Distant Metastasis in Colorectal Cancer Patients-Do We Have New Predicting Clinicopathological and Molecular Biomarkers? A Comprehensive Review.

Colorectal cancer (CRC) remains a serious health problem worldwide. Approximately half of patients will develop distant metastasis after CRC resection, usually with very poor prognosis afterwards. Because patient performance after distant metastasis surgery remains very heterogeneous, ranging from death within 2 years to a long-term cure, there is a clinical need for a precise risk stratification of patients to aid pre- and post-operative decisions. Furthermore, around 20% of identified CRC cases are at IV stage disease, known as a metastatic CRC (mCRC). In this review, we overview possible molecular and clinicopathological biomarkers that may provide prognostic and predictive information for patients with distant metastasis. These may comprise sidedness of the tumor, molecular profile and epigenetic characteristics of the primary tumor and arising metastatic CRC, and early markers reflecting cancer cell resistance in mCRC and biomarkers identified from transcriptome. This review discusses current stage in employment of these biomarkers in clinical practice as well as summarizes current experience in identifying predictive biomarkers in mCRC treatment.

Dermatomyositis with anti-TIF-1γ antibodies as a presenting symptom of underlying triple-negative breast cancer: a case report.

BACKGROUND: Dermatomyositis is an autoimmune myopathy characterized by proximal muscle weakness, muscle inflammation, and typical skin findings. It is a rare disease with an incidence of ~1/100 000. About 15-30 % of adult-onset cases are caused by underlying malignancy and dermatomyositis can be the first symptom of undiagnosed cancer, mainly in the case of anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies presence. TIF-1γ is a transcriptional cofactor which is implicated in TGFß signaling pathway that controls cell proliferation, differentiation, apoptosis, and tumorigenesis. Its expression was shown to be associated with younger age, higher tumor grade, more estrogen receptor negativity, tumors larger than 2 cm, and tendency towards poor outcome in early breast cancer. No association between anti-TIF-1γ antibodies and prognosis has been proposed yet. CASE PRESENTATION: We report a case of a 43-year-old premenopausal woman presenting with the symptoms of systemic rheumatic disease, the most prominent being a typical skin rash and muscle pain. After a series of investigations, the patient was diagnosed with anti-TIF-1γ positive dermatomyositis and concurrent triple-negative breast cancer (cT1c N3c M0) as an underlying cause. Immediate intravenous corticosteroid therapy relieved the symptoms and enabled anticancer therapy to be commenced. Considering the tumor stage, neoadjuvant therapy with 4 courses of AC (Doxorubicin/Cyclophosphamide) followed by 4 courses of Paclitaxel/Carboplatin was administered. However, no tumor regression was documented and radiotherapy was chosen as the definitive treatment. CONCLUSION: Early detection of anti-TIF-1γ autoantibodies can contribute to a rapid diagnosis of tumor-associated dermatomyositis and enable immediate anticancer treatment. We demonstrate the emerging role of anti-TIF-1γ antibodies in the diagnostics of tumor-associated dermatomyositis. Furthermore, we propose a potential role of anti-TIF-1γ antibodies as a prognostic marker in early breast cancer patients.

Treatment possibilities of ipilimumab-induced thrombocytopenia--case study and literature review.

Recently, new drugs targeting the immune system have been introduced to the standard care of metastatic malignant melanoma. One of these immunomodulatory drugs is ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4. The following case reports on a 54-year-old man with metastatic melanoma, who developed Grade 4 thrombocytopenia during treatment with ipilimumab already after first dose. Bone marrow examination confirmed a diagnosis of drug-induced, immune-mediated thrombocytopenia. Isolated thrombocytopenia has rarely been associated with ipilimumab and there is no standard treatment algorithm of such complication. This case demonstrates the importance of monitoring full blood count in all patients receiving ipilimumab and suggests a possible treatment algorithm.

Extracorporeal Elimination of Circulating Pegylated Liposomal Doxorubicin (PLD) to Enhance the Benefit of Cytostatic Therapy in Platinum-Resistant Ovarian Cancer Patients.

Ovarian cancer is the fifth most common malignancy in the world's female population and with the highest lethality index among gynecological tumors. The prognosis of metastatic disease is usually poor, especially in platinum-resistant cases. There are several options for the treatment of metastatic disease resistant to platinum derivates (e.g. paclitaxel, topotecan and pegylated liposomal doxorubicin), all of which are considered equipotent. Pegylated liposomal doxorubicin (PLD) is a liposomal form of the anthracycline antibiotic doxorubicin. It is characterized by more convenient pharmacokinetics and a different toxicity profile. Cardiotoxicity, the major adverse effect of conventional doxorubicin, is reduced in PLD as well as hematotoxicity, alopecia, nausea and vomiting. Skin toxicity and mucositis, however, emerge as serious issues since they represent dose and schedule-limiting toxicities. The pharmacokinetics of PLD (prolonged biological half-life and preferential distribution into tumor tissue) provide new possibilities to address these toxicity issues. The extracorporeal elimination of circulating liposomes after PLD saturation in the tumor tissue represents a novel and potent strategy to diminish drug toxicity. This article intends to review PLD characteristics and the importance of extracorporeal elimination to enhance treatment tolerance and benefits.

The outcome in patients with BRAF-mutated metastatic melanoma treated with anti-programmed death receptor-1 monotherapy or targeted therapy in the real-world setting.

BACKGROUND: Immunotherapy and targeted therapy are currently two alternative backbones in the therapy of BRAF-mutated malignant melanoma. However, predictive biomarkers that would help with treatment selection are lacking. METHODS: This retrospective study investigated outcomes of anti-programmed death receptor-1 monotherapy and targeted therapy in the first-line setting in patients with metastatic BRAF-mutated melanoma, focusing on clinical and laboratory parameters associated with treatment outcome. RESULTS: Data from 174 patients were analysed. The median progression-free survival (PFS) was 17.0 months (95% CI; 8-39) and 12.5 months (95% CI; 9-14.2) for immunotherapy and targeted therapy, respectively. The 3-year PFS rate was 39% for immunotherapy and 25% for targeted therapy. The objective response rate was 72% and 51% for targeted therapy and immunotherapy. The median overall (OS) survival for immunotherapy has not been reached and was 23.6 months (95% CI; 16.1-38.2) for targeted therapy, with a 3-year survival rate of 63% and 40%, respectively. In a univariate analysis, age < 70 years, a higher number of metastatic sites, elevated serum LDH and a neutrophil-lymphocyte ratio above the cut-off value were associated with inferior PFS regardless of the therapy received, but only serum LDH level and the presence of lung metastases remained significant predictors of PFS in a multivariate analysis. CONCLUSIONS: Present real-world data document the high effectiveness of immunotherapy and targeted therapy. Although targeted therapy had higher response rates, immunotherapy improved PFS and OS. While the prognostic value of LDH was confirmed, the potential use of blood cell count-derived parameters to predict outcomes needs further investigation.

MUC13-miRNA-4647 axis in colorectal cancer: Prospects to identifications of risk factors and clinical outcomes.

MUC13, a transmembrane mucin glycoprotein, is overexpressed in colorectal cancer (CRC), however, its regulation and functions are not fully understood. It has been shown that MUC13 protects colonic epithelial cells from apoptosis. Therefore, studying MUC13 and MUC13-regulated pathways may reveal promising therapeutic approaches for CRC treatment. Growing evidence suggests that microRNAs (miRs) are involved in the development and progression of CRC. In the present study, the MUC13-miR-4647 axis was addressed in association with survival of patients. miR-4647 is predicted in silico to bind to the MUC13 gene and was analyzed by RT-qPCR in 187 tumors and their adjacent non-malignant mucosa of patients with CRC. The impact of previously mentioned genes on survival and migration abilities of cancer cells was validated in vitro. Significantly upregulated MUC13 (P=0.02) in was observed tumor tissues compared with non-malignant adjacent mucosa, while miR-4647 (P=0.05) showed an opposite trend. Higher expression levels of MUC13 (log-rank P=0.05) were associated with worse patient's survival. The ectopic overexpression of studied miR resulted in decreased migratory abilities and worse survival of cells. Attenuated MUC13 expression levels confirmed the suppression of colony forming of CRC cells. In summary, the present data suggested the essential role of MUC13-miR-4647 in patients' survival, and this axis may serve as a novel therapeutic target. It is anticipated MUC13 may hold significant potential in the screening, diagnosis and treatment of CRC.

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer.

Despite distant metastases being the critical factor affecting patients' survival, they remain poorly understood. Our study thus aimed to molecularly characterize colorectal cancer liver metastases (CRCLMs) and explore whether molecular profiles differ between Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. This characterization was performed by whole exome sequencing, whole transcriptome, whole methylome, and miRNAome. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. Among the differently methylated and expressed genes were those involved in cell adhesion, extracellular matrix organization and degradation, neuroactive ligand-receptor interaction. The top up-regulated microRNAs were hsa-miR-135b-3p and -5p, and the hsa-miR-200-family while the hsa-miR-548-family belonged to the top down-regulated. MmCRC patients evinced higher tumor mutational burden, a wider median of duplications and deletions, and a heterogeneous mutational signature than SmCRC. Regarding chronicity, a significant down-regulation of SMOC2 and PPP1R9A genes in SmCRC compared to MmCRC was observed. Two miRNAs were deregulated between SmCRC and MmCRC, hsa-miR-625-3p and has-miR-1269-3p. The combined data identified the IPO5 gene. Regardless of miRNA expression levels, the combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signaling pathways, and intracellular second messenger signaling. The intersection between our and validation sets confirmed the validity of our results. We have identified genes and pathways that may be considered as actionable targets in CRCLMs. Our data also provide a valuable resource for understanding molecular distinctions between SmCRC and MmCRC. They have the potential to enhance the diagnosis, prognostication, and management of CRCLMs by a molecularly targeted approach.

The dynamics of telomere length in primary and metastatic colorectal cancer lesions.

Telomeric sequences, the structures comprised of hexanucleotide repeats and associated proteins, play a pivotal role in chromosome end protection and preservation of genomic stability. Herein we address telomere length (TL) dynamics in primary colorectal cancer (CRC) tumour tissues and corresponding liver metastases. TL was measured by multiplex monochrome real-time qPCR in paired samples of primary tumours and liver metastases along with non-cancerous reference tissues obtained from 51 patients diagnosed with metastatic CRC. Telomere shortening was observed in the majority of primary tumour tissues compared to non-cancerous mucosa (84.1%, p < 0.0001). Tumours located within the proximal colon had shorter TL than those in the rectum (p < 0.05). TL in liver metastases was not significantly different from that in primary tumours (p = 0.41). TL in metastatic tissue was shorter in the patients diagnosed with metachronous liver metastases than in those diagnosed with synchronous liver metastases (p = 0.03). The metastatic liver lesions size correlated with the TL in metastases (p < 0.05). Following the neoadjuvant treatment, the patients with rectal cancer had shortened telomeres in tumour tissue than prior to the therapy (p = 0.01). Patients with a TL ratio between tumour tissue and the adjacent non-cancerous mucosa of ≥ 0.387 were associated with increased overall survival (p = 0.01). This study provides insights into TL dynamics during progression of the disease. The results show TL differences in metastatic lesions and may help in clinical practice to predict the patient's prognosis.

Prognostic value of blood cell count-derived ratios in BRAF-mutated metastatic melanoma.

BACKGROUND: The treatment and prognosis of metastatic melanoma have changed during the last decade to include immunotherapy or targeted therapy as standard therapeutic options for BRAF-mutated melanoma. However, predictive and/or prognostic markers are lacking, especially in clinical situations where several options are available. The aim of this study was to determine the association of pre-therapeutic blood cell count-derived ratios (BCDR) with survival in patients with BRAF-mutated metastatic melanoma. METHODS: We evaluated the prognostic role of BCDR in therapy-naïve patients with BRAF-mutated metastatic melanoma treated with immune checkpoint inhibitors or targeted therapy. The impact of BCDR on survival was analysed using univariate and multivariate Cox proportional hazard models. RESULTS: We enrolled 46 patients treated with BRAF inhibitors and 20 patients who received anti-PD-1 checkpoint inhibitors. The median progression-free survival (PFS) and overall survival (OS) were 8.3 and 18.2 months, respectively, with no statistical difference between groups. The objective response rate was 39% (30% in the anti-PD-1 and 44% in the targeted therapy groups). Baseline BCDR values were associated with improved PFS and OS in the immunotherapy group. Only the platelet-to-lymphocyte ratio (PLR) was associated with OS and PFS in the targeted therapy group. Independent prognostic indicators for PFS were lactate dehydrogenase, PLR and the lymphocyte-to-monocyte ratio (LMR) and those for OS were LMR, toxicity and the number of initial metastases. CONCLUSION: BCDR had a substantial prognostic value in patients with BRAF-mutated metastatic melanoma treated with immune checkpoint inhibitors. However, a prognostic role for BCDR seemed less apparent in patients treated with targeted therapies.

Risk Factors for Infections, Antibiotic Therapy, and Its Impact on Cancer Therapy Outcomes for Patients with Solid Tumors.

Infections represent a significant cause of morbidity and mortality in cancer patients. Multiple factors related to the patient, tumor, and cancer therapy can affect the risk of infection in patients with solid tumors. A thorough understanding of such factors can aid in the identification of patients with substantial risk of infection, allowing medical practitioners to tailor therapy and apply prophylactic measures to avoid serious complications. The use of novel treatment modalities, including targeted therapy and immunotherapy, brings diagnostic and therapeutic challenges into the management of infections in cancer patients. A growing body of evidence suggests that antibiotic therapy can modulate both toxicity and antitumor response induced by chemotherapy, radiotherapy, and especially immunotherapy. This article provides a comprehensive review of potential risk factors for infections and therapeutic approaches for the most prevalent infections in patients with solid tumors, and discusses the potential effect of antibiotic therapy on toxicity and efficacy of cancer therapy.

Clinicopathological Characteristics and Prognostic Factors in Ovarian Metastases from Right- and Left-Sided Colorectal Cancer.

BACKGROUND: Secondary tumors of the ovary (STOs) account for 10-25% of all ovarian malignancies, including metastases from primary gynecological tumors. Colorectal cancer (CRC) has been recognized as one of the most common causes of STOs in Western countries. Despite it being well-known that CRC originating from the right versus left side of the colon/rectum differ substantially, there is a paucity of information regarding the effect of the primary tumor sidedness on the clinicopathological characteristics of STOs. METHODS: This retrospective, observational chart review study included patients with histologically confirmed STOs of CRC origin diagnosed between January 2000 and December 2019. The clinicopathological characteristics of STOs originating from left-sided and right-sided CRC were compared. Univariable and multivariable analyses employing elastic net Cox proportional hazard models were used to evaluate potential prognostic factors. Further, the role of imaging methods in STOs diagnostics was evaluated. RESULTS: Fifty-one patients with STOs of colorectal origin were identified. The primary tumor originated in the right and left colon/rectum in 39% and 61% of the cases, respectively. STOs originating from right-sided primary tumors were more frequently bilateral, associated with peritoneal carcinomatosis, had the ovarian surface affected by the tumor, and contained a mucinous component. The independent prognostic factors for overall survival in the whole cohort included: the presence of macroscopic residual disease after cytoreductive surgery, menopausal status, the application of systemic therapy, and the application of targeted therapy. In 54% of cases, the imaging methods failed to determine the laterality of the STOs correctly as compared to pathological reports and/or intraoperative findings. CONCLUSION: STOs originating from left-sided and right-sided CRC show distinct clinicopathological characteristics. Moreover, different metastatic pathways might be employed according to the primary tumor sidedness. Considering the discrepancies between radiological assessment and histopathological findings regarding the laterality of STOs, bilateral adnexectomy should be advised whenever feasible.

Administration of Nivolumab in Metastatic Renal Cell Cancer Following Treatment With mTOR Inhibitors.

BACKGROUND/AIM: Immunotherapy with checkpoint inhibitors is currently considered a cornerstone of metastatic renal clear cell cancer (mRCC) therapy. Despite the general improvement in the survival of patients with mRCC, there are some clinical situations that have not been specifically evaluated in clinical trials, such as the use of everolimus before nivolumab. PATIENTS AND METHODS: We performed a retrospective analysis evaluating the efficacy of nivolumab in the real-world setting, including a subset of patients with previous mTOR inhibitor therapy. RESULTS: From a total of 56 patients, 25 were pre-treated with everolimus before receiving nivolumab. The overall progression-free survival (PFS), overall survival (OS), and objective response rate were 10.3, 21.3 months, and 34%, respectively. There were no statistically significant differences in patients who were or were not pre-treated with everolimus. CONCLUSION: mRCC patients should be treated with checkpoint inhibitors and prior use of mTOR inhibitors should not be a definitive exclusion criterium.

Combined Therapy of Locally Advanced Oesophageal and Gastro-Oesophageal Junction Adenocarcinomas: State of the Art and Aspects of Predictive Factors.

The following main treatment approaches are currently used in locally advanced adenocarcinomas of the oesophagus and gastrooesophageal junction (GOJ): preoperative chemoradiotherapy and surgery, and perioperative chemotherapy and surgery. While preoperative chemoradiotherapy is used primarily in oesophageal tumours, perioperative chemotherapy is the treatment of choice in Western countries for gastric cancer. The optimal treatment strategy for GOJ adenocarcinoma is still not clear. In comparison to other malignancies, biomarkers are used as predictive factors in distal oesophageal and GOJ adenocarcinomas in a very limited way, and moreover, only in metastatic stages (e.g., HER2 status, or microsatellite instability status). The aim of the article is to provide an overview of current treatment options in locally advanced adenocarcinomas of oesophagus and GOJ based on the latest evidence, including the possible potential of predictive biomarkers in optimizing treatment.

Erratum: Filip, S.; et al. Therapeutic Apheresis, Circulating PLD, and Mucocutaneous Toxicity: Our Clinical Experience through Four Years. Pharmaceutics 2020, 12, 940.

The following correction has been made to this paper [...].

Therapeutic Apheresis, Circulating PLD, and Mucocutaneous Toxicity: Our Clinical Experience through Four Years.

Cancer treatment has been greatly improved by the combined use of targeted therapies and novel biotechnological methods. Regarding the former, pegylated liposomal doxorubicin (PLD) has a preferential accumulation within cancer tumors, thus having lower toxicity on healthy cells. PLD has been implemented in the targeted treatment of sarcoma, ovarian, breast, and lung cancer. In comparison with conventional doxorubicin, PLD has lower cardiotoxicity and hematotoxicity; however, PLD can induce mucositis and palmo-plantar erythrodysesthesia (PPE, hand-foot syndrome), which limits its use. Therapeutical apheresis is a clinically proven solution against early PLD toxicity without hindering the efficacy of the treatment. The present review summarizes the pharmacokinetics and pharmacodynamics of PLD and the beneficial effects of extracorporeal apheresis on the incidence of PPE during chemoradiotherapy in cancer patients.

Plasmafiltration as an effective method in the removal of circulating pegylated liposomal doxorubicin (PLD) and the reduction of mucocutaneous toxicity during the treatment of advanced platinum-resistant ovarian cancer.

PURPOSE: The present study evaluates the safety and efficacy of double-plasma filtration (PF) to remove the exceeding pegylated liposomal doxorubicin (PLD) in circulation, thus reducing mucocutaneous toxicity. METHODS: A total of 16 patients with platinum-resistant ovarian cancer were treated with 50 mg/m2 PLD applied in 1-h IV infusion every 28 days. PF was scheduled at 44-46 h post-infusion. The concentration of plasma PLD and non-liposomal doxorubicin (NLD) was monitored with high-performance liquid chromatography at 116 h post-infusion. A non-linear method for mixed-effects was used in the population pharmacokinetic model. The dose fraction of PLD eliminated by the patient prior to PF was compared with the fraction removed by PF. PLD-related toxicity was recorded according to CTCAE v4.0 criteria and compared to historical data. Anticancer effects were evaluated according to RECIST 1.1 criteria. RESULTS: The patients received a median of 3 (2-6) chemotherapy cycles. A total of 53 cycles with PF were evaluated, which removed 31% (10) of the dose; on the other hand, the fraction eliminated prior to PF was of 34% (7). Exposure to NLD reached only 10% of exposure to the parent PLD. PLD-related toxicity was low, finding only one case of grade 3 hand-foot syndrome (6.7%) and grade 1 mucositis (6.7%). Other adverse effects were also mild (grade 1-2). PF-related adverse effects were low (7%). Median progression-free survival (PFS) and overall survival (OS) was of 3.6 (1.5-8.1) and 7.5 (1.7-26.7) months, respectively. Furthermore, 33% of the patients achieved stable disease (SD), whereas that 67% progressed. CONCLUSION: PF can be considered as safe and effective for the extracorporeal removal of PLD, resulting in a lower incidence of mucocutaneous toxicity.

Nivolumab induced encephalopathy in a man with metastatic renal cell cancer: a case report.

BACKGROUND: Great progress has recently been made in the treatment of metastatic renal cell carcinoma, including the introduction of nivolumab, an immune checkpoint inhibitor. Despite promising results, this treatment brings a completely new spectrum of adverse events, distinct from those experienced with small-molecule kinase inhibitors. Neurologic immune-related adverse events may be serious and potentially life-threatening complications requiring immediate immunosuppressive therapy. Only a few cases of immune-related encephalitis induced by checkpoint inhibitors have been described and the data regarding the management of this serious adverse event are limited. CASE PRESENTATION: We report the case of a 63-year-old white man with metastatic renal cancer who developed severe chorea-like dyskinesia during nivolumab therapy. The findings on brain magnetic resonance imaging and flow cytometry of cerebrospinal fluid, and the positivity of anti-paraneoplastic antigen Ma2 immunoglobuline G class autoantibodies were consistent with a diagnosis of immune-related encephalitis. High-dose intravenous corticosteroid therapy was started immediately, with no signs of improvement, even when infliximab was added. Our patient refused further hospitalization and was discharged. Three weeks later, he presented with signs of severe urosepsis. Despite intensive treatment, he died 4 days after admission. CONCLUSIONS: The management of less frequent immune-related adverse events has not been fully established and more information is required to provide uniform recommendations. Immune-related encephalitis is a severe and potentially fatal complication requiring immediate hospital admission and extensive immunosuppressive therapy. The examination of cerebrospinal fluid for paraneoplastic antibodies, such as anti-N-methyl-D-aspartate receptor and anti-Ma2 antibodies, in order to distinguish autoimmune etiology from other possible causes is essential and highly recommended.

The pathogenesis, diagnosis, and management of metastatic tumors to the ovary: a comprehensive review.

Secondary tumors of the ovary account for 10-25% of all ovarian malignancies. The most common tumors that give rise to ovarian metastases include breast, colorectal, endometrial, stomach, and appendix cancer. The correct diagnosis of secondary ovarian tumors may be challenging as they are not infrequently misdiagnosed as primary ovarian cancer, particularly in the case of mucinous adenocarcinomas. The distinction from the latter is essential, as it requires different treatment. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extra-ovarian metastases and, furthermore, may suggest the primary tumor site. Despite extensive study, some cases remain equivocal even after assessing a broad spectrum of antigens. Therefore, gene expression profiling represents an approach able to further discriminate equivocal findings, and one that has been proven effective in determining the origin of cancer of unknown primary site. The available data concerning secondary ovarian tumors is rather limited owing to the relative heterogeneity of this group and the practical absence of any prospective trials. However, several intriguing questions are encountered in daily practice, including rational diagnostic workup, the role of cytoreductive surgery, and consequent adjuvant chemotherapy. This review seeks to address these issues comprehensively and summarize current knowledge on the epidemiology, pathogenesis, and management of secondary ovarian tumors, including further discussion on the different pathways of metastatisation, metastatic organotropism, and their possible molecular mechanisms.

Microsatellite instability in melanoma: a comprehensive review.

Microsatellite instability (MSI) and mismatch repair deficiency are an emerging issue in oncology and molecular pathology. Besides being associated with better clinical outcome in colon cancer, MSI also harbors the potential to predict response to chemotherapy and immunotherapy. MSI was also observed in other solid tumors, including endometrial cancer, ovarian cancer, and melanoma, besides colon cancer. Strong evidence shows that MSI is a frequent event in melanoma. However, the data on MSI prevalence, pathogenesis, and clinical consequences in melanoma are limited. Therefore, we summarize the current knowledge on MSI in melanoma and outline future perspectives and clinical implications, including its role as a prognostic and/or a predictive factor.

Microsatellite instability as a predictive factor for immunotherapy in malignant melanoma.

Immunotherapy has attracted attention as a novel treatment modality for malignant melanoma. Although the use of immunotherapy in metastatic melanoma has shown promising results, there remains a lack of predictive biomarkers indicating treatment benefit from immunotherapy. There is growing evidence suggesting that microsatellite instability (MSI) as a product of DNA mismatch repair deficiency, may be one of possible predictive markers in malignant melanoma. It has been proposed that the immunogenicity of some tumors might be determined by mutational heterogeneity and could be the key to the success of immune therapies. This is also supported by the fact that tumors with the highest amount of somatic mutations, such as malignant melanoma have showed positive results with immune checkpoint inhibitors. There are promising data regarding the association between MSI status and immunogenicity from studies with colorectal cancer, where MSI is linked to improved prognosis compared to microsatellite stable cancers. MSI in colon cancer is linked to a significant increase of immunocompetent cells responsible for the antitumor activity - CD3(+), CD8(+), CD45RO(+), and T-bet(+) lymphocytes and decrease of inhibition factors such as Foxp3, IL-6, IL-17, and TGF-ß. On the other hand, taking into account the progression-dependent accumulation of somatic mutations in MSI tumors and consequent high levels of neo-antigens, the possible drug resistance of MSI tumors to traditional treatment, and the presence of inhibition checkpoints within the MSI tumors, there is a solid rationale for the use of novel therapeutic strategies such as immunotherapy in MSI melanomas. We presume that the MSI phenotype in malignant melanoma might be helpful to identify patients, who would be more likely to profit from immunotherapy than from conventional therapy.