Folinic Acid Potentiates the Liver Regeneration Process after Selective Portal Vein Ligation in Rats

Liver resection remains the gold standard for hepatic metastases. The future liver remnant (FLR) and its functional status are two key points to consider before performing major liver resections, since patients with less than 25% FLR or a Child–Pugh B or C grade are not eligible for this procedure. Folinic acid (FA) is an essential agent in cell replication processes. Herein, we analyze the effect of FA as an enhancer of liver regeneration after selective portal vein ligation (PVL). Sixty-four male WAG/RijHsd rats were randomly distributed into eight groups: a control group and seven subjected to 50% PVL, by ligation of left portal branch. The treated animals received FA (2.5 m/kg), while the rest were given saline. After 36 h, 3 days or 7 days, liver tissue and blood samples were obtained. FA slightly but significantly increased FLR percentage (FLR%) on the 7th day (91.88 ± 0.61%) compared to control or saline-treated groups (86.72 ± 2.5 vs. 87 ± 3.33%; p < 0.01). The hepatocyte nuclear area was also increased both at 36 h and 7days with FA (61.55 ± 16.09 µm2, and 49.91 ± 15.38 µm2; p < 0.001). Finally, FA also improved liver function. In conclusion, FA has boosted liver regeneration assessed by FLR%, nuclear area size and restoration of liver function after PVL.

Liver-Directed Therapy for Neuroendocrine Metastases: From Interventional Radiology to Nuclear Medicine Procedures

Neuroendocrine neoplasms (NENs) are rare and heterogeneous epithelial tumors most commonly arising from the gastroenteropancreatic (GEP) system. GEP-NENs account for approximately 60% of all NENs, and the small intestine and pancreas represent two most common sites of primary tumor development. Approximately 80% of metastatic patients have secondary liver lesions, and in approximately 50% of patients, the liver is the only metastatic site. The therapeutic strategy depends on the degree of hepatic metastatic invasion, ranging from liver surgery or percutaneous ablation to palliative treatments to reduce both tumor volume and secretion. In patients with grade 1 and 2 NENs, locoregional nonsurgical treatments of liver metastases mainly include percutaneous ablation and endovascular treatments, targeting few or multiple hepatic metastases, respectively. In the present work, we provide a narrative review of the current knowledge on liver-directed therapy for metastasis treatment, including both interventional radiology procedures and nuclear medicine options in NEN patients, taking into account the patient clinical context and both the strengths and limitations of each modality.

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.

Gemcitabine Maintenance Therapy in Patients With Metastasized Soft Tissue Sarcomas

BackgroundMetastasized soft-tissue sarcomas still pose a significant therapeutic challenge given the limited efficacy of currently available multimodal treatment strategies. Recent progress in molecular characterization of sarcoma subtypes has enabled successful personalized therapy approaches in a minority of selected patients with targetable mutations. However, in the majority of patients with refractory soft tissue sarcomas, long-term survival remains poor.MethodsWe report on three adult patients with various soft tissue sarcomas subjected to Gemcitabine maintenance therapy. Tumor entities included leiomyosarcoma of the pancreas (patient 1), undifferentiated pleomorphic sarcoma of the right femur (patient 2), and peri-aortic leiomyosarcoma (patient 3). Metastatic sites encompassed liver, lung, and bones. All patients received Gemcitabine maintenance therapy until disease progression following prior salvage chemotherapy with Docetaxel and Gemcitabine. Patients were treated outside of clinical trials. Response assessment was based on radiological imaging.ResultsIn response to salvage chemotherapy with Docetaxel and Gemcitabine, one patient exhibited a partial remission, and two patients showed stable disease. Patient 1 exhibited stable disease for 6 months during Gemcitabine maintenance therapy before suffering rapid progression of hepatic metastases. Patient 2 underwent 21 months of Gemcitabine maintenance therapy, which was discontinued after progressive pulmonary metastases were detected. Patient 3 is still being treated with Gemcitabine maintenance therapy. Remarkably, owing to significant chemotherapy-associated hematotoxicity, the dose of Gemcitabine dose was reduced by two-thirds. Nevertheless, stable disease with constant pulmonary metastases has been maintained in this patient for 14 months.ConclusionsGemcitabine maintenance therapy following prior Docetaxel and Gemcitabine chemotherapy is manageable and reveals potential benefits for patients with aggressive metastasized soft tissue sarcomas. Prospective trials evaluating Gemcitabine maintenance therapy are encouraged.

Peptide receptor radionuclide therapy as a tool for the treatment of severe hypoglycemia in patients with primary inoperable insulinoma

Objectives Severe hypoglycemia in a course of inoperable insulinoma may be life-threating and often it is not well controlled, even by high doses of diazoxide requiring second line treatment. Among available methods PRRT is characterized by relatively low toxicity and is connected with favorable antitumor effect. The aim of the study was an evaluation of the PRRT effectiveness in control of hypoglycemia in patients with primary inoperable insulinoma. Methods Three patients (female with metastatic insulinoma, male with primary inoperable pancreatic tumor, female with MEN1 syndrome and hepatic metastases) were treated with PRRT due to severe hypoglycemia poorly controlled by diazoxide in course of primary inoperable insulinoma. Results Patient 1 baseline fasting glucose concentration increased from 2.4 mmol/L [3.30–5.60] to 5.9 mmol/L after PRRT. In patient 2 fasting glucose level 2.30 mmol/L increased after PRRT to 7.0 mmol/L, while baseline insulin level initially 31.15 uU/mL [2.6–24.9] decreased to 15.4 uU/mL. In patients 3, baseline fasting glucose level 2.5 mmol/L increased after PRRT to 7.9 mmol/L, and insulin decreased from 57.9 uU/mL to 6.3 uU/mL. In imaging there was partial response (PR) in patient 1 and 2 and stabilization of the tumor size in patient 3. In patient 2 reduction of tumor infiltration let for curative surgery performed 4 months after PPRT. Conclusions PRRT may be effective as a first or second line treatment in management of hypoglycemia for patients with hormonally active inoperable insulinoma.

Diagnostic Benefit of High b-Value Computed Diffusion-Weighted Imaging in Patients with Hepatic Metastasis

Diffusion-weighted imaging (DWI) has rapidly become an essential tool for the detection of malignant liver lesions. The aim of this study was to investigate the usefulness of high b-value computed DWI (c-DWI) in comparison to standard DWI in patients with hepatic metastases. In total, 92 patients with histopathologic confirmed primary tumors with hepatic metastasis were retrospectively analyzed by two readers. DWI was obtained with b-values of 50, 400 and 800 or 1000 s/mm2 on a 1.5 T magnetic resonance imaging (MRI) scanner. C-DWI was calculated with a monoexponential model with high b-values of 1000, 2000, 3000, 4000 and 5000 s/mm2. All c-DWI images with high b-values were compared to the acquired DWI sequence at a b-value of 800 or 1000 s/mm2 in terms of volume, lesion detectability and image quality. In the group of a b-value of 800 from a b-value of 2000 s/mm2, hepatic lesion sizes were significantly smaller than on acquired DWI (metastases lesion sizes b = 800 vs. b 2000 s/mm2: mean 25 cm3 (range 10–60 cm3) vs. mean 17.5 cm3 (range 5–35 cm3), p < 0.01). In the second group at a high b-value of 1500 s/mm2, liver metastases were larger than on c-DWI at higher b-values (b = 1500 vs. b 2000 s/mm2, mean 10 cm3 (range 4–24 cm3) vs. mean 9 cm3 (range 5–19 cm3), p < 0.01). In both groups, there was a clear reduction in lesion detectability at b = 2000 s/mm2, with hepatic metastases being less visible compared to c-DWI images at b = 1500 s/mm2 in at least 80% of all patients. Image quality dropped significantly starting from c-DWI at b = 3000 s/mm2. In both groups, almost all high b-values images at b = 4000 s/mm2 and 5000 s/mm2 were not diagnostic due to poor image quality. High c-DWI b-values up to b = 1500 s/mm2 offer comparable detectability for hepatic metastases compared to standard DWI. Higher b-value images over 2000 s/mm2 lead to a noticeable reduction in imaging quality, which could hamper diagnosis.

Impact of Metformin Use on Survival in Patients Undergoing Liver Resection for Colorectal Cancer Metastases

Introduction Resection of colorectal liver metastases provides the best chance for survival in patients with Stage IV colorectal cancer; however, hepatic recurrence is frequent and the main cause of death. Multiple epidemiological studies have documented an association between metformin and anti-neoplastic effects in a variety of cancers. Given the vast literature, we evaluated the incidence on recurrence and survival of patients on metformin who undergo surgery for colorectal liver metastasis (CRLM). Methods We selected 270 consecutive patients with known CRLM who underwent hepatic metastases resection at our institution between January 1st 2012 and December 31st 2019. Patients were divided based on their use of metformin (n = 62) or no metformin (n = 208). Adjusted analysis of recurrence-free (RFS) and overall survival (OS) was performed. Results Patients on metformin had significantly longer RFS (HR: .44, 95% CI: .26-.75, P < .002; Median RFS: 49 months vs 33 months) and OS (HR .60, 95% CI .31-.97, P < .048, Median OS: 72 months vs 60 months). Additional factors associated with shorter RFS on univariate analysis included the following: CEA > 200 ng/ml (HR: 2.23, 95% CI 1.21-4.03, P < .010), positive liver margin (HR: 3.70, 95% CI 2.27-6.03, P < .001), and >1 tumor (HR: 1.98, 95% CI 1.26-3.09, P < .003). Liver margin remained a significant factor for predicting shorter OS (HR: 4.99, 95% CI 2.49-10.0, P < .001). Conclusion In this study, we found that patients with CRLM on metformin have prolonged RFS and OS postliver resection. Further prospective randomized trials need to be carried out to evaluate the anti-neoplastic effect of metformin in diabetic and non-diabetic cancer patients.

Circulating Tumor DNA as a Predictive Marker of Recurrence for Patients With Stage II-III Breast Cancer Treated With Neoadjuvant Therapy

BackgroundPatients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been proven to be a marker of disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).MethodsPlasma was sampled at the initial diagnosis (defined as before NAT) and after breast surgery and neoadjuvant therapy(defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. ctDNA positivity was marked by the detection of alterations, such as mutations and copy number variations.ResultsA total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients exhibited ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p &lt; 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, patients who did not achieve pCR were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.ConclusionsThis study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.