Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.

Background: Cachexia is a body wasting syndrome that significantly affects well-being and prognosis of cancer patients, without effective treatment. Serum metabolites take part in pathophysiological processes of cancer cachexia, but apart from altered levels of select serum metabolites, little is known on the global changes of the overall serum metabolome, which represents a functional readout of the whole-body metabolic state. Here, we aimed to comprehensively characterize serum metabolite alterations and analyze associated pathways in cachectic cancer patients to gain new insights that could help instruct strategies for novel interventions of greater clinical benefit. Methods: Serum was sampled from 120 metastatic cancer patients (stage UICC IV). Patients were grouped as cachectic or non-cachectic according to the criteria for cancer cachexia agreed upon international consensus (main criterium: weight loss adjusted to body mass index). Samples were pooled by cachexia phenotype and assayed using non-targeted gas chromatography-mass spectrometry (GC-MS). Normalized metabolite levels were compared using t-test (p < 0.05, adjusted for false discovery rate) and partial least squares discriminant analysis (PLS-DA). Machine-learning models were applied to identify metabolite signatures for separating cachexia states. Significant metabolites underwent MetaboAnalyst 5.0 pathway analysis. Results: Comparative analyses included 78 cachectic and 42 non-cachectic patients. Cachectic patients exhibited 19 annotable, significantly elevated (including glucose and fructose) or decreased (mostly amino acids) metabolites associating with aminoacyl-tRNA, glutathione and amino acid metabolism pathways. PLS-DA showed distinct clusters (accuracy: 85.6%), and machine-learning models identified metabolic signatures for separating cachectic states (accuracy: 83.2%; area under ROC: 88.0%). We newly identified altered blood levels of erythronic acid and glucuronic acid in human cancer cachexia, potentially linked to pentose-phosphate and detoxification pathways. Conclusion: We found both known and yet unknown serum metabolite and metabolic pathway alterations in cachectic cancer patients that collectively support a whole-body metabolic state with impaired detoxification capability, altered glucose and fructose metabolism, and substrate supply for increased and/or distinct metabolic needs of cachexia-associated tumors. These findings together imply vulnerabilities, dependencies and targets for novel interventions that have potential to make a significant impact on future research in an important field of cancer patient care.

Potential for cure and predictors of long-term survival after radiofrequency ablation for colorectal liver metastases: A 20-years single-center experience.

BACKGROUND: Additional radiofrequency ablation (RFA) of liver-limited colorectal liver metastases (CRLM) improves overall (OS) and recurrence-free survival (RFS) over systemic therapy alone. We aimed to assess the potential and predictive factors of long-term survival and cure to optimize patient selection for RFA application. METHODS: Retrospective review of a prospectively maintained single-center database of consecutive patients undergoing RFA for liver-limited CRLM after systemic therapy between 2002 and 2020. Clinicopathologic characteristics and KRAS/BRAF-genotype data (tested routinely since 2010) were correlated to RFS and OS. Cure was defined as ≥10-years RFS (long-term survival as ≥5-years OS) following RFA. RESULTS: For the entire cohort of 158 patients (median follow-up 13.6 years), co-occurrence of three factors, RECIST-defined response, number of ≤3 CRLM, and ≤3 cm maximum size determined a survival plateau that distinguished cured from non-cured patients (10-years RFS: 15.5% vs 0%, p < 0.0001). Among 59 patients (37.3%) being tested, 4(6.8%) were BRAF-mt, 15(25.4%) KRAS-mt, and 40(67.8%) KRAS/BRAF-wt. OS (median follow-up 8.3 years) was estimated to be higher with KRAS/BRAF-wt compared to a mutant KRAS or BRAF status (5-years OS: 22.8% vs 3.4%, p = 0.0018). CONCLUSION: This study indicates about 15% chance of cure following RFA of low-volume liver-limited CRLM after downsizing by systemic therapy and a negative effect of KRAS or BRAF mutation on long-term survival after CRLM ablation. These findings may improve clinical decision-making in patients potentially candidate to RFA of CRLM and encourage further investigations on molecular factors determining an oligometastatic state of CRLM curable with focal ablative therapy.

MicroRNAs in blood act as biomarkers of colorectal cancer and indicate potential therapeutic targets.

Association studies have linked alterations of blood-derived microRNAs (miRNAs) with colorectal cancer (CRC). Here, we performed a microarray-based comparison of the profiles of 2549 miRNAs in 80 blood samples from healthy donors and patients with colorectal adenomas, colorectal diverticulitis and CRC at different stages. Confirmation by quantitative real-time PCR (RT-PCR) was complemented by validation of identified molecules in another 36 blood samples. No variations in miRNA levels were observed in samples from patients with colorectal adenomas and diverticulitis or from healthy donors. However, there were 179 CRC-associated miRNAs of differential abundance compared to healthy controls. Only three - miR-1225-5p, miR-1207-5p and miR-4459 - exhibited increased levels at all CRC stages. Most deregulated miRNAs (128/179, 71%) specifically predicted metastatic CRC. Pathway analysis found several cancer-related pathways to which the miRNAs contribute in various ways. In conclusion, miRNA levels in blood vary throughout CRC progression and affect cellular functions relevant to haematogenous CRC progression and dissemination. The identified biomarker and therapeutic candidates require further confirmation of their clinical relevance.

[Benign multicystic peritoneal mesothelioma (BMPM) - a surprising differential diagnosis in case of an expected intraabdominal abscess formation]. / Das benigne multizystische peritoneale Mesotheliom (BMPM) ­ Eine überraschende Differenzialdiagnose bei Verdacht auf einen intraabdominellen Abszess.

The benign multicystic peritoneal mesothelioma is a rare disease. Most frequently, young women in reproductive age are affected by this disease. Nevertheless, there are known cases of multicystic peritoneal mesothelioma in male patients. The pathogenesis remains uncertain. Whereas asbestos fibers can cause the development of malignant mesothelioma, the exposure to asbestos particles cannot induce this type of mesothelioma. An inflammatory genesis is discussed as well as the idea of a neoplastic development. Since a high rate of recurrence after surgery is observed, an aggressive surgical treatment is recommended. The complete resection of affected tissue is recently considered to be the therapy of choice. The combination of complete surgical tumor reduction with an intraperitoneal hyperthermic chemotherapy (HIPEC) seems to be promising. Although malignant transformation is detected very rarely a close follow up in centers with high surgical and oncological expertise is recommended.

Impact of Systemic Therapy and Recurrence Pattern on Survival Outcome after Radiofrequency Ablation for Colorectal Liver Metastases.

Background: Most patients undergoing radiofrequency ablation (RFA) of colorectal liver metastasases (CLM) develop disease recurrence, but little is known about the effect of recurrence patterns and/or systemic therapy on outcome. In this study, we examined the recurrence patterns and survival after systemic therapy plus RFA in patients with unresectable CLM without extrahepatic disease. The aims were to analyze the effect of recurrence patterns on survival and to assess the relative benefit contributed by systemic therapy and local ablation to disease control and patient outcome. Methods: From January 2002 to December 2012, 113 patients underwent RFA of liver-limited CLM after systemic therapy. Univariate and multivariate analyses for associations between clinical and/or treatment-related variables, recurrence-free survival (RFS), recurrence patterns, and overall survival (OS) were carried out. Results: Of 113 patients, 105 (92.8%) had disease recurrence (median RFS: 6.1 months). Lower post-recurrence OS was observed after early (≤6 months) than after late recurrence (8.5 versus 24.0 months, p < 0.001). Recurrence sites were RFA-sites only (4.8%), liver-only (57.1%), lung-only (10.5%), or multiple (27.6%); the corresponding post-recurrence OS was 21, 19, 39, and 7 months (p < 0.001), respectively. Response to pre-RFA systemic therapy was the strongest predictor for OS (hazard ratio [HR] 5.28), RFS (HR 3.30), early (odds ratio [OR] 6.34) and multiple-site recurrence (OR 3.83) (p < 0.01), respectively; only responders achieved 5-year OS and RFS (29% and 12% versus 0% and 0% for non-responders, p < 0.001, respectively). Conclusions: Survival after RFA for liver-limited CLM is strongly linked to the timing and pattern of non-local disease recurrence. Local ablation efficacy is necessary but not sufficient to obtain long-term disease control. Effective pre-RFA systemic therapy does favourably affect the incidence, timing and patterns of recurrence and long-term survival and appears essential for the tailoring of RFA application to maximize patient benefit.

Selection criteria for radiofrequency ablation for colorectal liver metastases in the era of effective systemic therapy: a clinical score based proposal.

BACKGROUND: At present, there are no widely accepted criteria for the use of radiofrequency ablation (RFA) for the treatment of colorectal liver metastases (CLM) in the context of effective modern-agent therapies. We aimed to define selection criteria for patients with liver-limited CLM who may benefit from adding RFA to systemic therapy with respect to long-term disease control. METHODS: Between 2002 and 2007, 88 consecutive patients received RFA for liver-only CLM during partial remission (PR), stable disease (SD), or progressive disease (PD) after systemic therapy. At a median follow-up of 8.2 years (range 5.2-11.1 years), clinical data were correlated to overall survival (OS) and recurrence-free survival (RFS). RESULTS: Poor OS and RFS correlated significantly with PD to systemic therapy before RFA (HR 5.46; p < 0.0001; and HR 6.46; p < 0.0001), number of ≥4 CLM (HR 3.13; p = 0.0005; and HR 1.77; p = 0.0389), and carcinoembryonic antigen (CEA) level of ≥100 ng/ml (HR 1.67; p = 0.032; and HR 1.67; p = 0.044). The presence of four criteria (PR, ≤3 CLM, ≤3 cm maximum size, and CEA ≤100 ng/ml) selected a subgroup (n = 23) with significantly higher probabilities for OS and RFS at 5 years (39% and 22%,respectively) compared to those without any or up 3 of these criteria (0-27% and 0-9%, p < 0.001, respectively). CONCLUSIONS: A score based on four criteria (response to systemic therapy, ≤3 CLM, ≤3 cm size, low CEA value) may allow to select patients with liver-only CLM for whom additional use of RFA most likely adds benefit in an attempt to achieve long-term disease control. Almost one-fourth of patients fulfilling these four criteria may achieve 5-year survival without disease recurrence following effective systemic plus local RFA treatment.

Real-time ultrasonography-computed tomography fusion imaging for staging of hepatic metastatic involvement in patients with colorectal cancer: initial results from comparison to US seeing separate CT images and to multidetector-row CT alone.

OBJECTIVES: To prospectively evaluate the role of real-time ultrasonography (US)-computed tomography (CT) fusion imaging (US-CT) in comparison with US seeing separate CT images (US + CT) and multidetector-row CT (MDCT) for the correct staging of hepatic metastatic involvement in patients with colorectal cancer. METHODS: Sixty-four patients with newly diagnosed colorectal cancer and who were referred for abdominopelvic staging before primary tumor resection underwent same-day MDCT, US + CT, and US-CT. Examinations were evaluated on-site by 2 investigators in consensus. Investigators recorded the size and location of detected lesions on segmental liver maps, classified them as being benign, malignant, or indeterminate, and finally assessed the M stage of the liver as being M0, M1, or Mx (indeterminate). All patients underwent surgical exploration including intraoperative US. Reference standard diagnosis was based on findings at surgery, intraoperative US, histopathology, and MDCT follow-up imaging. Differences among investigated modalities were analyzed using McNemar's test. RESULTS: The reference standard verified 109 (45 < or = 1 cm) hepatic lesions in 25 patients, including 65 (25 < or = 1 cm) metastases in 16 patients (M1). Regarding the 45 < or = 1 cm liver lesions, rates for detection were significantly higher (P < 0.05) for MDCT (80%, 36/45) and US-CT (77.8%, 35/45) than for US + CT (64.4%, 29/45); the rate for correct classification by US-CT (71.1%, 32/45) was significantly higher than for US + CT (48.9%, 22/45) and MDCT (31.1%, 14/45) (all P < 0.05). On patient-based analysis, specificity of MDCT (85.4%, 41/48) was significantly lower (P < 0.05) than for US-CT (97.9%, 47/48) and US + CT (93.7%, 45/48); the positive predictive value of MDCT (63.1%, 12/19) was not significantly different (P = 0.27) compared with US + CT (82.3%, 14/17) but significantly lower (P < 0.05) than for US-CT (93.7%, 15/16). In 13 patients (59 lesions) with only benign (stage M0) or coexistent benign and malignant lesions (stage M1), indeterminate lesion ratings and indeterminate liver stagings (Mx) occurred both significantly lower (P < 0.05) with US-CT (3.4%, 2/59; and 0%, 0/13) than with US + CT (11.9%, 7/59; and 23.1%, 3/13) or with MDCT (30.5%, 18/59; and 53.8%, 7/13). CONCLUSIONS: Based on these initial diagnostic experiences, complementary US-CT fusion imaging of small CT-indeterminate liver lesions may have value in staging patients with colorectal cancer, focusing on patients who were likely to harbor only benign or coexisting benign and malignant liver lesions and in whom change of M staging would change the clinical management.