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. BRAFV600E 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.

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.

Reliability of patient-reported toxicities during adjuvant chemotherapy.

BACKGROUND: Patient-reported outcomes (PROs) are validated tools to assess the impact of efficacy and toxicities of cancer treatments on patients' health status. Because of the demonstrated little reliability of humans in reporting memories of painful experiences, this work explores the reliability of cancer patients in reporting chemotherapy-related toxicities. AIM: This study aims to evaluate the concordance between toxicities experienced by the patients during chemotherapy and toxicities reported to the doctor at the end of the cycles. METHODS: Questionnaires concerning chemotherapy-related toxicities were administered on days 2, 5, 8, 11, 14, and 17 of each chemo cycle and at the end of the same cycle to patients undergoing adjuvant chemotherapy. The co-primary end-points were Lins's concordance correlation coefficient (CCC) and mean difference between real-time and retrospective toxicity assessments. RESULTS: In total, 7182 toxicity assessments were collected from 1096 questionnaires. Concordance was observed between the retrospective evaluations and the toxicity assessments at early (day 2), peak (maximum toxicity), late (day 14 or 17), and mean real-time evaluations for each chemotherapy cycle (CCC for mean ranging from 0.52 to 0.77). No systematic discrepancy was found between real-time and retrospective evaluations, except for peak, which was systematically underestimated retrospectively. CONCLUSIONS: Toxicities reported by the patients to the doctor at the end of each chemotherapy cycle reflect what they actually experienced without any substantial distortion. This result is very relevant both for the clinical implications in daily patients' management and in the light of the current growing impact on digital monitoring of PROs.

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.

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.

Prognostic and predictive molecular biomarkers in advanced colorectal cancer.

The revolution of precision medicine has produced unprecedented seismic shifts in the treatment paradigm of advanced cancers. Among the major killers, colorectal cancer (CRC) is far behind the others. In fact, the great successes obtained in breast, NSCLC, melanoma, and genitourinary tract tumors have been observed only in fewer than 5 % metastatic colorectal cancer (mCRC): those with the mismatch repair deficiency (dMMR), a well-known predictive factor for to the outstanding efficacy of checkpoint inhibitors (CPI). The treatment of the remaining vast majority mCRC patients is still based upon only two molecular determinants: the RAS and BRAF mutational status. New promising biomarkers include HER2, tumor mutational burden (TMB) for its possible implications on CPI efficacy, and the extremely rare NTRK fusions. The Consensus Molecular Subtypes classification (CMS) is a good example of the efforts to combine different molecular features of this disease, although its relevance in clinical practice is still under investigation. In this Review, we focus on all these prognostic and predictive biomarkers, analyzing data from the most important clinical trials of the last years. We also try to rank them according to their prognostic and predictive power.

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.

Rare anti-VEGFR therapy-induced toxicity and long-term response to immunotherapy in a rare non-clear cell renal cell carcinoma patient.

Advanced non-clear cell renal cell carcinoma (nccRCC) has a poor prognosis and clinical data on the therapeutic options currently available, including immunotherapy, are generally limited highlighting an unmet clinical need. Moreover, the onset of rare adverse events raises the need of a better therapeutic management of limited treatment options. We report the clinical case of a 63-year-old man with the diagnosis of metastatic mucinous tubular and spindle cell carcinoma, a rare nccRCC, with sarcomatoid differentiation who developed two episodes of posterior reversible encephalopathy syndrome (PRES) to first-line sunitinib. It appeared after 5 months the start of the targeted therapy and reappeared at the reintroduction of the therapy. PRES is a rare and unusual adverse event to anti-vascular endothelial growth factor receptor (VEGFR) therapies, which is characterized by acute neurological disorders along with typical changes on neurological imaging, especially MRI. Moreover, this rare histotype of RCC experienced a long-term response to immunotherapy which is lasting more than 2 years. This clinical case is interesting for its rarity as a rare neurological adverse event developed twice in a rare type of RCC which also experienced an unusual long-term benefit to immunotherapy.

How to Protect Ovarian Function before and during Chemotherapy?

A significant number of women receive a cancer diagnosis before their age of natural menopause. Among these patients, the most frequent neoplasms are breast cancer, gynecological, and hematological malignancies. Premature ovarian insufficiency and infertility are among the most feared short- to long-term consequences of anticancer treatments in premenopausal patients. Both patient- and treatment-related characteristics are key factors in influencing the risk of gonadotoxicity with the use of chemotherapy. The cryopreservation of oocytes/embryos is a standard strategy for fertility preservations offered to young women interested in future family planning, but it does not allow gonadal function protection during chemotherapy. Ovarian suppression with gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy is now recommended as an option to reduce the risk of gonadotoxicity in order to avoid the negative consequences of premature ovarian insufficiency in premenopausal women receiving cytotoxic therapy, including those not interested in fertility preservation. This review summarizes the risk of treatment-induced gonadotoxicity in premenopausal patients and the evidence available on the protective role of administering GnRHa during chemotherapy to preserve ovarian function.

Comparing the Gonadotoxicity of Multiple Breast Cancer Regimens: Important Understanding for Managing Breast Cancer in Pre-Menopausal Women.

Over the last several decades, improvements in breast cancer treatment have contributed to increased cure rates for women diagnosed with this malignancy. Consequently, great importance should be paid to the long-term side effects of systemic therapies. For young women (defined as per guideline ≤40 years at diagnosis) who undergo chemotherapy, one of the most impactful side effects on their quality of life is premature ovarian insufficiency (POI) leading to fertility-related problems and the side effects of early menopause. Regimens, type, and doses of chemotherapy, as well as the age of patients and their ovarian reserve at the time of treatment are major risk factors for treatment-induced POI. For these reasons, childbearing desire and preservation of ovarian function and/or fertility should be discussed with all premenopausal patients before planning the treatments. This manuscript summarizes the available fertility preservation techniques in breast cancer patients, the risk of treatment-induced POI with different anticancer treatments, and the possible procedures to prevent it. A special focus is paid to the role of oncofertility counseling, as a central part of the visit in this setting, during which the patient should receive all the information about the potential consequences of the disease and of the proposed treatment on her future life.

Beyond First-Line Immunotherapy: Potential Therapeutic Strategies Based on Different Pattern Progressions: Oligo and Systemic Progression.

First-line immune-checkpoint inhibitor (ICI)-based therapy has deeply changed the treatment landscape and prognosis in advanced non-small cell lung cancer (aNSCLC) patients with no targetable alterations. Nonetheless, a percentage of patients progressed on ICI as monotherapy or combinations. Open questions remain on patients' selection, the identification of biomarkers of primary resistance to immunotherapy and the treatment strategies to overcome secondary resistance to first-line immunotherapy. Local ablative approaches are the main therapeutic strategies in oligoprogressive disease, and their role is emerging in patients treated with immunotherapy. Many therapeutic strategies can be adapted in aNSCLC patients with systemic progression to personalize the treatment approach according to re-characterization of the tumors, previous ICI response, and type of progression. This review's aim is to highlight and discuss the current and potential therapeutic approaches beyond first-line ICI-based therapy in aNSCLC patients based on the pattern of disease progression (oligoprogression versus systemic progression).

Immunotherapy retreatment: case report, review of the literature and proposal for the definition of different scenarios.

Immune checkpoint inhibitors have improved the treatment landscape of different tumors and one of the emerging issues is the reintroduction of immunotherapy after discontinuation. Scarce evidence is currently available and different definitions have been used. The case of a patient with pretreated advanced urothelial cancer, who responded to immunotherapy retreatment after long-term benefit from the previous course, is reported. Based on a review of the different clinical scenarios, a definition of immunotherapy retreatment was proposed, as rechallenge or reintroduction, based on the reasons of discontinuation of the previous course. Clinical factors potentially associated with clinical benefit from immunotherapy retreatment are discussed, even though ad hoc studies are needed to assess the efficacy and safety of the different immunotherapy retreatment strategies.

Lay abstract Immunotherapy is an effective treatment option for several types of cancer. It is unclear whether a rechallenge with this treatment could be effective following its discontinuation due to disease progression, treatment toxicity or completion. This is a relevant issue as patients with metastatic cancer have few therapeutic options. Therefore, we share our clinical experience and a literature review about this topic. We report the clinical course of a patient affected by metastatic urothelial cancer whose disease responded to retreatment with immunotherapy after a previous long-term benefit from the same treatment, which was discontinued after 2 years having reached the maximum established treatment duration. We describe the different clinical scenarios of immunotherapy retreatment and factors potentially associated with a benefit from this therapeutic strategy.

The Prognostic Role of Baseline Metabolic Tumor Burden and Systemic Inflammation Biomarkers in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Radium-223: A Proof of Concept Study.

Over the last years has emerged the urgent need for the identification of reliable prognostic biomarkers able to potentially identify metastatic castration-resistant prostate cancer (mCRPC) patients most likely to benefit from Radium-223 (Ra-223) since baseline. In the present monocentric retrospective study, we analyzed the prognostic power of systemic inflammation biomarkers and 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET)-derived parameters and their potential interplay in this clinical setting. The following baseline laboratory parameters were collected in 59 mCRPC patients treated with Ra-223: neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelets-to-lymphocyte ratio (PLR), and systemic inflammation index (SII), while maximum Standardized Uptake Value, Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG) were calculated in the 48 of them submitted to baseline FDG-PET. At the univariate analysis, NLR, dNLR, MTV, and TLG were able to predict the overall survival (OS). However, only NLR and MTV were independent predictors of OS at the multivariate analysis. Additionally, the occurrence of both increased NLR and MTV at baseline identified mCRPC patients at higher risk for lower long-term survival after treatment with Ra-223. In conclusion, the degree of systemic inflammation, the quantification of the metabolically active tumor burden and their combination might represent potentially valuable tools for identifying mCRPC patients who are most likely to benefit from Ra-223. However, further studies are needed to reproduce these findings in larger settings.

Adjuvant Chemotherapy for Stage II Colon Cancer.

In stage II colon cancer management, surgery alone has shown a high cure rate (about 80%), and the role of adjuvant chemotherapy is still a matter of debate. Patients with high-risk features (T4, insufficient nodal sampling, grading, etc.) have a poorer prognosis and, usually, adjuvant chemotherapy is recommended. The purpose of the present study is to highlight and discuss what is still unclear and not completely defined from the previous trials regarding risk stratification and therapeutic benefit of adjuvant chemotherapy. With all the limitations of generalizing, we make the effort of trying to quantify the relative contribution of each prognostic factor and the benefit of adjuvant chemotherapy for stage II colon cancer. Finally, we propose a decision algorithm with the aim of summarizing the current evidence and translating it to clinical practice.

Assessing the Impact of the COVID-19 Outbreak on the Attitudes and Practice of Italian Oncologists Toward Breast Cancer Care and Related Research Activities.

PURPOSE: To investigate the impact of the COVID-19 outbreak on the attitudes and practice of Italian oncologists toward breast cancer care and related research activities. METHODS: A 29-question anonymous online survey was sent by e-mail to members of the Italian Association of Medical Oncology and the Italian Breast Cancer Study Group on April 3, 2020. Only medical oncologists (both those in training and specialists) were invited to complete the questionnaire. RESULTS: Out of 165 responding oncologists, 121 (73.3.%) worked in breast units. In the (neo)adjuvant setting, compared with before the emergency, fewer oncologists adopted weekly paclitaxel (68.5% v 93.9%) and a dose-dense schedule for anthracycline-based chemotherapy (43% v 58.8%) during the COVID-19 outbreak. In the metastatic setting, compared with before the emergency, fewer oncologists adopted first-line weekly paclitaxel for HER2-positive disease (41.8% v 53.9%) or CDK4/6 inhibitors for luminal tumors with less-aggressive characteristics (55.8% v 80.0%) during the COVID-19 outbreak. A significant change was also observed in delaying the timing for monitoring therapy with CDK4/6 inhibitors, assessing treatment response with imaging tests, and flushing central venous devices. Clinical research and scientific activities were reduced in 80.3% and 80.1% of respondents previously implicated in these activities, respectively. CONCLUSION: Medical oncologists face many challenges in providing cancer care during the COVID-19 outbreak. Although most of the changes in their attitudes and practice were reasonable responses to the current health care emergency without expected major negative impact on patient outcomes, some potentially alarming signals of undertreatment were observed.

Impact of influenza syndrome and flu vaccine on survival of cancer patients during immunotherapy in the INVIDIa study.

Aim: INVIDIa was a retrospective, multicenter study, exploring the clinical efficacy of influenza vaccine in 300 cancer patients undergoing immunotherapy. Overall survival (OS) was immature at the initial report. Methods: We reported the final OS analysis from the original study population and within subgroups. Results: Both at the univariate and multivariate analysis, the occurrence of influenza syndrome (IS) was significantly related to better OS in the overall population (OR: 0.53 [95% CI: 0.32-0.88]; p = 0.01). In the lung cancer subgroup, receiving flu vaccine and/or developing IS was related to better OS (p = 0.04). Within elderly patients, the flu vaccine was the main variable for the relative OS advantage (p = 0.05). Conclusion: Receiving the flu vaccine and/or developing IS was related to better OS within the INVIDIa population.

[Omentopexy associated with the use of Redon catheters in post-cardiac surgery mediastinitis with vascular prosthesis infection: immediate results in five patients]. / Omentopessi associata all'utilizzo dei cateteri di Redon nelle mediastiniti post-cardiochirurgiche con infezione di protesi vascolari: risultati immediati in cinque pazienti.

BACKGROUND: Post-cardiac surgery mediastinitis is a dangerous complication with an elevated mortality risk particularly when infection affects vascular prostheses. In this paper we report our experience with the use of extensive disinfection and washing of the mediastinum with iodopovidone, followed by omental transposition into the chest with the use of Redon catheters. METHODS: Between September 2001 and March 2007, 5 patients were treated with this technique (submitted to Bentall intervention in 2 cases, substitution of the ascending aorta, Bentall intervention with substitution of the aortic arch and substitution of the aortic arch in 1 case, respectively), due to a sternomediastinitis and correlated infection of the vascular prosthesis. Among them, 3 consisted of a redo surgery. RESULTS: One patient with unstable hemodynamic conditions died of multiorgan failure following a state of generalized sepsis; the remaining 4 patients had complete resolution of the clinical picture. None showed complications related to the procedure. The 4 survived patients were followed up at 1 month and underwent clinical and instrumental evaluation by chest computed tomography, which yielded negative results without signs of infection. CONCLUSIONS: Our limited experience definitely encourages us to use these combined techniques in the treatment of post-cardiac surgery mediastinitis in patients with vascular prostheses.

Clinical outcomes of mitral valve repair with the Colvin-Galloway Future Band: a single-center experience.

OBJECTIVES: In 2001, a semirigid band (Colvin-Galloway Future Band, Medtronic, Inc., Minneapolis, Minnesota, USA) for mitral valve repair came onto the market. We report our experience of the correction of all types of mitral regurgitation using this device. METHODS: From August 2003 to December 2006, 140 patients (71% men, mean age 64 +/- 11 years) underwent valvuloplasty with this device for all types of mitral regurgitation: 94 (67%) degenerative, 34 (24%) postischemic, 11 (8%) dilative cardiomyopathy, and one (1%) postendocarditic. The patients underwent clinical and echocardiographic evaluation preoperatively, postoperatively before discharge, and after a median follow-up of 7 months (25th-75th percentile, 4-24 months). RESULTS: Total mortality was 6.4% (nine out of 140 patients): four patients (2.8%) died within 30 days (early death) and five died subsequently (the cause was cardiac in one case). Predischarge echocardiographic examination revealed a reduction in mitral regurgitation of at least 2 degrees in 99.2% of patients and the absence of systolic anterior movement. At the last follow-up, we recorded an improvement in New York Heart Association functional class (2.4 +/- 0.9 vs. 1.1 +/- 0.4, P < 0.0001), a significant reduction in the degree of mitral regurgitation (3.5 +/- 0.9 vs. 0.9 +/- 0.5, P < 0.0001), an increase in ejection fraction (54 +/- 11 vs. 55 +/- 9, P = 0.09), and a significant reduction in end-diastolic diameter (59 +/- 6 vs. 55 +/- 6, P < 0.0001). Two patients were reoperated on for mitral valve replacement, and no postoperative thromboembolic events occurred. CONCLUSION: Our experience shows that the Colvin-Galloway Future Band yields good results in mitral valvuloplasty for all types of mitral regurgitation. We are encouraged to continue using this device.

[Bentall operation after previous repair of tetralogy of Fallot]. / Intervento di Bentall in paziente con pregresso intervento di correzione di tetralogia di Fallot.

Pathologies that involve the ascending aorta are described in case reports of patients after complete repair of tetralogy of Fallot. Here, we present a case report. Preoperative tests showed an aortic ratio of > 1.5. The patient was operated on replacement of the ascending aorta according to the Bentall technique. At present, the guidelines for replacement of the ascending aorta recommend an aortic ratio of > 1.5 and in case of Marfan syndrome of > 1.3. In these patient subsets, cystic medial necrosis and an increased risk of aortic dissection have been described. Therefore, as for Marfan syndrome, why an aortic ratio of >1.3 should not be considered a proper surgical indication also for these patients?