Perineural invasion score system and clinical outcomes in resected pancreatic cancer patients.

BACKGROUND/OBJECTIVES: Perineural invasion (PNI), classified according to its presence or absence in tumor specimens, is recognized as a poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC) patients. Herein, we identified five histological features of PNI and investigated their impact on survival outcomes of PDAC resected patients. METHODS: Five histopathological features of PNI (diameter, number, site, sheath involvement, and mitotic figures within perineural invasion) were combined in an additional final score (ranging from 0 to 8), and clinical data of PDAC patients were retrospectively analyzed. PNI + patients were stratified in two categories according to the median score value (<6 and ≥ 6, respectively). Impact of PNI on disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: Forty-five patients were enrolled, of whom 34 with PNI (PNI+) and 11 without PNI (PNI-). The DFS was 11 months vs. not reached (NR) (p = 0.258), while the OS was 19 months vs. NR (p = 0.040) in PNI+ and PNI- patients, respectively. A ≥6 PNI was identified as an independent predictor of worse OS vs. <6 PNI + patients (29 vs. 11 months, p < 0.001) and <6 PNI+ and PNI- patients (43 vs. 11 months, p < 0.001). PNI ≥6 was an independent negative prognostic factor of DFS vs. <6 PNI+ and PNI- patients (13 vs. 6 months, p = 0.022). CONCLUSIONS: We report a PNI scoring system that stratifies surgically-treated PDAC patients in a graded manner that correlates with patient prognosis better than the current dichotomous (presence/absence) definition. However, further and larger studies are needed to support this PNI scoring system.

KRAS-related miR-143 expression is associated with lymph node involvement and correlates with outcome in pancreatic adenocarcinoma patients.

Introduction: Pancreatic adenocarcinoma (PC) is one of the most lethal malignancies; even after resection the patients' 5-year disease-free survival (DFS) is lower than 26%. The genetic mutational landscape of PC is dominated by activating KRAS mutations, that have been reported in approximately 90% of cases; however, beyond KRAS - direct mutations, several KRAS-targeting miRNAs appear to be downregulated, strengthening the already activated RAS signaling. In addition, the interplay between miRNAs and RAS includes poorly investigated downstream miRNAs. The aim of this study was to determine the prognostic value of some of these candidate KRAS-related miRNAs. Patients and methods: Between 2015 and 2022, 44 patients with pathologically confirmed PC, who received surgery and were enrolled by the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy). PC Total RNA was extracted from FFPE sections, retro-transcribed and the resulting cDNA was then used for qPCR analysis. A panel of KRAS-related miRNA (miR-155, miR-206 and miR-143) was analyzed. Results: In this observational study patients sex distribution was unequal with 34.1% being male and 65.9% female. The most frequent tumor localization was the head of the pancreas (65.9%) and the pathological stages were pT1-2 (45.5%), pT3 (54.5%), pN0 (22.7%), pN+ (77.3%). Adjuvant therapy was administered to 63.6% of patients; disease recurrence was observed in 69% of cases. Twenty-three patients, whose RNA was of adequate quality, were used in the mRNAs expression studies. When comparing the miRNA expression between PC and a pool of healthy tissues, miR-155 was overexpressed and miR-206 downregulated in PC, while miR-143 expression was unchanged. However, when categorized in low- and high- miR-143 expressing PC (according to the median value), high miR-143 was associated with nodal involvement (pN+) (p=0.029), who in turn was linked with shorter DFS (p=0.009) and overall survival (OS) (p=0.021) compared to pN0. A trend toward inferior DFS was observed for higher expression of miR-206 (p=0.095) and miR-143 (p=0.092). Finally, responders to a first-line treatment for advanced disease had miR-155 overexpressed (p=0.048). Conclusions: miRNAs are involved in PC tumorigenesis and metastatic spread. In light of miR-143 association with lymphatic spread and poor prognosis, a comprehensive analysis of miRNA interplay with KRAS deserves further investigation.

Early changes in circulating tumor DNA (ctDNA) predict treatment response in metastatic KRAS-mutated colorectal cancer (mCRC) patients.

The detection of RAS mutations and co-mutations in liquid biopsy offers a novel paradigm for the dynamic management of metastatic colorectal cancer (mCRC) patients. Expanding the results of the prospective OMITERC (OMIcs application from solid to liquid biopsy for a personalized ThERapy of Cancer) project, we collected blood samples at specific time points from patients who received a first-line chemotherapy (CT) for KRAS-mutated mCRC. CTC quantification was performed by CellSearch® system. Libraries from cfDNA were prepared using the Oncomine™ Colon cfDNA Assay to detect tumour-derived DNA in cfDNA. The analysis involved >240 hotspots in 14 genes. Twenty patients with KRAS-mutated mCRC treated at the Medical Oncology Unit of Careggi University Hospital were prospectively enrolled. Nine patients had available data for longitudinal monitoring of cfDNA. After 6 weeks of first-line CT an increase of KRAS-mutated clone was reported in the only patient who did not obtain disease control, while all patients with decrease of KRAS clones obtained disease control. Overall, in patients with a short (<9 months) progression-free survival (PFS) we registered, at 6 weeks, an increase in cfDNA levels and in KRAS mutations or other co-mutations, i.e. PIK3CA, FBXW7, GNAS, and TP53. In selected cases, co-mutations were able to better anticipate radiological progressive disease (PD) than the increase of KRAS-mutated clones. In conclusion, our study confirms plasma ctDNA as a crucial tool for anticipating PD at an early time point and highlights the value of a comprehensive assessment of clonal dynamics to improve the management of patients with mCRC.

The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs.

Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention. In a cohort of GC patients who received perioperative FLOT (i.e., Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) or FOLFOX (i.e., Leucovorin, 5-Fluouracil, and Oxaliplatin), non-responder patients showed an increased expression of tumor CAIX compared to responder group. Moreover, GC cell lines induced to be resistant to 5-Fluouracil, Paclitaxel, Cisplatin, or the combination of 5-Fluorouracil, Oxaliplatin, and Docetaxel, overexpressed CAIX compared to the control. Accordingly, CAIX-high-expressing GC cells showed increased therapy resistance compared to low-expressing cells. Notably, SLC0111 significantly improved the therapy response of both wild-type and resistant GC cells. Overall, these data suggest a correlation between CAIX and GC drug resistance highlighting the potential of SLC-0111 in re-sensitizing GC cells to pCT.

MRI of Peliosis Hepatis: A Case Series Presentation With a 2022 Systematic Literature Update.

BACKGROUND: Peliosis hepatis (PH) is a rare benign condition, characterized by hepatic sinusoidal dilatation and blood-filled cystic cavities, often found incidentally, with still challenging diagnosis by imaging due to polymorphic appearance. PURPOSE: Based on a retrospective analysis of our series (12 patients) and systematic literature review (1990-2022), to organize data about PH and identify features to improve characterization. STUDY TYPE: Retrospective case series and systematic review. POPULATION: Twelve patients (mean age 48 years, 55% female) with pathology-proven PH and 49 patients (mean age 52 years, 67% female) identified in 33 studies from the literature (1990-2022). FIELD STRENGTH/SEQUENCE: 1,5-T; T1-weighted (T1W), T2-weighted (T2W), diffusion-weighted (DW), contrast-enhanced (CE) T1W imaging. ASSESSMENT: We compared our series and literature data in terms of demographic (gender/age/ethnicity), clinical characteristics (symptoms/physical examination/liver test), associated conditions (malignancies/infectious/hematologic/genetic or chronic disorders/drugs or toxic exposure) percentage. On magnetic resonance imaging lesion numbers/shape/mean maximum diameter/location/mass effect/signal intensity were compared. PH pathological type/proposed imaging diagnosis/patient follow-up were also considered. STATISTICAL TESTS: Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports/Series quality assessment. Intraclass correlation and Cohen's kappa coefficients for levels of inter/intrareader agreement in our experience. RESULTS: Patients were mainly asymptomatic (92% vs. 70% in our study and literature) with associated conditions (83% vs. 80%). Lesions showed homogeneous T1W-hypointensity (58% vs. 65%) and T2W-hyperintensity (58% vs. 66%). Heterogeneous nonspecific (25% vs. 51%), centrifugal (34% vs. 8%), or rim-like centripetal (25% vs. 23%) patterns of enhancement were most frequent, with hypointensity on the hepatobiliary phase (HBP), without restricted diffusivity. Good inter- and intrareader agreement was observed in our experience. Concerning JBI Checklist, 19 out of 31 case reports met at least 7 out of 8 criteria, whereas 2 case series fulfilled 5 and 6 out of 10 items respectively. DATA CONCLUSION: A homogeneous, not well-demarcated T1W-hypointense and T2W-hyperintense mass, with heterogeneous nonspecific or rim-like centripetal or centrifugal pattern of enhancement, and hypointensity on HBP, may be helpful for PH diagnosis. Among associated conditions, malignancies and drug exposures were the most frequent. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis.

INTRODUCTION: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. METHODS: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). RESULTS: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III-IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. CONCLUSION: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.

Prognostic role of hERG1 Potassium Channels in Neuroendocrine Tumours of the Ileum and Pancreas.

hERG1 potassium channels are widely expressed in human cancers of different origins, where they affect several key aspects of cellular behaviour. The present study was designed to evaluate the expression and clinical relevance of hERG1 protein in cancer tissues from patients suffering from neuroendocrine tumours (NETs) of ileal (iNETs) and pancreatic (pNETs) origin, with available clinicopathological history and follow-up. The study was carried out by immunohistochemistry with an anti-hERG1 monoclonal antibody. In a subset of samples, a different antibody directed against the hERG1/ß1 integrin complex was also used. The analysis showed for the first time that hERG1 is expressed in human NETs originating from either the ileum or the pancreas. hERG1 turned out to have a prognostic value in NETs, showing (i) a statistically significant positive impact on OS of patients affected by ileal NETs, regardless the TNM stage; (ii) a statistically significant positive impact on OS of patients affected by aggressive (TNM stage IV) disease, either ileal or pancreatic; (iii) a trend to a negative impact on OS of patients affected by less aggressive (TNM stage I-III) disease, either ileal or pancreatic. Moreover, in order to evaluate whether ERG1 was functionally expressed in a cellular model of pNET, the INS1E rat insulinoma cell line was used, and it emerged that blocking ERG1 with a specific inhibitor of the channel (E4031) turned out in a significant reduction in cell proliferation.

Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.

Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.

hERG1 Potassium Channel Expression in Colorectal Adenomas: Comparison with Other Preneoplastic Lesions of the Gastrointestinal Tract.

Preneoplastic lesions represent a useful target for early diagnosis and follow-up of gastrointestinal malignancies. hERG1 channel expression was tested by immunohistochemistry (IHC) in a cohort of colorectal adenoma samples belonging to Italian subjects. Overall, hERG1 was expressed in 56.5% of cases with both high staining intensity and a high percentage of positive cells. Moreover, hERG1 was expressed in a higher percentage of dysplastic adenomas with respect to hyperplastic lesions, and the proportion of positive samples further increased in patients with high-grade dysplasia. Comparing hERG1 expression in other preneoplastic lesions of the GI tract (gastric dysplasia and Barrett's esophagus), it emerged that in all the conditions, hERG1 was expressed with a diffused pattern, throughout the cell, with variable staining intensity within the samples. The highest expression was detected in gastric dysplasia samples and the lowest in Barrett's esophagus at similar levels observed in colorectal adenomas. Our results show that hERG1 is aberrantly expressed in human preneoplastic lesions of the gastrointestinal tract and has a different pattern of expression and role in the different sites. Overall, the detection of hERG1 expression in preneoplastic lesions could represent a novel diagnostic or prognostic marker of progression in the gastrointestinal tract.

Correlation of CT radiomic features for GISTs with pathological classification and molecular subtypes: preliminary and monocentric experience.

PURPOSE: Our primary purpose was to search for computed tomography (CT) radiomic features of gastrointestinal stromal tumors (GISTs) that could potentially correlate with the risk class according to the Miettinen classification. Subsequently, assess the existence of features with possible predictive value in differentiating responder from non-responder patients to first-line therapy with Imatinib. METHODS: A retrospective study design was carried out using data from June 2009 to December 2020. We analyzed all the preoperative CTs of patients undergoing surgery for GISTs. We segmented non-contrast-enhanced CT (NCECT) and contrast-enhanced venous CT (CECT) images obtained either on three different CT scans (heterogeneous cohort) or on a single CT scan (homogeneous cohort). We then divided the patients into two groups according to Miettinen classification criteria and based on the predictive value of response to first-line therapy with Imatinib. RESULTS: We examined 54 patients with pathological confirmation of GISTs. For the heterogeneous cohort, we found a statistically significant relationship between 57 radiomic features for NCECT and 56 radiomic features for CECT using the Miettinen risk classification. In the homogeneous cohort, we found the same relationship between 8 features for the NCECT and 5 features for CECT, all included in the heterogeneous cohort. The various radiomic features are distributed with different values in the two risk stratification groups according to the Miettinen classification. We also found some features for groups predictive of response to first-line therapy with Imatinib. CONCLUSIONS: We found radiomic features that correlate with statistical significance for both the Miettinen risk classification and the molecular subtypes of response. All features found in the homogeneous study cohort were also found in the heterogeneous cohort. CT radiomic features may be useful in assessing the risk class and prognosis of GISTs.

Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation.

Voltage-gated Na+ channels (VGSCs) are expressed widely in human carcinomas and play a significant role in promoting cellular invasiveness and metastasis. However, human tissue-based studies and clinical characterization are lacking. In several carcinomas, including colorectal cancer (CRCa), the predominant VGSC is the neonatal splice variant of Nav1.5 (nNav1.5). The present study was designed to determine the expression patterns and clinical relevance of nNav1.5 protein in human CRCa tissues from patients with available clinicopathological history. The immunohistochemistry was made possible by the use of a polyclonal antibody (NESOpAb) specific for nNav1.5. The analysis showed that, compared with normal mucosa, nNav1.5 expression occurred in CRCa samples (i) at levels that were significantly higher and (ii) with a pattern that was more delineated (i.e., apical/basal or mixed). A surprisingly high level of nNav1.5 protein expression also occurred in adenomas, but this was mainly intracellular and diffuse. nNav1.5 showed a statistically significant association with TNM stage, highest expression being associated with TNM IV and metastatic status. Interestingly, nNav1.5 expression co-occurred with other biomarkers associated with metastasis, including hERG1, KCa3.1, VEGF-A, Glut1, and EGFR. Finally, univariate analysis showed that nNav1.5 expression had an impact on progression-free survival. We conclude (i) that nNav1.5 could represent a novel clinical biomarker ('companion diagnostic') useful to better stratify CRCa patients and (ii) that since nNav1.5 expression is functional, it could form the basis of anti-metastatic therapies including in combination with standard treatments.

Circulating tumour cells and cell-free DNA as a prognostic factor in metastatic colorectal cancer: the OMITERC prospective study.

BACKGROUND: Within the OMITERC prospective study (OMIcs application from solid to liquid biopsy for a personalised ThERapy of Cancer), we explored the prognostic role of liquid biopsy encompassing cell-free DNA (cfDNA) and circulating tumour cells (CTCs) in KRAS mutated metastatic colorectal cancer (mCRC). METHODS: We defined a workflow including pre-analytical and analytical procedures collecting blood before therapy and every 3 months until disease progression (PD). CTCs were counted by CellSearch® and isolated by DEPArray™. NGS sequencing of CTCs and cfDNA was performed using a panel of cancer/CRC related genes respectively. RESULTS: KRAS mutational status was mostly concordant between tumour tissues and liquid biopsy. The percentage of cfDNA samples with mutations in CRC driver genes was in line with literature. In longitudinal monitoring circulating biomarkers anticipated or overlapped conventional diagnostic tools in predicting PD. The presence of CTCs at baseline was confirmed a negative prognostic marker. CONCLUSIONS: Cell-free DNA and CTCs are readily available candidates for clinical application in mCRC. While CTCs demonstrated a prognostic significance at baseline, cfDNA was confirmed an easily accessible material for monitoring the mutational status of the tumour over time. Moreover, in the longitudinal study, the two markers emerged as complementary in assessing disease progression.

KRAS and NRAS mutation detection in circulating DNA from patients with metastatic colorectal cancer using BEAMing assay: Concordance with standard biopsy and clinical evaluation.

Patients with metastatic colorectal cancer (mCRC) are routinely screened for either K- and N-RAS to select the appropriate treatment. The present study aimed to evaluate the concordance between K- and NRAS status in the tissue (either primary tumor or metastasis) and the plasma of patients with mCRC and to identify the associations between K- and NRAS mutations in ctDNA and the clinicopathological parameters. Samples from a total of 31 patients with mCRC with measurable disease according to the Response Evaluation Criteria in Solid Tumors were analyzed. For all patients, K- and NRAS status was determined in the tissue by matrix-assisted laser desorption/ionization time of flight mass spectrometry. For the detection of RAS mutations in cell-free tumor DNA also defined as circulating tumor DNA (ctDNA), the OncoBEAM® RAS CRC kit (Sysmex Inostics) was used. A total of 6/31 tissue samples expressed wild-type KRAS, whereas 25/31 presented mutations. In addition, 7/31 plasma samples expressed wild-type KRAS, mutations were detected in 22/31 patients, and for 2/31 patients, the test did not provide a conclusive result. A total of 24/31 patients expressed wild-type NRAS, 6/31 had mutations and 1/21 was not informative. For the KRAS mutational status, a moderate concordance (agreement, 85.18%; Cohen's k, 0.513) between the tissue and plasma analysis was observed; for NRAS, a fair agreement (agreement, 83.33%; Cohen's k, 0.242) was obtained. In conclusion, both tissue and plasma analyses should be performed for the management of patients with mCRC. To better exploit the beads, emulsions, amplification, magnetics (BEAMing) technique in the clinical setting, studies aimed at determining the RAS status to monitor therapy and during follow-up are warranted.

Temozolomide alone or in combination with capecitabine in patients with advanced neuroendocrine neoplasms: an Italian multicenter real-world analysis.

PURPOSE: Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors. METHODS: Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O6-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing. RESULTS: From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6-48.7) and 14.7 months (10.1-18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity. CONCLUSIONS: This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting.

ROS1 rearrangements are uncommon in biliary tract cancers.

Biliary tract cancers (BTCs) are a pool of diseases with poor prognosis and there is no orphan drug available. Currently, no molecular targets have been tested as druggable oncogenic drivers. C-ros oncogene 1 (ROS1) rearrangements have been previously described in various tumors, including BTCs; however, data regarding their incidence and biological significance are controversial. Therefore, a retrospective multicenter study was performed to assess the incidence of ROS1 rearrangements in BTCs by means of immunohistochemistry and fluorescence in situ hybridization (FISH). The present study failed to demonstrate ROS1 expression in a multicenter series of 150 cases with BTCs and revealed that D4D6 was the most specific clone compared with other ROS1 primary antibodies, namely PA1-30318 and EPMGHR2. Notably, negative results obtained with D4D6 completely matched to data sorted out by FISH analysis, thus confirming a lack of ROS1 gene rearrangements in BTCs and false positive results when PA1-30318 and EPMGHR2 clones were used. These results suggest that ROS1 rearrangements may not be targets for molecular therapy of BTCs with specific inhibitors.

Evaluation of RAS mutational status through BEAMing assay to monitor disease progression of metastatic colorectal cancer: a case report.

Since the introduction of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (moAbs), the treatment of metastatic colorectal cancer (mCRC) has become crucially dependent on the mutation profile of the tumour over the last two decades. Recently, rechallenge strategy with cetuximab-based chemotherapy has demonstrated to be active in a subgroup of patients whose tumour maintained wild-type RAS and RAF status. In this setting, liquid biopsy may replace tissue sample for the identification of specific subgroups of pretreated patients that may benefit from the reintroduction of anti-EGFR moAbs. In November 2014, a 64-year-old man with IVB stage BRAF, KRAS and NRAS wild-type mCRC was admitted in our hospital. He received FOLFIRI cetuximab as first-line treatment with deep and long-lasting partial response (PR), followed by cetuximab maintenance therapy until January 2016. At the time of disease progression, FOLFIRI cetuximab regimen was reintroduced resulting in stabilization of disease and he continued with capecitabine cetuximab therapy until disease progression in October 2016. Then, the patient consecutively received FOLFOX bevacizumab, TAS-102, regorafenib and FOLFIRI followed by de Gramont maintenance treatment. Finally, he was retreated with FOLFIRI cetuximab with disease progression within 3 months and died in May 2019. During his clinical course, liquid biopsy detected two mutations: one in KRAS Cd.12 and one in NRAS Cd. 61. The longitudinal assessment of RAS status offers considerable advantages in order to avoid side effects and economic costs for ineffective treatment choices. Liquid biopsy could help better monitor the disease and provide molecularly guided treatments.

hERG1 and HIF-2α Behave as Biomarkers of Positive Response to Bevacizumab in Metastatic Colorectal Cancer Patients.

BACKGROUND: In search of novel biomarkers of response to bevacizumab in metastatic colorectal cancer (mCRC), we analyzed the expression and prognostic role of several proteins related to angiogenesis. METHODS: A retrospective, multicenter study on 80 surgical samples from mCRC patients treated in first line with bevacizumab plus chemotherapy was accomplished. The following proteins were analyzed by immunohistochemistry: hERG1 potassium channel, ß1-integrin, pAKT, NFkB, HIF-1α, HIF-2α, p53, VEGF-A, GLUT-1, and CA-IX. Data were analyzed in conjunction with the clinicopathological characteristics of the patients, KRAS status, response to bevacizumab, and follow-up. RESULTS: (1) All the proteins were expressed in the samples, with statistically significant associations between HIF-1α and gender, HIF-2α and left colon, hERG1 and VEGF-A, ß1-integrin and HIF-2α, GLUT-1 and both HIF-1α and HIF-2α, and CA-IX and VEGF-A. (2) At the univariate analysis, positivity for hERG1, VEGF-A, and the active form of HIF-2α (aHIF-2α), and the G3 histological grade showed a positive impact on progression-free survival (PFS). (3) hERG1 and aHIF-2α maintained their positive impact on PFS at the multivariate analysis. (4) hERG1 behaved as a protective factor for PFS independently on KRAS status. CONCLUSIONS: hERG1 and aHIF-2α might help to identify patients who would benefit from bevacizumab treatment.

Metastatic intracranial solitary fibrous tumors/hemangiopericytomas: description of two cases with radically different behaviors and review of the literature.

Solitary fibrous tumor/hemangiopericytoma with primary tumor location in the central nervous system accounts for less than 1% of all central nervous system tumors. Despite the relatively indolent clinical course, extracranial metastases are reported in 28% of cases. In recent years, NAB2-STAT6 gene fusion has been recognized as the pathognomonic molecular feature of solitary fibrous tumor/hemangiopericytoma and STAT6 immunohistochemistry has been shown to be a sensitive and specific surrogate for the identification of the gene fusion in these patients. Here we report two cases of patients who experienced occurrence of diffuse extracranial metastases several years after successful surgery for an intracranial solitary fibrous tumor/hemangiopericytoma. In the first patient, the metastases had maintained similar histological features to the primary tumor; in contrast, in the second case, a dedifferentiation occurred with loss of expression of CD34 and Bcl-2. These different histological features were associated with radically different behaviors. Whereas the first case experienced an indolent course of the disease, the second patient had a rapid disease progression and deterioration of clinical conditions. The molecular imaging findings in these two cases and the role of functional imaging for tumor detection, disease staging and monitoring in this rare cancer are also discussed. Recurrences and metastases maintained high expression of somatostatin receptors confirmed by somatostatin receptor imaging in the first case. In contrast, in the second patient, the abrupt transition into a highly aggressive form was associated with the absence of somatostatin receptors at 111In Pentetreotide scan and intense hypermetabolism at 18F-FDG PET.