Noncoding RNA in cholangiocarcinoma

Cholangiocarcinomas (CCAs) are tumors with a dismal prognosis. Early diagnosis is a key challenge because of the lack of specific symptoms, and the curability rate is low due to the difficulty in achieving a radical resection and the intrinsic chemoresistance of CCA cells. Noncoding RNAs (ncRNAs) are transcripts that are not translated into proteins but exert their functional role by regulating the transcription and translation of other genes. The discovery of the first ncRNA dates back to 1993 when the microRNA (miRNA) lin-4 was discovered in Caenorhabditis elegans. Only 10 years later, miRNAs were shown to play an oncogenic role in cancer cells and within 20 years miRNA therapeutics were tested in humans. Here, the authors review the latest evidence for a role for ncRNAs in CCA and discuss the promise and challenges associated with the introduction of ncRNAs into clinical practice

Oligometastatic gastric cancer: an emerging clinical entity with distinct therapeutic implications

Gastric cancer (GC) remains responsible for a high burden worldwide being the third leading cause of cancer-related mortality. Most of patients present at an advanced stage at diagnosis and are thus candidates to standard chemotherapy resulting in median survival of less than 1 year. Oligometastatic gastric cancer is an increasingly recognized clinical entity characterized by limited metastatic spread that has been showing to benefit from aggressive multimodality strategies encompassing chemotherapy and surgery. The ongoing RENAISSANCE/AIO-FLOT5 (NCT02578368) phase III trial is aimed at evaluating if perioperative chemotherapy with FLOT in combination with surgical resection of the primary tumour and metastases could become the new standard of care for oligometastatic GC. In the meantime, in addition to currently available clinical parameters, the emerging predictive/prognostic role of biomarkers such mismatch repair deficiency/microsatellite instability high status needs to be specifically addressed also in this subgroup of GC to assist in patient selection

Epidemiological overview of Hodgkin lymphoma across the Mediterranean Basin

The epidemiology of Hodgkin lymphoma (HL) has always been a source of fascination to researchers due to its heterogeneous characteristics of presentation. HL is an uncommon neoplasm of B-cell origin with an incidence that varies significantly by age, sex, ethnicity, geographic location and socioeconomic status. This complex pattern was also found to be replicated among Mediterranean basin populations. HL incidence rates progressively decreased from industrialized European countries such as France (ASR=2.61) and Italy (ASR=2.39) to less developed nations such as Albania (ASR=1.34) and Bosnia Herzegovina (ASR=1.1). Regarding HL mortality we have found that countries with the lowest incidence rates show the highest number of deaths from this cancer and viceversa. Finally, a wide gap in terms of survival was showed across the Mediterranean basin with survival rates ranged from 82.3% and 85.1% among Italian men and women, to 53.3 % and 59.3% among Libyan men and women, respectively. Factors such as the degree of socio-economic development, the exposure to risk factors westernization-related, the availability of diagnostic practices along with different genetic susceptibilities to HL may explain its variation across Mediterranean countries. Furthermore, the lack of health resources decisively contribute to the poor prognosis recorded in less developed region. In the future, the introduction of appropriate and accessible treatment facilities along with an adequate number of clinical specialists in the treatment of HL and other cancers are warranted in order to improve the outcomes of affected patients and treat a largely curable type of cancer in disadvantaged regions

Durable remission in a patient with leptomeningeal relapse of a MYC/BCL6-positive double-hit DLBCL treated with lenalidomide monotherapy

Secondary central nervous system involvement is an uncommon event that typically occurs early in the natural history of diffuse large B-cell lymphoma and presents as leptomeningeal dissemination in two-thirds of cases. The prognosis of this event is dismal, and treatment options are meagre. Although major validated risk factors for central nervous system dissemination are clinical, concomitant MYC/BCL2 rearrangements as well as MYC/BCL2 protein expression have been recently associated with an increased risk of this complication. Here we present the first case, to our knowledge, of a MYC/BCL6-positive double-hit diffuse large B-cell lymphoma relapsing in the leptomeninges that achieved an outstanding durable remission with single-agent lenalidomide following salvage chemotherapy

Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25-30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment. METHODS: Pre-treatment serum concentrations of tryptophan (trp) and kynurenine (kyn) were measured by high-performance liquid chromatography tandem mass spectrometry in NSCLC patients treated with second-line nivolumab. The IDO activity was expressed with kyn/trp ratio. The associations between kyn/trp ratio and early progression, performance status (PS), age, sex, brain metastases, pleural effusion, progression free survival (PFS) and overall survival (OS) were analyzed using Spearman test and Mann-Whitney test. RESULTS: Twenty-six NSCLC patients were included in our study; 14 of them (54%) presented early progression (< 3 months) to nivolumab treatment. The median value of kyn/trp ratio was 0.06 µg/ml and the median value of quinolinic acid was 68.45 ng/ml. A significant correlation between early progression and higher kyn/trp ratio and quinolinic acid concentration was observed (p = 0.017 and p = 0.005, respectively). Patients presenting lower values of kyn/trp ratio and quinolinic acid levels showed longer PFS (median PFS not reached versus 3 months; HR: 0.3; p = 0.018) and OS (median OS not reached vs 3 months; HR: 0.18; p = 0.0005). CONCLUSION: IDO activity, expressed as kyn/trp ratio, is associated with response to immunotherapy; in particular, higher kyn/trp ratio could predict resistance to anti-PD-1 treatment. These preliminary results suggest the possibility of using anti-PD-1 plus IDO inhibitor in those patients with high level of kyn/trp ratio

Surgery or Locoregional Approaches for Hepatic Oligometastatic Pancreatic Cancer: Myth, Hope, or Reality?

Despite extensive research, pancreatic ductal adenocarcinoma (PDAC) remains a difficult-to-treat cancer associated with poor survival. Due to the known aggressive disease biology, palliative chemotherapy is the only routinely recommended treatment in the metastatic setting in patients with adequate performance status. However, in a subset of patients with oligometastatic disease, multimodality treatment with surgery and/or locoregional approaches may provide long-term disease control and prolong survival. In fact, in highly selected cases, median overall survival has been reported to extend to 56 months in patients treated with surgery. In particular, liver and extraregional nodal resections may provide long-term tumor control with acceptable morbidity. Current guidelines do not recommend surgery for patients with metastatic PDAC and, in the case of PDAC with oligometastases, there are no published randomized controlled trials regarding locoregional or surgical approaches. Here we review the literature on surgical and locoregional approaches including radiofrequency ablation, irreversible electroporation, and stereotactic body radiation, and focus on patients with hepatic oligometastatic pancreatic cancer. We provide a summary regarding survival outcomes, morbidity and mortality and discuss selection criteria that may be useful to predict the best outcomes for such strategies

The Role of Anti-Angiogenics in Pre-Treated Metastatic BRAF-Mutant Colorectal Cancer: A Pooled Analysis

: Background. FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF-mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated BRAF-mutant CRC. Methods. We monitored patients in randomized, controlled studies who had advanced CRC and were undergoing second-line chemotherapy in addition to utilizing Bevacizumab, Ramucirumab or Aflibercept treatments. These data were pooled together with the data and results of BRAF-mutant patients enrolled in two phase III trials (TRIBE and TRIBE-2 study), who had been treated with second-line treatment both with or without Bevacizumab. Overall survival (OS), in relation to BRAF mutational status, was the primary focus. Results. Pooled analysis included 129 patients. Anti-angiogenics were found to have a significant advantage over the placebo in terms of OS (HR 0.50, 95%CI 0.29-0.85) (p = 0.01). Conclusions. Our pooled analysis confirms the efficacy of anti-angiogenics in pre-treated BRAF-mutant CRC, establishing the combination of chemotherapy plus Bevacizumab or Ramucirumab or Aflibercept as a valid treatment option

The Impact of Locoregional Treatment on Response to Nivolumab in Advanced Platinum Refractory Head and Neck Cancer: The Need Trial

Background: Previous locoregional treatment could affect the response to nivolumab in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). The aim of this study is to evaluate the impact of the clinicopathological characteristics and previous treatment in predicting early progression to nivolumab in a real-world population. Methods: This is an observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received nivolumab 240 mg every 2 weeks from October 2018 to October 2019. We analyzed the association between previous treatment, clinicopathological characteristics, and early progression (within 3 months). Results: Data from 61 pts were reviewed. Median age was 67 years (30–82). Forty-two pts (69%) received previous locoregional treatment. Early progression to nivolumab occurred in 36 pts (59%), while clinical benefit (stable disease and partial response) was achieved in 25 pts (41%). Early progression to nivolumab was significantly associated to previous locoregional treatment both at univariate and multivariate analysis (p = 0.005 and p = 0.048, respectively). Conclusion: nivolumab in R/M HNSCC is burdened with a high early progression rate. Previous wide neck dissection and high dose radiotherapy may compromise the efficacy of nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response

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

Development and Multicenter Validation of a Novel Immune-Inflammation-Based Nomogram to Predict Survival in Western Resectable Gastric and Gastroesophageal Junction Adenocarcinoma (GEA): The NOMOGAST

Background. More than 50% of operable GEA relapse after curative-intent resection. We aimed at externally validating a nomogram to enable a more accurate estimate of individualized risk in resected GEA. Methods. Medical records of a training cohort (TC) and a validation cohort (VC) of patients undergoing radical surgery for c/uT2-T4 and/or node-positive GEA were retrieved, and potentially interesting variables were collected. Cox proportional hazards in univariate and multivariate regressions were used to assess the effects of the prognostic factors on OS. A graphical nomogram was constructed using R software’s package Regression Modeling Strategies (ver. 5.0-1). The performance of the prognostic model was evaluated and validated. Results. The TC and VC consisted of 185 and 151 patients. ECOG:PS > 0 (p < 0.001), angioinvasion (p < 0.001), log (Neutrophil/Lymphocyte ratio) (p < 0.001), and nodal status (p = 0.016) were independent prognostic values in the TC. They were used for the construction of a nomogram estimating 3- and 5-year OS. The discriminatory ability of the model was evaluated with the c-Harrell index. A 3-tier scoring system was developed through a linear predictor grouped by 25 and 75 percentiles, strengthening the model’s good discrimination (p < 0.001). A calibration plot demonstrated a concordance between the predicted and actual survival in the TC and VC. A decision curve analysis was plotted that depicted the nomogram’s clinical utility. Conclusions. We externally validated a prognostic nomogram to predict OS in a joint independent cohort of resectable GEA; the NOMOGAST could represent a valuable tool in assisting decision-making. This tool incorporates readily available and inexpensive patient and disease characteristics as well as immune-inflammatory determinants. It is accurate, generalizable, and clinically effectivex