disappointing. However, the near future, might reserve interesting results for ICIs in GEP-NEN from a total of nine different ICI drugs, used throughout 19 randomised controlled trials. Such numbers highlight the growing attention gathering around NENs and ICIs, in response to the need of stronger evidences supporting such therapy.For the future, the most important aspect will be to study strategies that can make NETs more susceptible to response to ICI and, thus, enhance the effectiveness of these treatments. Therefore, the combination of conventional therapy, target therapy and immunotherapy deserve attention and warrant to be explored. A sequential chemotherapy, possibly inducing an increase in tumor mutational burden and tested before immunotherapy, could be a hypothesis deserving more consideration. A radiation treatment that increases tumor-infiltrating lymphocytes, could be another approach to explore before ICIs in NENs. Equally essential will be the identification of biomarkers useful for selecting patients potentially responsive to this type of treatment.

Cancer Patient With Unusual Dyspnea in the COVID-19 Era: Challenging Management of a Rare Cardiac Tumor.

Heart failure symptoms, in particular dyspnea, may be difficult to frame in a patient with cancer. We report the case of an oncological patient whose dyspnea could have been attributable to various causes and whose management was challenging in the context of the coronavirus disease-2019 pandemic. (Level of Difficulty: Beginner.).

Management of patients with early-stage colon cancer: guidelines of the Italian Medical Oncology Association.

About 75% of colorectal cancers are diagnosed as early stage, in which radical surgery is achievable. In the last decade, in Italy, the overall incidence of colorectal cancer has remained stable, while mortality gradually decreased, which is attributable to early diagnosis and improved medical, surgical and locoregional treatments. The Italian Medical Oncology Association formulated guidelines to manage early-stage colon cancer, including screening, diagnosis, treatment and follow-up, which we herein present.