Repeat hepatectomy justified in patients with early recurrence of colorectal cancer liver metastases: A systematic review and meta-analysis

BackgroundThe benefit of repeat hepatectomy in patients with early recurrence of colorectal cancer liver metastases (CRLM) is questioned, in particular in those suffering from recurrence within three to six months following initial hepatectomy. The aim of this review was therefore to assess whether disease-free interval was associated with overall survival in patients undergoing repeat hepatectomy for recurrent CRLM.MethodsA systematic review and meta-analysis was conducted, according to PRISMA guidelines. PubMed, Embase and Cochrane Library databases were searched from database inception to 6th June 2020. Observational studies describing results of repeat hepatectomy for recurrent CRLM, including (disease-free) interval between hepatic resections and overall survival were included. Patients undergoing repeat hepatectomy within three months or additional resection of extrahepatic disease were excluded from meta-analysis.ResultsThe initial search identified 2159 records, of which 28 were included for qualitative synthesis. A meta-analysis of 15 cohort studies was performed, comprising 1039 eligible patients. Median overall survival of 54.0 months [95 %-CI: 38.6–69.4] was observed after repeat hepatectomy in patients suffering from recurrent CRLM between three to six months compared to 53.0 months [95 %-CI: 44.3–61.6] for patients with recurrent CRLM between seven to twelve months (adjusted HR = 0.89, 95 %-CI: 0.66–1.18; p = 0.410), and 60.0 months [95 %-CI: 52.7–67.3] for patients with recurrent CRLM after twelve months (adjusted HR = 0.70, 95 %-CI: 0.53−0.92; p = 0.012).ConclusionsDisease-free interval is considered a prognostic factor for overall survival, but should not be used as selection criterion per se for repeat hepatectomy in patients suffering from recurrent CRLM.     

Arginase as a useful factor for the diagnosis of colorectal cancer liver metastases

The present work is a continuation of studies on arginase as a marker in the diagnosis of colorectal cancer liver metastases (CRCLM). The purpose of the study was the evaluation of the arginase test in comparison with other colorectal cancer tests such as CEA, CA 19-9 and biochemical markers of liver function such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The studies were conducted on blood serum from 85 patients with CRCLM obtained one to two days before tumor resection. The control group comprised 140 healthy blood donors and 81 patients with various non-malignant gastrointestinal diseases. Raised arginase activity was observed in serum of 85% of CRCLM patients, whereas elevated levels of CEA and CA 19-9 were found in 63% and 42% of patients, respectively. The combination of CEA or CA 19-9 with the arginase assay improved their sensitivity, but the sensitivity of the combined parameters was not higher than that of the arginase test itself. AST and ALT activities were increased in about 30% of CRCLM patients. The specificity of the arginase test calculated for 221 control subjects was 76%. It can thus be concluded that the determination of serum arginase activity can be helpful in the diagnosis of patients with colorectal cancer liver metastases.     

原发性肝癌患者经肝动脉化疗栓塞术后舌苔菌群变化特征研究

对比分析原发性肝癌（PLC）患者和经肝动脉化疗栓塞术（TACE）后患者舌苔菌群多样性变化和菌群结构差异。

收集我院20例确诊肝癌患者和10例同期体检无异常的健康组（HC组）,根据确诊的肝癌患者治疗期间是否行TACE术,进一步分为原发性肝癌初诊组10例（NL组）,原发性肝癌患者TACE术后患者组10例（LIT组）,总纳入人数30例。采用16S rDNA高通量测序技术分析各组舌苔菌群结构并比较菌群差异。

舌苔菌群ɑ-多样性分析结果显示,NL组、LIT组Chao1、Shannon、Ace、Simpson指数与HC相比,差异无统计学意义（P＞0.05）。β-多样性分析表明,三组样本的舌苔菌群组间结构有差异,与LIT组相比,NL组与HC组的舌苔菌群构成差异更小,更接近于HC组。在科水平上,与HC组相比,NL组和LIT组的消化链球菌科丰度显著升高（P＜0.05）,LIT组的瘤胃球菌科、支原体科、丰度明显下降,差异具有统计学意义（P＜0.05）。与NL组相比,LIT组舌苔拟杆菌纲、普雷沃菌科和瘤胃球菌科丰度显著降低（P＜0.05）。

原发性肝癌患者的舌苔菌群失调,TACE治疗可能一定程度调节舌苔菌群的丰度,降低致病菌,恢复口腔微环境的稳态。

     

Update and review of the multidisciplinary management of stage IV colorectal cancer with liver metastases

Background

The management of stage IV colorectal cancer with liver metastases has historically involved a multidisciplinary approach. In the last several decades, there have been great strides made in the therapeutic options available to treat these patients with advancements in medical, surgical, locoregional and adjunctive therapies available to patients with colorectal liver metastases(CLM). As a result, there have been improvements in patient care and survival. Naturally, the management of CLM has become increasingly complex in coordinating the various aspects of care in order to optimize patient outcomes.

Review

A review of historical and up to date literature was undertaken utilizing Medline/PubMed to examine relevant topics of interest in patients with CLM including criterion for resectability, technical/surgical considerations, chemotherapy, adjunctive and locoregional therapies. This review explores the various disciplines and modalities to provide current perspectives on the various options of care for patients with CLM.

Conclusion

Improvements in modern day chemotherapy as allowed clinicians to pursue a more aggressive surgical approach in the management of stage IV colorectal cancer with CLM. Additionally, locoregional and adjunctive therapies has expanded the armamentarium of treatment options available. As a result, the management of patients with CLM requires a comprehensive, multidisciplinary approach utilizing various modalities and a more aggressive approach may now be pursued in patients with stage IV colorectal cancer with CLM to achieve optimal outcomes.     

Activation of tumor-specific T lymphocytes after laser-induced thermotherapy in patients with colorectal liver metastases

Purpose  To asses if laser-induced thermotherapy (LITT) induces a specific cytotoxic T cell response in patients treated with LITT for colorectal cancer liver metastases. Methods  Eleven patients with liver metastases of colorectal cancer underwent LITT. Blood was sampled before and after LITT. Peripheral T cell activation was assessed by an interferon gamma (IFNg) secretion assay and flow cytometry. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. T cells were stained for CD3/CD4/CD8 and IFNg to detect activated T cells. The ratio of IFNg positive to IFNg negative T cells was determined as the stimulation index (SI). To assess cytolytic activity, T cells were co-incubated with human colorectal cancer cells (CaCo) and cytosolic adenylate kinase release was measured by a luciferase assay. Results  IFNg secretion assay: before LITT SI was 12.73 (±4.83) for CD3+, 4.36 (±3.32) for CD4+ and 3.64 (±1.77) for CD8+ T cells against autologous tumor tissue. Four weeks after LITT SI had increased to 92.09 (±12.04) for CD3+ (P < 0.001), 42.92 (±16.68) for CD4+ (P < 0.001) and 47.54 (±15.68) for CD8+ T cells (P < 0.001) against autologous tumor tissue. No increased SI was observed with normal liver tissue at any time point. Cytotoxicity assay: before LITT activity against the respective cancer cells was low, with RLU = 1,493 (±1,954.68), whereas after LITT cytolytic activity had increased to RLU = 7,260 [±3,929.76 (P < 0.001)]. Conclusion  Patients with liver metastases of colorectal cancer show a tumor-specific cytotoxic T cell stimulation and a significantly increased cytolytic activity of CD3+, CD4+ and CD8+ T cells after LITT against an allogenic tumor (CaCo cell line).     

Current x-ray studies in the diagnosis of colorectal metastases to the liver

Computed tomography was made in 90 patients to reveal the specific features of images of hepatic metastatic foci of colorectal cancer of various sites. All the patients were divided into three groups. Group 1 included patients with rectal cancer; Group 2 comprised patients with sigmoid cancer, and Group 3 consisted of those with transverse colon cancer. The study was performed in native, arterial, and venous, and delayed phases. The number of foci, their localization, sizes, and shape were analyzed. In addition, the density of a focus, its homogeneity, the presence of a cancer rim, inclusion of calcium salts, and outline sharpness were determined. Computed tomography revealed no substantial differences in the image of foci of hepatic metastases from rectal, sigmoid, and transverse colon cancers.     

Oncolytic viral therapy for human colorectal cancer and liver metastases using a multi-mutated herpes simplex virus type-1 (G207).

G207 is a multi-mutated, replication-competent type-1 herpes simplex virus designed to target, infect, and lyse neurological tumors. This study examines the feasibility of using G207 in the treatment of human colorectal cancer and defines the biological determinants of its antitumor efficacy. This virus was tested on five human colorectal cancer cell lines in vitro to determine efficacy of infection and tumor cell kill. These results were correlated to measures of tumor cell proliferation. In vivo testing was performed through direct injections of G207 into xenografts of human colorectal cancer tumors grown in flanks of athymic rats. To evaluate an alternate method of administration, hepatic portal vein infusion of G207 was performed in a syngeneic model of liver metastases in Buffalo rats. Among the five cell lines tested, infection rates ranged between 10% and 90%, which correlated directly with S-phase fraction (8.6%-36.6%) and was proportional to response to G207 therapy in vitro (1%-93%). Direct injection of G207 into nude rat flank tumors suppressed tumor growth significantly vs. control (0.58 +/- 0.60 cm(3) vs. 9.16 +/- 3.70 cm(3), P<0. 0001). In vivo tumor suppression correlated with in vitro effect. In the syngeneic liver tumor model, portal infusion resulted in significant reduction in number of liver nodules (13 +/- 10 nodules in G207-treated livers vs. 80 +/- 30 nodules in control livers, P<0.05). G207 infects and kills human colorectal cancer cells efficiently. In vitro cytotoxicity assay and tumor S-phase fraction can be used to predict response to treatment in vivo. This antineoplastic agent can be delivered effectively by both direct tumor injection and regional vascular infusion. G207 should be investigated further as therapy for colorectal cancer and liver metastases.     

Boron neutron capture therapy (BNCT) for the treatment of liver metastases: biodistribution studies of boron compounds in an experimental model

We previously demonstrated the therapeutic efficacy of different boron neutron capture therapy (BNCT) protocols in an experimental model of oral cancer. BNCT is based on the selective accumulation of (10)B carriers in a tumor followed by neutron irradiation. Within the context of exploring the potential therapeutic efficacy of BNCT for the treatment of liver metastases, the aim of the present study was to perform boron biodistribution studies in an experimental model of liver metastases in rats. Different boron compounds and administration conditions were assayed to determine which administration protocols would potentially be therapeutically useful in in vivo BNCT studies at the RA-3 nuclear reactor. A total of 70 BDIX rats were inoculated in the liver with syngeneic colon cancer cells DHD/K12/TRb to induce the development of subcapsular tumor nodules. Fourteen days post-inoculation, the animals were used for biodistribution studies. We evaluated a total of 11 administration protocols for the boron compounds boronophenylalanine (BPA) and GB-10 (Na(2)(10)B(10)H(10)), alone or combined at different dose levels and employing different administration routes. Tumor, normal tissue, and blood samples were processed for boron measurement by atomic emission spectroscopy. Six protocols proved potentially useful for BNCT studies in terms of absolute boron concentration in tumor and preferential uptake of boron by tumor tissue. Boron concentration values in tumor and normal tissues in the liver metastases model show it would be feasible to reach therapeutic BNCT doses in tumor without exceeding radiotolerance in normal tissue at the thermal neutron facility at RA-3.     

A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer

BACKGROUND/AIMS: To evaluate the safety and feasibility of immunotherapy based on autologous dendritic cells (DC) for patients with unresectable primary liver cancer (PLC). METHODS: A total of ten patients were enrolled and immunized with DCs. Autologous DCs were generated ex vivo in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Cells were then pulsed with tumor lysate (TL), tumor necrosis factor-alpha (TNF-alpha) and keyhole limpet hemocyanin (KLH). Non-adherent cells were collected on day 9 and cells were administered into the inguinal lymph node. Each patient received 1-10 x 10(6) cells four times at weekly intervals. RESULTS: Immunization was well tolerated in all patients without significant toxicity. DC vaccination induced delayed-type hypersensitivity (DTH) against KLH in seven out of ten patients. In one patient, one of the two liver tumors (tumor in segment 7, 13 mm in diameter) decreased in size to 7 mm and showed necrotic change on computed tomography examination after eight immunizations. In two patients, serum levels of tumor markers decreased after vaccination. CONCLUSION: The present clinical trial suggested that immunization by TL-pulsed DCs is feasible in patients with unresectable PLC without any toxicity. Further improvement in the clinical results of immunotherapy might be expected by modifying the therapeutic protocol.     

Surgical treatment of liver metastases of gastric cancer: state of the art

ABSTRACT: BACKGROUND: The prognosis of patients with liver metastases from gastric cancer (LMGC) is dismal, and little is known about prognostic factors in these patients; so justification for surgical resection is still controversial. Furthermore the results of chemotherapy for these patients are disappointing. The purpose of this study was to review recent outcomes of hepatectomy for LMGC and to determine the suitable candidates for surgery, assessing the surgical results and clinicopathologic features. Moreover we compare these results with those obtained with alternative treatments.     

Immune evasion mechanisms in colorectal cancer liver metastasis patients vaccinated with TroVax (MVA-5T4)

We have recently reported the results of a phase II trial in which two TroVax [modified vaccinia ankara (MVA) encoding the tumour antigen 5T4] vaccinations were given to patients both pre- and post-surgical resection of liver metastases secondary to colorectal cancer (CRC). 5T4-specific cellular responses were assessed at the entry and 2 weeks after each vaccination by proliferation of fresh lymphocytes and ELISA for antibody responses; 18 from the 19 CRC patients mounted a 5T4-specific cellular and/or humoral response. Here, we present a comparison of individual and between patient responses over the course of the treatments using cryopreserved peripheral blood mononuclear cells (PBMC) samples from the baseline until after the fourth vaccination at 14 weeks. Assays used were proliferation assay with 5T4-Fc fusion protein, overlapping 32mer 5T4 peptides, MVA-LacZ and MVA-5T4 infected autologous monocytes. Responses to 5T4 protein or one or more peptide pools were pre-existing in 12/20 patients and subsequently 10 and 12 patients showed boosted and/or de novo responses, respectively. Cumulatively, 13/20 patients showed proliferative responses by week 14. We also assessed the levels of systemic T regulatory cells, plasma cytokine levels, phenotype of tumour-infiltrating lymphocytes including T regulatory cells and tumour HLA class I loss of expression. More than half of the patients showed phenotypes consistent with relative immune suppression and/or escape highlighting the complexity of positive and negative factors challenging any simple correlation with clinical outcome.     

Active specific immunotherapy with Newcastle-diseasevirus-modified autologous tumor cells following resection of liver metastases in colorectal cancer

Summary A group of 23 colorectal cancer patients were treated by a new type of active specific immunotherapy (ASI) following complete surgical resection of liver metastases (R0 resection). For ASI treatment we used a vaccine consisting of 1 × 10⁷ autologous, irradiated (200 Gy) metastases-derived tumor cells incubated with 32 hemagglutination units (HU) of Newcastle disease virus (NDV). The adjuvant vaccine therapy was started 2 weeks after surgery and was repeated five times at 14-days intervals followed by one boost 3 months later. The delayed-type hypersensitivity (DTH) skin reactions to the vaccine were measured as well as the DTH reactions to a challenge test of 1 × 10⁷ non-virus-modified autologous tumor cells from liver metastases or 1 × 10⁷ autologous normal liver cells. In addition 32 HU NDV alone and a standard antigen test (Merieux test) were applied pre- and post-vaccination. The vaccination was well tolerated. In 13 of 23 patients an increasing reactivity against the vaccine was observed during the vaccination procedure. Nine patients (40%) experienced an increased DTH reactivity against autologous tumor cells following vaccination, while 17% or fewer showed an increased reactivity to Merieux test antigens, NDV, or normal liver cells. The increased antitumor response was not correlated to responsiveness to NDV alone, autologous liver cells, enzymes and culture medium used for vaccine preparation or standard antigens (Merieux test). After a follow-up of at least 18 months 61% of the vaccinated patients developed tumor recurrence in comparison to 87% of a matched control groups from the same institution that had been only surgically treated. The results of this phase II trial are encouraging and should stimulate further prospective randomized studies.     

Targeting the angiotensin II type 2 receptor (AT2R) in colorectal liver metastases

Background  

Blockade of the angiotensin (ANG) II type 1 receptor (AT1R) inhibits tumour growth in several cancers, including colorectal cancer (CRC) liver metastases. While AT1R blockade has been extensively studied, the potential of targeting the antagonistically acting AT2R in cancer has not been investigated. This study examined the effect of AT2R activation with the agonist CGP42112A in a mouse model of CRC liver metastases.     

Motexafin gadolinium injection for the treatment of brain metastases in patients with non-small cell lung cancer

Despite recent advances in technology, targeting, and chemotherapy, brain metastasis from non-small cell lung cancer (NSCLC) remains a significant problem. The vast majority of patients with this diagnosis undergo whole brain radiation therapy (WBRT). However, outcomes are still quite poor with median survivals measured in only months. In an effort to enhance outcomes from external beam radiation treatments, radiosensitizers have been investigated. Motexafin gadolinium (MGd) (Xcytrin, Sunnyvale, CA, USA) is a novel radiation sensitizer with a unique mechanism of action that may increase the therapeutic index of WBRT for patients with brain metastases, particularly in those with NSCLC histologies. Here we review the rationale for the use of this drug as well as its current and future role as a radiation enhancer in the management of NSCLC brain metastasis.     

Bevacizumab for the treatment of surgically unresectable cervical cord hemangioblastoma: a case report

ABSTRACT: INTRODUCTION: Hemangioblastomas are highly vascular tumors that can arise within the central nervoussystem as well as other organ systems within the body. They can arise sporadically or as partof Von Hippel Lindau syndrome. Those arising in critical locations within the central nervoussystem can be difficult to resect surgically and therefore pose a significant challenge andresult in morbidity and even mortality. Hemangioblastomas express high levels of vascularendothelial growth factor that drives angiogenesis and tumor progression. We hypothesizedthat bevacizumab through its inhibitory effect on vascular endothelial growth factor willresult in hemangioblastoma tumor regression as well as a meaningful clinical response. CASE PRESENTATION: We present the case of a 51-year-old Caucasian man with surgically unresectable cervicalcord hemangioblastoma presenting with progressive weakness leading to quadriparesis. Hewas treated with bevacizumab and his follow up magnetic resonance imaging scans showedmarked tumor regression. After only six cycles of intravenous bevacizumab (10mg/kg everytwo weeks), he started ambulating after being wheelchair bound. He is currently stillreceiving treatment almost two years after initiation of bevacizumab. CONCLUSIONS: We have shown for the first time that bevacizumab can result in significant tumor regressionand a sustained clinical improvement in a patient with an otherwise unresectable spinal cordhemangioblastoma. This novel approach can be immensely useful for patients with difficultto resect hemangioblastomas or those with multiple lesions such as in Von Hippel Lindausyndrome.     

Predictive and prognostic factors in the complex treatment of patients with colorectal cancer

Colon cancer is the second most prevalent lethal cancer. The main cause for high mortality rate is that the prognosis for progressed metastatic colon cancer is most unfavorable. Recent data suggest that disease outcome can be further improved by the addition of targeted biological agents to the first- or second-line treatment. As a result of molecularly targeted anti-EGFR therapies (cetuximab and panitumumab) complementing chemotherapy, liver metastases can reduce in size and become operable in certain patients, which can contribute to the complete recovery of the patient. The main problem, however, is the fact that a positive response only occurs in one third of the patients, even in the case of chemotherapy combined protocol, and the side effects are considerable. For the application of individually tailored treatments, it is an urgent need to develop a system of biomarkers that can predict the effect of treatment and provide information about the optimal selection of both chemotherapy and biological treatment. It should be clarified what the most important requirements of a good and reliable biomarker are. As currently there is no precise predictive molecular diagnostics at our disposal, oncologists have to make one of two choices: they treat a large number of patients with anti-EGFR agents which has negative effects on the quality of life and also reduces the patient's chances of getting appropriate treatment or, if the oncologists refuse to take risks, they omit the use of anti-EGFR treatment in which case those patients for whom this would have been the appropriate treatment are also denied the chance of short-term survival or recovery. Clinical data (response rate, time to progression (TTP) and overall survival (OS)) of 130 colorectal cancer patients have been retrospectively analyzed. Patients have received different chemotherapy protocols in combination with anti-VEGF antibody or with anti-EGFR antibody therapies. EGFR expression was evaluated with immunohistochemistry, KRAS, BRAF and PIK3CA mutations were evaluated by direct sequencing and high resolution melting analysis in the archived formalin-fixed, paraffin-embedded tissue samples. The study found similar efficacy of first-line therapeutic protocols. Protocols combining chemotherapy with biological therapies achieved better overall survival but this difference was not significant (OS: 35.9 versus 36.7 months). The frequency of KRAS mutations was 44% (n=100). None of the KRAS mutant tumors responded to the anti-EGFR monotherapy. TTP in the case of cetuximab monotherapy was twice longer (208 months) than in the KRAS mutant tumors (104 months). One BRAF mutant tumor was also identified (4%) This tumor was also resistant to cetuximab monotherapy. The KRAS and BRAF mutations excluded each other. Except one case, the KRAS status was identical in both the primary tumor and the metastasis. In contrast, PIK3CA mutations were heterogeneous in different tumor samples. In 5 out of 6 cases the mutation status of PIK3CA was different in the primary tumor and the metastasis. New biological therapies provide an additional clinical benefit only for a subset of patients. We need biomarkers to identify these patients. KRAS and most probably BRAF testing can double the efficacy of the anti-EGFR therapies, but we need additional molecular diagnostic tests. PIK3CA is an important candidate but we might need to take biopsy directly from the metastasis or we have to evaluate the circulating tumor cells to judge the molecular status of distant metastasis.