Treating an Advanced Combined Hepatocellular-Cholangiocarcinoma with a Multikinase Inhibitor.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is an aggressive hepatic cancer that has characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). For resectable disease, liver resection is the preferred first treatment option. As for the advanced or metastatic setting, and due to its rarity, there is still no consensus on which is the optimal systemic treatment. As such, regimens used in both HCC and CC have often been used as first-line treatment options. We report a case of a male patient in his 50s, diagnosed with a cHCC-CC with lymph node and adrenal metastasis, with an extensive portal vein tumour thrombosis, that started treatment with a multikinase inhibitor - lenvatinib.

HER2 Status in RAS and BRAF Wild-Type Metastatic Colorectal Cancer: A Portuguese Study.

INTRODUCTION: Colorectal cancer (CRC) is the second-most deadly cancer worldwide. However, there remains a scarcity of precision treatments available for this type of cancer. Amplification or overexpression of human epidermal growth factor receptor 2 (HER2+) is a well-established therapeutic target in gastric and breast cancer. HER2 is positive in approximately 5% of CRC cases and has been implicated in resistance to therapy with anti-epidermal growth factor receptor antibodies. The aim of this study was to evaluate HER2 status in RAS and BRAF wild-type metastatic CRC (mCRC) and its correlation with survival outcomes. MATERIALS AND METHODS: A single-center retrospective analysis of RAS and BRAF wild-type mCRC patients undergoing systemic treatment was conducted from July 2014 to September 2020. Tissue HER2 status was determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) and/or chromogenic in situ hybridization (CISH). HER2+ was defined as IHC3 (+) or IHC2 (+) through FISH or CISH (+). RESULTS: Fifty-nine patients were included. The median age of all the included patients was 64 years (33-82). Four patients had HER2+ tumors (7%). Four patients had HER2+ tumors (7%). The majority of HER2+ mCRC cases were males (n=3) and left-sided CRC (n=3). All patients received FOLFIRI plus cetuximab as first-line treatment. At the median follow-up of 24.0 months, patients with HER2-negative mCRC presented with a median overall survival (mOS) of 39.4 months (95% confidence interval (CI) 32.7-46.0) and the four patients with HER2+ mCRC had a mOS of 20.4 months (95% CI; 9.5-31.3; p=0.07). In HER2-negative patients, the median PFS (mPFS) was 11.3 months (95% CI; 9.2-13.4) vsHER2-positive patients with a mPFS of 10.9 months (95% CI; 1.3-20.4; p=0.47). CONCLUSIONS: To our knowledge, this is the first study reporting HER2+ in mCRC patients in a Portuguese population and the HER2+ rate was consistent with previous studies. Our study suggests that HER2+ may potentially be a marker that is able to predict poor prognosis in RAS and BRAF wild-type mCRC.

NGS Data Repurposing Allows Detection of tRNA Fragments as Gastric Cancer Biomarkers in Patient-Derived Extracellular Vesicles.

Transfer RNA fragments (tRFs) have gene silencing effects similarly to miRNAs, can be sorted into extracellular vesicles (EVs) and are emerging as potential circulating biomarkers for cancer diagnoses. We aimed at analyzing the expression of tRFs in gastric cancer (GC) and understanding their potential as biomarkers. We explored miRNA datasets from gastric tumors and normal adjacent tissues (NATs) from TCGA repository, as well as proprietary 3D-cultured GC cell lines and corresponding EVs, in order to identify differentially represented tRFs using MINTmap and R/Bioconductor packages. Selected tRFs were validated in patient-derived EVs. We found 613 Differentially Expressed (DE)-tRFs in the TCGA dataset, of which 19 were concomitantly upregulated in TCGA gastric tumors and present in 3D cells and EVs, but barely expressed in NATs. Moreover, 20 tRFs were expressed in 3D cells and EVs and downregulated in TCGA gastric tumors. Of these 39 DE-tRFs, 9 tRFs were also detected in patient-derived EVs. Interestingly, the targets of these 9 tRFs affect neutrophil activation and degranulation, cadherin binding, focal adhesion and the cell-substrate junction, highlighting these pathways as major targets of EV-mediated crosstalk with the tumor microenvironment. Furthermore, as they are present in four distinct GC datasets and can be detected even in low quality patient-derived EV samples, they hold promise as GC biomarkers. By repurposing already available NGS data, we could identify and cross-validate a set of tRFs holding potential as GC diagnosis biomarkers.

Adapter dimer contamination in sRNA-sequencing datasets predicts sequencing failure and batch effects and hampers extracellular vesicle-sRNA analysis.

Small RNA (sRNA) profiling of Extracellular Vesicles (EVs) by Next-Generation Sequencing (NGS) often delivers poor outcomes, independently of reagents, platforms or pipelines used, which contributes to poor reproducibility of studies. Here we analysed pre/post-sequencing quality controls (QC) to predict issues potentially biasing biological sRNA-sequencing results from purified human milk EVs, human and mouse EV-enriched plasma and human paraffin-embedded tissues. Although different RNA isolation protocols and NGS platforms were used in these experiments, all datasets had samples characterized by a marked removal of reads after pre-processing. The extent of read loss between individual samples within a dataset did not correlate with isolated RNA quantity or sequenced base quality. Rather, cDNA electropherograms revealed the presence of a constant peak whose intensity correlated with the degree of read loss and, remarkably, with the percentage of adapter dimers, which were found to be overrepresented sequences in high read-loss samples. The analysis through a QC pipeline, which allowed us to monitor quality parameters in a step-by-step manner, provided compelling evidence that adapter dimer contamination was the main factor causing batch effects. We concluded this study by summarising peer-reviewed published workflows that perform consistently well in avoiding adapter dimer contamination towards a greater likelihood of sequencing success.

A prospective cohort study of TIMP1 as prognostic biomarker in gastric and colon cancer.

BACKGROUND: Tissue inhibitor metalloproteinase 1 (TIMP1) inhibits proteins which has proteolytic activity, but in cancer it contributes for tumoral invasion and metastization. The authors investigated the expression of TIMP1 in different digestive cancer types. The aim of this study was to test TIMP1 as a serum marker since in clinical practice there is a lack of biomarkers to monitor the response to treatments or to detect early relapses. METHODS: It was performed a prospective study with recently diagnosed patients with gastrointestinal cancers. Patients with esophageal, gastric, colon, rectal, hepatocarcinoma, and cholangiocarcinoma at any stage, that did not perform any type of treatment, were included. Enzyme-linked immunosorbent assays and chemiluminescence were used to quantify levels of TIMP1. The differences of the Kaplan-Meier survival curves were tested for statistical significance with the log rank test, and the 95% confidence intervals were calculated. Multivariate analysis was done using the COX proportional hazard model and a forward stepwise method. Statistical analyses were done using the IBM SPSS Statistics version 26.0. P value inferior to 0.05 was considered significant. RESULTS: A total of 190 patients were recruited: 54.7% males, median age of 68 years old, 57.9% with colorectal cancer followed by esophagogastric disease with 22.6%. TIMP1 level were increased in 29.5%. In colon cancer, patients with higher levels of TIMP1 are associated with worse progression free survival (PFS) (P=0.007) and overall survival (OS) (P=0.036). No relationship was seen with Rat sarcoma virus (RAS), B-raf (BRAF) and Microsatellite instability status (MSI). In gastric cancer, patients with higher levels of TIMP1 are associated with worse OS (P=0.020), with no difference in PFS. CONCLUSIONS: Higher TIMP1 levels in gastric and colon cancer patients are associated with worse prognosis. Further studies are needed: higher number of patients and sequential measurements of TIMP1 during patient treatments.

The effect of prognostic factors at baseline on the efficacy of trifluridine/tipiracil in patients with metastatic colorectal cancer: A Portuguese exploratory analysis.

BACKGROUND: The RECOURSE trial supported trifluridine/tipiracil as a treatment option in metastatic colorectal cancer (mCRC). Subsequent analysis demonstrated that low tumour burden and indolent disease are good prognosis factors improving progression-free survival (PFS) and overall survival (OS). This study aimed to evaluate the impact of prognosis group in the OS, PFS and safety of trifluridine/tipiracil in patients with mCRC. METHODS: Single-centre, retrospective, and observational study of patients with mCRC who started trifluridine/tipiracil between February 2018 and July 2019. Patients were divided into good prognosis characteristics (GPC) [low tumour burden (less than 3 metastasis site) and indolent disease (≥18 months from first metastasis diagnosis)] and poor prognostic characteristics (PPC) group [high tumour burden (3 or more metastasis sites) and/or aggressive disease (<18 months since the first metastasis diagnosis)]. RESULTS: Median age was 67 years (48-82), 67.3% of the patients were male, and 65.3% had stage IV disease at baseline. Overall, median OS was 7.5 months (95%CI:5.7-9.3). Twenty-two patients (44.9%) presented GPC and 29 (59.1%) had PPC. GPC patients had longer median OS [11.4 (95%CI:6.2-16.7)] versus 3.9 months [(95%CI: 3.3-4.6),p < 0.0001] and PFS [4.9 (95%CI:3.0-6.9) versus 2.6 months (95%CI:2.2-2.8),p < 0.0001]. These differences were more pronounced in GPC patients with no liver metastasis. Grade ≥3 adverse events incidence didn't vary between GPC and PPC subgroups. CONCLUSION: Our study validates the improved trifluridine/tipiracil efficacy in patients with GPC in comparison with PPC while maintaining a well-tolerated safety profile. Indolent disease, low tumour burden and the absence of liver metastasis were shown to be good prognosis factors influencing sustained response to trifluridine/tipiracil.

Metastatic lymph node ratio as a better prognostic tool than the TNM system in colorectal cancer.

Background: The minimum number of lymph nodes that should be evaluated in colon cancer to adequately categorize lymph node status is still controversial. The lymph node ratio (LNR) may be a better prognostic indicator. Materials & methods: We studied 1065 patients treated from 1 January 2000 to 31 August 2012. Results: Significant differences in survival were detected according to regional lymph nodes (pN) (p < 0.001) and LNR (p < 0.001). LRN and pN are independent prognostic factors. Spearman correlation analysis showed a significant correlation between the total number of dissected lymph nodes and pN (rs = 0.167; p < 0.001), but the total number of dissected lymph nodes is not significantly correlated with LNR (rs = -0.019; p = 0.550). Interpretation: In this study, LNR seems to demonstrate a superior prognostic value compared with the pN categories, in part due to its greater independence regarding the extent of lymphadenectomy.

Lay abstract The prognosis of colon cancer is determined by tumor dimensions, number of metastatic lymph nodes and the presence of distant metastasis. Altogether, these criteria comprise the TNM (tumor-node-metastasis) staging system. Some societies consider a minimum of 12 lymph nodes to access the prognosis, but it is not always possible to resect this number of lymph nodes during the surgery. The lymph node ratio, calculated as the division between the number of metastatic lymph nodes and the number of resected lymph nodes, seems to demonstrate a superior prognostic value because it is independent from the extent of lymphadenectomy.

Current opinion about antimicrobial therapy in palliative care: an update.

PURPOSE OF REVIEW: The review englobes the latest studies published regarding the problem of antimicrobial usage with palliative intent. RECENT FINDINGS: In the advanced stages of illness like cancer, dementia, or neurodegenerative diseases, important decisions have to be made concerning the global treatment plan. Infections are very common among this kind of patients as they typically have multiple comorbidities and are incapacitated. These infections, in a majority of the cases, will be treated with antimicrobial therapy because this is a standard medical procedure. For a health professional, the decision of whether to treat, withhold, or withdraw a treatment can be difficult. In fact, in palliative care, the challenge is to balance compassionate care for people suffering from end-of-life diseases with the need for responsible antibiotic usage. Antimicrobial treatment could alleviate symptoms from an infection and make patients more comfortable, on the other hand, its overuse of it could bring a broader public health risk. SUMMARY: On the contrary, in 18 months there are few studies about this problem, what reveals no concern about the use of antimicrobians in end-of-life patients.

Antimicrobial therapy in palliative care: an overview.

In the advanced stages of illness, patients often face challenging decisions regarding their treatment and overall medical care. Terminal ill patients are commonly affected by infections. However, in palliative care, the use of antimicrobials can be an ethical dilemma. Deciding whether to treat, withhold, or withdraw the antimicrobial treatment for an infection can be difficult. Antimicrobial administration can lead to adverse outcomes but the two main benefits, longer survival and symptom relief, are the main reasons why physicians prescribe antimicrobial when treating terminally ill patients. For the patient who has an irreversible advanced heart or lung disease, or an advanced dementia, or a metastatic cancer, it is easier the decision of withholding mechanical ventilation, tube feeding, and dialysis than antibiotherapy. To characterize infections, agents, and their treatments in palliative care, we conducted a review of the literature. We also included some tips to help health professionals to guide their clinical approach.

Bone Metastases: An Overview.

Bone is a frequent site of metastases and typically indicates a short-term prognosis in cancer patients. Once cancer has spread to the bones it can rarely be cured, but often it can still be treated to slow its growth. The majority of skeletal metastases are due to breast and prostate cancer. Bone metastasis is actually much more common than primary bone cancers, especially in adults. The diagnosis is based on signs, symptoms and imaging. New classes of drugs and new interventions are given a better quality of life to these patients and improved the expectancy of life. It is necessary a multidisciplinary approach to treat patients with bone metastasis. In this paper we review the types, clinical approach and treatment of bone metastases.

Association between bevacizumab-related hypertension and response to treatment in patients with metastatic colorectal cancer.

BACKGROUND: Bevacizumab has become standard of care as first-line treatment of metastatic colorectal cancer (mCRC), after proving increased response rates and improvement in survival outcomes. Hypertension (HTN) is a common complication of the treatment with bevacizumab and, owing to its close relation with antiangiogenic mechanism, may represent a clinical biomarker to predict the efficacy of the treatment. The aim of this study was to retrospectively evaluate if HTN grades 2 to 3 were correlated with response to treatment with bevacizumab in first line, as well as with improved progression-free survival (PFS) and overall survival (OS), in a series of patients with mCRC. METHODS: Retrospective evaluation of clinical records of patients with histologically proven mCRC, treated with bevacizumab as first-line treatment, between January 2008 and December 2013. RESULTS: 79 patients were evaluated. 51.9% of patients developed HTN G2-G3 during chemotherapy-bevacizumab treatment. In the group of patients who developed bevacizumab-related HTN, 73.2% showed response to treatment (complete response (CR)+ partial response (PR)) and 97.6% achieved disease control (CR, PR or stable disease) compared to 18.4% of patients with response and 63.2% with disease control in the group that did not (OR 12.08; 95% CI 4.13 to 35.29; p<0.001 responders vs non-responders; OR 20.8; 95% CI 2.56 to 168.91; p 0.005 controlled vs non controlled disease). The median OS was 28 months (22.7-33.3). Significant statistical difference was obtained in PFS between the two groups (p<0.001). In the group that developed bevacizumab-related HTN, the median OS was 33 months (25.7-40.3), and in the group that did not, it was 21 months (16.5-25.5) with no significant statistical difference between the two groups (p 0.114). CONCLUSIONS: In this subset of patients, HTN G2-3 was predictive of response to treatment with bevacizumab and of PFS but not of OS.

Eosinophilic colitis.

A 57-year-old man, diagnosed with colon cancer stage III in July/2010, underwent surgery and received adjuvant chemotherapy with FOLFOX 4 (5-fluorouracil; calcium folinate and oxaliplatin), which ended in March/2011 after 12-cycles. It was then decided to maintain periodical surveillance. About 1 year later, the patient developed several episodes of diarrhoea, mainly during the night, and presented persistent peripheral eosinophilia in the blood count (range 585-1300 eosinophils/µL). Colonoscopy was performed, with the histological result showing eosinophilic infiltration of the colon, compatible with eosinophilic colitis. The patient was treated with a short course of budesonide, achieving resolution of symptoms, and has remained asymptomatic.