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Supplementary Table S4

Supplementary methods and Figures S1-S17

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.

Over the years, a growing body of literature has confirmed as beneficial the implementation of a multidisciplinary approach in the so-often-intricate scenario of cancer patients' management. Together with the consolidation of tumor-board experience in clinical practice, certain aspects have emerged as controversial and a source of current debate. In this systematic literature review, we focused our attention on the impact of multidisciplinary tumor boards, assessing benefits and limitations as a result of the dissemination of such approaches. On the bright side, adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes have been recognized as advantages. On the other side, our analysis highlights a few limitations that should be taken into account to optimize cancer patients' management. Of note, some issues, such as costs, legal responsibility, geographic barriers, and treatment delays, have yet to be resolved. In order partly to address this matter, software platforms and novel methods of computational analysis may provide the needed support. Therefore, the aim of our analysis was to describe the multidisciplinary approach in cancer care in terms of adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes through a systematic review of the literature.

Hyponatremia, defined as serum sodium concentration

Background Coronavirus disease 2019 (COVID-19) has triggered the disruption of health care on a global scale. With Italy tangled up in the pandemic response, oncology care has been largely diverted and cancer screenings suspended. Our multicenter Italian study aimed to evaluate whether COVID-19 has impacted access to diagnosis, staging, and treatment for patients newly diagnosed with colorectal cancer (CRC), compared with pre-pandemic time. Methods All consecutive new CRC patients referred to 8 Italian oncology institutions between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. Results A reduction (29%) in newly diagnosed CRC cases was seen when compared with 2019 (360 vs 506). New CRC patients in 2020 were less likely to be diagnosed with early stage (stages I-II-III) CRC (63% vs 78%, P < .01). Gender and sidedness were similar regardless of the year. The percentage of tumors with any mutation among BRAF, NRAS, and KRAS genes were significantly different between the 2 years (61% in 2020 vs 50% in 2019, P = .04). Timing of access to cancer diagnosis, staging, and treatment for patients with CRC has not been negatively affected by the pandemic. Significantly shorter temporal intervals were observed between symptom onset and first oncological appointment (69 vs 79 days, P = .01) and between histological diagnosis and first oncological appointment (34 vs 42 days, P < .01) during 2020 compared with 2019. Fewer CRC cases were discussed in multidisciplinary meetings during 2020 (38% vs 50%, P = .01). Conclusions Our data highlight a significant drop in CRC diagnosis after COVID-19, especially for early stage disease. The study also reveals a remarkable setback in the multidisciplinary management of patients with CRC. Despite this, Italian oncologists were able to ensure diagnostic–therapeutic pathways proper operation after March 2020.

Neurotoxicity is one of the most common side effects of oxaliplatin-based therapy. Most patients who receive at least 3–4 months of treatment suffer from peripheral sensory neurotoxicity (PSN), characterised by the loss or impairment of tactile and proprioceptive sensory function. Motor impairment, such as muscle weakness or palsy, has been rarely described, and the physiopathology of PSN, as well as the motor symptoms due to oxaliplatin-based treatment, are not adequately understood. Here we report the case of a patient who experienced severe acute peripheral motor neuropathy as a side effect of oxaliplatin-based treatment. We also review other cases of PSN published in the literature and suggest a novel hypothesis on the physiopathology of this particular event. Take-away lessons: Not all of the neurological symptoms observed during oxaliplatin-based treatment can be traced back directly to the oxaliplatin itself, and other factors, such as electrolyte imbalances, may contribute to the symptoms. Patients with gastro-intestinal malignancies are the patients most affected by neurotoxicity due to the side effects of chemotherapy and the disease itself. Electronic Supplementary Material The online version of this article (10.1007/s40487-019-00102-3) contains supplementary material, which is available to authorized users.

Background: The Gustave Roussy Immune (GRIm)-Score takes into account neutrophil-to-lymphocyte ratio (NLR), serum albumin concentration and lactate dehydrogenase (LDH) and its prognostic value has been investigated in patients treated with immune check-point inhibitors (ICIs). To further assess the prognostic and predictive value of baseline GRIm-Score (GRImT0) in advanced non-small cell lung cancer (aNSCLC) patients, we separately investigated two cohorts of patients treated with first-line pembrolizumab or chemotherapy. We also investigated whether GRIm-Score at 45 days since treatment initiation (GRImT1) and GRIm-Score difference between the two timepoints may better predict clinical outcomes (GRImΔ = GRImT0 − GRImT1). Methods: We retrospectively evaluated 222 aNSCLC patients: 135 treated with pembrolizumab and 87 treated with chemotherapy as the first-line regimen. NLR, serum albumin and LDH concentrations were assessed at T0 and at T1. According to the GRIm-Score, patients were assigned 1 point if they had NLR &gt, 6, LDH &gt, upper limit normal or albumin &lt, 3.5 g/dL. Patients with a GRIm-Score &lt, 2 were considered as having a low Score. Results: In both cohorts, no difference in terms of overall survival (OS) between patients with low and high GRImT0 was found. Otherwise, median OS and progression free survival (PFS) of the low GRImT1 group were significantly longer than those of the high GRImT1 group in pembrolizumab-treated patients, but not in the CHT cohort (pembrolizumab cohort: low vs. high, median OS not reached vs. 9.2 months, p = 0.004, median PFS 10.8 vs. 2.3 months, p = 0.002). Patients receiving pembrolizumab with stable/positive GRImΔ had better OS (median OS not reached vs. 12.0 months, p &lt, 0.001), PFS (median PFS 20.6 vs. 2.6 months, p &lt, 0.001) and objective response rate (58.2% vs. 7.6%, p = 0.003) compared to patients with negative GRImΔ. Conclusion: Our data shown that GRImT1 and GRImΔ are more reliable peripheral blood biomarkers of outcome compared to GRImT0 in aNSCLC patients treated with pembrolizumab and might represent useful biomarkers to drive clinical decisions in this setting.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) detains a dismal prognosis and has a limited number of prognostic factors. Inflammation has been demonstrated to play a key role both in PDAC initiation and progression and several inflammation-based prognostic scores have been investigated in a wide range of malignancies. We compared the most analyzed inflammation-based prognostic scores in order to establish their potential impact on prediction of the outcome in advanced PDAC patients. METHODS: A total of 234 advanced PDAC patients undergoing first-line chemotherapy in our institute were retrospectively analyzed. Baseline clinicopathological and pre-treatment laboratory data were collected. Survival was estimated using Kaplan-Meier method and survival differences were evaluated using the log-rank test. Level of statistical significance P was set at 0.05. Only those variables that proved to be associated with statistically significant differences in outcome were compared in multivariate analysis using multiple Cox regression, as to identify their independent role and their relative power against each other. RESULTS: In the whole cohort, median overall survival (OS) was 8.7 months (95% CI: 7.8–9.4 months), median progression-free survival (PFS) was 3.8 months (95% CI: 3.1–4.2 months). At univariate analysis high systemic immune-inflammation index (SII) was related to shorter OS [hazard ratio (HR) =2.04, 95% CI: 1.59–4.19, P=0.0001] and PFS (HR =1.52, 95% CI: 1.11–2.20, P=0.01). This was maintained at multivariate analysis both for OS (HR =2.11, 95% CI: 1.29–3.46, P=0.003) and PFS (HR =1.64, 95% CI: 1.14–2.37, P=0.008), whereas other inflammation-based scores lost their independent role. Elevated SII (≥1,200) was associated with low albumin levels (P=0.03) and with elevated lactate dehydrogenase (LDH) (P=0.01). CONCLUSIONS: Elevated SII represents an independent negative prognostic factor above all others for both OS and PFS in advanced PDAC patients treated with first-line chemotherapy, thus confirming a pivotal role of systemic inflammation on PDAC progression and on patient outcome.

Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.

Over the years, a growing body of literature has confirmed as beneficial the implementation of a multidisciplinary approach in the so-often-intricate scenario of cancer patients’ management. Together with the consolidation of tumor-board experience in clinical practice, certain aspects have emerged as controversial and a source of current debate. In this systematic literature review, we focused our attention on the impact of multidisciplinary tumor boards, assessing benefits and limitations as a result of the dissemination of such approaches. On the bright side, adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes have been recognized as advantages. On the other side, our analysis highlights a few limitations that should be taken into account to optimize cancer patients’ management. Of note, some issues, such as costs, legal responsibility, geographic barriers, and treatment delays, have yet to be resolved. In order partly to address this matter, software platforms and novel methods of computational analysis may provide the needed support. Therefore, the aim of our analysis was to describe the multidisciplinary approach in cancer care in terms of adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes through a systematic review of the literature.

Background: By the end of 2020, coronavirus disease 2019 (COVID-19) would have indelibly marked the cancer care setting. With Italy at the forefront of pandemic, unprecedented measures were adopted to tackle the quality care issue. As a result of pausing screening programs, diagnostic delays might affect the years to come. Aim of our multicenter Italian study is to evaluate whether the COVID-19 outbreak has impacted on likelihood of receiving timely diagnosis, staging and treatment for colorectal cancer (CRC) patients (pts) after March 2020 compared to pre-pandemic time. Methods: Medical records of all consecutive newly diagnosed CRC pts referred to 4 Italian Oncology Departments between March and December 2020 were examined. Access rate (number of pts/days) and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. Differences between the two years were evaluated using Fisher’s exact test or chi-square test for categorical variables and unpaired Student t test, or the Mann-Whitney U test for continuous variables. Results: A reduction (20%) in newly diagnosed CRC cases was seen when compared with 2019 (214 vs 268). The decline was greater in the lockdown period compared to the other months (percentage drop 40 % vs 12%). Newly CRC pts in 2020 were less likely to be diagnosed with early stage (stage I-II-III) CRC (67% vs 72%). Other clinical and tumor characteristics were similar regardless of the year. Looking at pts management, no differences emerged in terms of interval between symptom onset and radiological diagnosis (median 19 days in 2020 vs 28 days in 2019, p = 0.88), symptom onset and cytohistological diagnosis (25 vs 36 days, p = 0.27), symptom onset and treatment start (median 86 vs 100 days, p = 0.79). However, less CRC were discussed in multidisciplinary tumor meetings during the 2020 (45% vs 54%, p = 0.07). Conclusions: While COVID-19 repercussions will be likely felt for decades to come, our data suggest an alarming drop in early-stage CRC diagnoses during the first pandemic year. Conversely, our study draws the attention on the efforts made to ensure diagnostic-therapeutic pathways proper operation. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Introduction: Since December 2019, coronavirus disease 2019 (COVID-19) has spread to every country, taking on pandemic proportions in few months. Physicians were asked to redefine ordinary hospital organization, reprogramming clinically differentiable activities. Materials and Methods: During the COVID pandemic our Institution was supported by a call center (CC, named TOPS s.r.l.) to make a triage for cancer patients (pts) scheduled for follow-up in our outpatient clinics: C1 (dedicated to female tumors), C2 (for gastrointestinal, urogenital,and thoracic tumors) and D1 (for tumors in over 5 years’ follow-up). We report preliminary data referred to the period 7th April-24th May, 2020. The activity was divided into two phases (F): April (F1) and May (F2). In F2 pts were interviewed about their preferred visit modality. Physical examination was not postponed in case of clinical needs and first visits. Moreover, CC asked about programmed radiologic examinations and collected patients’ feedback about the service. Results: A total of 587 pts have been contacted: 341 during F1 and 246 in F2. 317/341 (93%) of the contacts in F1 were successful. A gender-stratified analysis showed a majority of patients were female (72.4%). The CC was able to get in touch with 42.8% C1 pts, 34.6% C2 pts, and 22.6% D1 pts. During F2 246 pts (96.5%) of 255 planned were efficiently contacted; female maintained the predominance (74.5%). 170 pts (69.1%) were scheduled in C1, 53 pts (21.5%) in C2, and 23 pts (9.4%) in D1. During F2, among the options provided 97 pts (39.4%) selected the phone call, 142 pts (57.7%) decided for video chat (whatsapp), and 2 (0.8%) for video conference with a dedicated platform (google.meet). Only 5 pts (2.1%) expressed their intention to come to the hospital for examination. In 69.1% of cases (170 pts) the programmed radiologic examinations were confirmed during the pandemic. According to some favorable reports, the service was helpful in preserving continuum of care and preventing cancer pts from being left aside in the emergency. Conclusions: This study show that cancer patients do appreciate technology-mediated follow-up visits, mainly including video chat (whatsapp), and therefore we should take this into consideration. Furthermore, a dedicated CC may be helpful to organize follow-up activities during COVID-19 and to strengthen the doctor-patient relationship in such a critical moment. Citation Format: Mariangela Torniai, Giulia Marcantognini, Ilaria Fiordoliva, Giulia Mentrasti, Veronica Agostinelli, Alessandra Pagliacci, Rossana Berardi, Michele Caporossi. Technology-mediated communication with patients is a challenge for oncologists in the digital and pandemic era… and the winner is WhatsApp! [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-039.

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies. Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270–85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213. This article is highlighted in the In This Issue feature, p. 1195

Background: \ud Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging.\ud \ud Patients and methods: \ud Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo ‘stopwatch’. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively ‘carbon date’ the malignant progression.\ud \ud Results: \ud The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity.\ud \ud Conclusion: \ud Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.

KRAS mutations in circulating tumour DNA (ctDNA) in MRI-defined, high-risk, locally-advanced rectal cancer (LARC) patients (pts) from the EXPERT-C trial