Immune Checkpoint Blockade in Melanoma - Earlier is Better?

Neoadjuvant immunotherapy is a promising approach for resectable stage III melanoma. It has shown higher response rates and improved tumor regression compared to adjuvant therapy alone. Neoadjuvant ICIs also demonstrate favorable survival outcomes. Recent trials, such as one with pembrolizumab, reported significantly improved event-free survival. Neoadjuvant ICIs offer advantages like T cell expansion, early-stage efficacy, treatment assessment through surgical specimens, and potential tumor size reduction for better surgical outcomes. However, further research is needed to optimize patient selection and treatment protocols.

Harnessing ctDNA in Advanced Melanoma: A Promising Tool for Informed Clinical Decisions.

Cutaneous melanoma, an aggressive malignancy, has undergone significant transformation in clinical management with the introduction of immune checkpoint inhibitors (ICIs) and targeted therapies. Current monitoring methods, such as imaging scans, present limitations, prompting exploration of alternative biomarkers. This review comprehensively explores the role of circulating tumor DNA (ctDNA) in advanced melanoma, covering technical aspects, detection methods, and its prognostic and predictive value. Recent findings underscore ctDNA's potential applications and implications in clinical practice. This review emphasizes the need for precise and dynamic biomarkers in melanoma care, positioning ctDNA as a promising blood-based tool for prognosis, treatment response, and resistance mechanisms. The technical nuances of ctDNA detection, association with melanoma mutations, and its role in guiding therapeutic decisions for immunotherapy and targeted therapy underscore its multifaceted utility, marking a paradigm shift in clinical decision-making and offering a promising trajectory for personalized and informed care in advanced melanoma.

Efficacy of Sunitinib in Patients With Favorable and Intermediate Risk Metastatic Renal Cell Carcinoma - Lithuanian National Cancer Institute Experience.

BACKGROUND/AIM: According to the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) recommendations, sunitinib is one of the recommended regimens for favorable and intermediate-risk metastatic renal cell carcinoma (mRCC) patients. The objective of this study was to evaluate sunitinib efficacy as a first-line treatment for mRCC patients with favorable/intermediate prognostic risk in a real-world setting. PATIENTS AND METHODS: Patients diagnosed with mRCC and confirmed as appropriate candidates for the first-line systemic treatment were included in this retrospective study. The prognostic risk was evaluated according to the model of the International Metastatic RCC Database Consortium (IMDC). RESULTS: Patients received sunitinib as a first-line treatment. A total of 94 patients were enrolled from 2019 to the 2020and 67 of them were included in the detailed analysis. Median progression-free survival (PFS) was 23.4 (95%CI=17.3-29.5), and median overall survival (OS) was 66 months (95%CI=44.9-87.1). The age over 60 years was a significant negative predictor for PFS and OS. Regarding the IMDC model for disease risk prediction, the number of two risk factors in the intermediate risk group was a significant predictor for a shorter response to the first-line therapy. CONCLUSION: Sunitinib is an effective tyrosine kinase inhibitor, which can be used as a first-line treatment in favorable/intermediate-risk groups of patients with mRCC, especially in countries where novel systemic treatment modalities are not yet available.

Atezolizumab Retains Cellular Binding to Programmed Death Ligand 1 Following Aerosolization via Mesh Nebulizer.

BACKGROUND/AIM: Cytotoxic inhalable drugs were shown to be advantageous in treating malignancies of the respiratory tract. However, these drugs have not always presented a safe profile and were reported to induce local adverse events. Protein-based anticancer drugs, such as immune checkpoint and vascular endothelial growth factor inhibitors, do not induce tissue injury, nor do they exhibit vesicant properties upon direct contact with tissues. Protein drugs are susceptible to the heat and stress encountered during droplet generation for delivery by nebulization. The aim of this study was to investigate the capacity of atezolizumab, an antibody to programmed death ligand 1, to bind target cells after nebulization with a vibrating mesh (VM) nebulizer. MATERIALS AND METHODS: We compared Fourier-transformed infrared (FTIR) and Raman spectra of native atezolizumab (60 mg/ml) and its nebulized form following 10-min nebulization in a piezoceramic VM nebulizer. The binding of atezolizumab to DU-145 prostate cancer cells was evaluated using competitive blocking of anti-CD274 staining. RESULTS: Nebulization did not induce Raman or FTIR spectral modification nor did it affect the binding capacity of atezolizumab. Conversely, heat-inactivated atezolizumab lost its cell-binding capacity and did not reduce anti-CD274 immunostaining. Native and nebulized atezolizumab displayed identical spectra, whereas the FTIR spectra of the heat-inactivated drug was significantly altered. CONCLUSION: VM nebulization does not obliterate the functionality of the drug atezolizumab. The integrity of a nebulized form can be rapidly assessed by FTIR and Raman spectrometry.

Sequential treatment of metastatic renal cell carcinoma patients after first-line vascular endothelial growth factor targeted therapy in a real-world setting: epidemiologic, noninterventional, retrospective-prospective cohort multicentre study.

PURPOSE: The purpose of our study was to determine whether data on the clinical effectiveness of second-line therapy collected in a real-world setting provide additional valuable information on the optimal sequence of metastatic renal cell carcinoma (mRCC) treatment. METHODS: Patients diagnosed with mRCC who were treated with at least one dose of first-line vascular endothelial growth factor (VEGF)-targeted therapy with either sunitinib or pazopanib and with at least one dose of second-line everolimus, axitinib, nivolumab, or cabozantinib were included. The efficacy of different treatment sequences was analyzed based on the time to the second objective disease progression (PFS2) and the time to the first objective disease progression (PFS). RESULTS: Data from 172 subjects were available for analysis. PFS2 was 23.29 months. The 1-year PFS2 rate was 85.3%, and the 3-year PFS2 rate was 25.9%. The 1-year overall survival rate was 97.0%, and the 3-year overall survival rate was 78.6%. Patients with a lower IMDC prognostic risk group had a significantly (p < 0.001) longer PFS2. Patients with metastases in the liver had a shorter PFS2 than patients with metastases in the other sites (p = 0.024). Patients with metastases in the lungs and lymph nodes (p = 0.045) and patients with metastases in the liver and bones (p = 0.030) had lower PFS2 rates than patients with metastases in other sites. CONCLUSIONS: Patients with a better IMDC prognosis have a longer PFS2. Metastases in the liver lead to a shorter PFS2 than metastases in other sites. One metastasis site means a longer PFS2 than 3 or more metastasis sites. Nephrectomy performed in an earlier stage of disease or metastatic setting means higher PFS and higher PFS2. No PFS2 difference was found between different treatment sequences of TKI-TKI or TKI-immune therapy.

Changing epidemiology and age-specific incidence of cutaneous malignant melanoma in Lithuania: an analysis of national cancer registration data by gender and anatomical site, 1991-2015.

Introduction: The purpose of this study was to investigate the gender-specific and anatomical site-specific incidence of cutaneous melanoma. Material and methods: All cases of primary skin melanoma reported to the Lithuanian Cancer Registry during the period 1991-2015 were included. For the analyses, patients were categorized by sex and melanoma site. Results: Overall age-standardized rate (ASR) of melanoma in the trunk increased 0.8-3.3, while in limbs the ASR increased 1.0-3.4. The highest increase in new cases per 100,000 population (in both sexes) was detected in limbs and it increased over time (from 2.01 per 100,000 in 1991 to 3.65 per 100,000 in 2015). The highest increase in the number of new cases was in limbs with ASR, with a more than 3-fold increase from 1991-2015 (1.4-4.6). A statistically significant increase was observed in mortality of skin melanoma between 1991 and 2015, with the highest annual percentage change (APC) of 5.5 in the trunks of men (95% CI: 5.2-5.9; p < 0.05) and women with APC 3.9 (95% CI: 3.5-4.4, p < 0.05). Conclusions: In our study, we found higher incidence rates of skin melanoma in females. Melanoma was more commonly diagnosed in the trunk of males and limbs of females, with the highest mortality increase in trunk melanoma in both genders.

The Impact of the COVID-19 Pandemic on Cancer Patient's Management-Lithuanian Cancer Center Experience.

The pandemic spread of the COVID-19 virus significantly affected daily life, but the highest pressure was piled on the health care system. Our aim was to evaluate an impact of COVID-19 pandemic management measures on cancer services at the National Cancer Institute (NCI) of Lithuania. We assessed the time period from 1 February 2020 to 31 December 2020 and compared it to the same period of 2019. Data for our analysis were extracted from the NCI Hospital Information System (HIS) and the National Health Insurance Fund (NHIF). Contingency table analysis and ANOVA were performed. The COVID-19 pandemic negatively affected the cancer services provided by NCI. Reductions in diagnostic radiology (-16%) and endoscopy (-29%) procedures were accompanied by a decreased number of patients with ongoing medical (-30%), radiation (-6%) or surgical (-10%) treatment. The changes in the number of newly diagnosed cancer patients were dependent on tumor type and disease stage, showing a rise in advanced disease at diagnosis already during the early period of the first lockdown. The extent of out-patient consultations (-14%) and disease follow-up visits (-16%) was also affected by the pandemic, and only referrals to psychological/psychiatric counselling were increased. Additionally, the COVID-19 pandemic had an impact on the structure of cancer services by fostering the application of modified systemic anticancer therapy or hypofractionated radiotherapy. The most dramatic drop occurred in the number of patients participating in cancer prevention programs; the loss was 25% for colon cancer and 62% for breast cancer screening. Marked restriction in access to preventive cancer screening and overall reduction of the whole spectrum of cancer services may negatively affect cancer survival measures in the nearest future.

Do the benefits of being a smoker hint at the existence of PD-1/PD-L1 sensitizers for patients on single-agent immunotherapy?

Multiple studies demonstrate significantly better therapeutics outcomes in smokers as compared with never smokers when single-agent immunotherapy is applied. Non-smoker patients usually need a combination of chemoimmunotherapy to achieve comparable or slightly better therapeutic results. This effect is thought to be due to tobacco product-induced upregulation of PD-L1/PD-1 expression and tumor mutational burden score. Genomic transformation, however, cannot entirely explain the upregulation of PD-L1/PL-1 expression in cells following short-term exposure to cytotoxic compounds. Cytotoxic drugs, crude tobacco products, benzo(a)pyrene, nicotine, and multiple other toxic compounds were shown to exhibit rapid PD-L1/PD-1 upregulation. A significant immunomodulatory effect of nicotine via acetylcholine receptors is well documented. However, nicotine activity rapidly subsides when the drug is withdrawn. We hypothesize that smoking cessation might mitigate the benefits of monoimmunotherapy for some patients. Further studies of the nicotinic acetylcholine receptor stimulus of immunocytes are needed and might lead to characterization and clinical implementation of new immunotherapy sensitizer products.

Retrospective cohort study of androgen deprivation therapy and the risk of diabetes in men with prostate cancer in Lithuania.

OBJECTIVES: To examine the risk of type 2 diabetes in patients with prostate cancer and its association with androgen deprivation therapy (ADT). DESIGN AND PARTICIPANTS: We performed a retrospective cohort study of patients diagnosed with prostate cancer in the Lithuanian male population between 1 January 2003 and 31 December 2012 who were identified through the Lithuanian Cancer registry. All prostate cancer cases were linked to the National Health Insurance Fund database to obtain information regarding the diagnosis of diabetes mellitus and information on prescriptions of antiandrogens and gonadotropin-releasing hormone (GnRH) agonists. Patients with prostate cancer were followed up until the diagnosis of type 2 diabetes, or 31 December 2017, or date of death, whichever came first. Cox proportional hazard models were used to estimate the risk of type 2 diabetes in patients with prostate cancer with or without ADT exposure. RESULTS: 27 580 men were diagnosed with prostate cancer, out of whom 14 502 (52.6%) did not receive ADT and 13 078 (47.4%) were treated with ADT. The incidence of type 2 diabetes for all patients with prostate cancer was 7.4/1000 person-years, for men on GnRH agonists 9.0/1000 person-years and 5.8/1000 person-years for men on antiandrogens. There was an increased risk of developing type 2 diabetes comparing ADT users and non-users (HR=1.49, 95% CI 1.34 to 1.66). CONCLUSION: This study showed an increased risk of diabetes in patients with prostate cancer treated with ADT in comparison to ADT-free patient cohort. GnRH agonist users showed higher susceptibility, while the group on antiandrogen monotherapy showed no such increase.

Trends in Incidence and Mortality of Skin Melanoma in Lithuania 1991-2015.

BACKGROUND: We aimed to investigate age-specific and sex-specific incidence trends of melanoma in Lithuania from 1991 to 2015. METHODS: Analysis was based on data from the population-based Lithuanian Cancer Registry database for 1991-2015, and 6024 cases of skin melanoma were identified. Age-adjusted rates (ASRs) by sex and age group were calculated. Adjustment for ASRs was done using the old European standard population, where a total of three age groups were considered: 0-39, 40-59 and 60+. Additionally, the annual percent change (APC) was calculated, and 95% confidence intervals for APC were calculated. RESULTS: Between 1991 and 2015, the overall melanoma rates increased by an annual percent change (APC) of 3.9% in men (95% CI, 3.6-4.1%) and 2.3% in women (95% CI, 2.1-2.5%). The highest incidences of new cutaneous melanoma cases were observed between old adults (60+) of both sexes, while the lowest incidence rates were observed in the young adult group (up to 39 years old), with the lowest APC (1.6% in males and 0.4% in females). The overall number of melanoma deaths during 1991 and 2015 increased from 64 to 103 deaths per year, and the age-standardized rate (ASR) increased 1.3 times (from 1.8 to 2.4). CONCLUSIONS: The incidence and mortality of skin melanoma seem to be increased in all age groups. These trends indicate that skin protection behavior is not sufficient in our population and more efforts need to be taken in order to decrease incidence and mortality rates.

The impact of metformin on survival in patients with melanoma-national cohort study.

PURPOSE: The primary study outcome was melanoma-specific mortality in patients with type 2 diabetes mellitus (T2DM) using metformin. METHODS: Data regarding patients were provided by the Lithuanian Cancer Registry and were linked with National Health Insurance Fund in accordance with unique personal identification numbers during the period of thirteen years. RESULTS: About 2817 patients met eligibility criteria and were included in the retrospective cohort study. About 163 patients had pre-existing T2DM and 103 of them were treated with metformin. In the multivariable analysis, there was significant risk difference in melanoma-specific survival between diabetic, metformin-using patients, and nondiabetic patients (P=0.02) in favor of metformin users. CONCLUSION: Melanoma patients with T2DM treated with metformin had lower risk of melanoma-specific mortality; however, prospective controlled studies are mandatory to confirm this finding.

Reproductive Factors and Breast Cancer Risk in Lithuanian Women: A Population-Based Cohort Study.

ABSTRACT BACKGROUND: Although the relationship between reproductive factors and breast cancer is internationally proved, reliable data on former USSR countries are scarce. This study examines the association of parity, age at the first childbirth, number of children, and breast cancer risk in Lithuanian women. METHODS: The study that included women from 40 to 79 years old was based on a dataset that was made up linking all records from the 2001 census, all cancer incidence records from the Lithuanian Cancer Registry and all death records from Statistics Lithuania between 6th April 2001 and 31st December 2009. Cox's proportional hazards regression models were used to estimate the hazard ratios (HRs) for parity, age at the first childbirth, and number of children. RESULTS: If compared to nulliparous women, parous women had a lower risk of breast cancer (HR=0.84, 95% CI 0.78-0.89) and this risk further decreased with an increasing number of children. Women who gave birth after the age of 25 had a significantly higher risk of breast cancer. This disadvantage became statistically insignificant or decreased after controlling for total number of children. CONCLUSIONS: Parity and age at the first childbirth are strong predictors of breast cancer risk among Lithu-anian women.

Positive effect of metformin treatment in colorectal cancer patients with type 2 diabetes: national cohort study.

We aimed to estimate colorectal cancer risk in patients with type 2 diabetes mellitus (T2DM) using metformin. Patients with colorectal cancer and diabetes from 2000 to 2012 were identified form Lithuanian Cancer Registry and the National Health Insurance Fund database. Standardized incidence ratios (SIRs) for colorectal cancers as a ratio of observed number of cancer cases in people with diabetes to the expected number of cancer cases in the underlying general population was calculated. We analysed 111 109 patients with diabetes. Overall, 1213 colorectal cancers were observed versus 954.91 expected within a period of observation entailing an SIR of 1.27 [95% confidence interval (CI): 1.20-1.34]. Significantly higher risk of colorectal cancer was found both in male and female patients with diabetes in all age groups. Higher risk was found for both colon and rectum cancers 1.36 (95% CI: 1.27-1.46) and 1.11 (95% CI: 1.01-1.22), respectively. There were no differences in risk over time since initial diabetes diagnosis. Never-users of metformin had twice higher risk of colorectal cancer compared to general population (SIR: 2.14, 95% CI: 1.95-2.35). Among metformin users, risk was lover (SIR: 1.47, 95% CI: 1.36-1.58) and colorectal cancer risk decreased with increasing cumulative dose of metformin (P < 0.001). Patients with T2DM had increased risk of colorectal cancer compared with the general Lithuanian population. Decreasing colorectal cancer risk with increasing cumulative dose of metformin indicates that metformin may be a protective agent for colorectal cancer development.

Skin Melanoma and Subsequent Risk of Prostate Cancer: A Lithuanian Cancer Registry Study.

Emerging data indicates that melanoma may be linked to prostate cancer. We evaluated if the incidence of melanoma was associated with subsequent risk of prostate cancer (PC). We extracted data from the Lithuanian cancer registry from 1993 to 2012. We calculated the standardized incidence ratios (SIRs) for PC as a ratio of observed number of cancer cases in people with previous melanoma diagnosis to the expected number of cancer cases in the underlying general population. Therein, 95% confidence intervals for the SIRs were estimated assuming the number of observed cancer cases follows the Poisson distribution. Overall, 65 PCs were observed versus 52.5 expected (SIR 1.24; 95% CI: 0.97-1.58) within a period of 24 years. A significantly increased risk of PC was found in patients with melanoma diagnosis over 70 years (SIR 1.62; 95% CI: 1.11-2.39) and in two periods of diagnosis (SIRs 1.76 and 1.62 in 1993-1997 and 2009-2012, respectively). A significantly increased risk was also found five to nine years after melanoma diagnosis (SIR 1.58; 95% CI: 1.05-2.38). Further studies are needed to evaluate the relationship between melanoma and subsequent risk of prostate cancer.

Metformin increases cancer specific survival in colorectal cancer patients-National cohort study.

PURPOSE: We aimed to assess oncological outcomes in colorectal cancer patients with type 2 diabetes mellitus (T2DM) using metformin. METHODS: Patients with colorectal cancer and T2DM during 2000-2012 period were identified form Lithuanian Cancer Registry and the National Health Insurance Fund database. Colorectal cancer-specific survival (CS) was the primary outcome. It was measured from date of colorectal cancer diagnosis to date of death due to colorectal cancer, or last known date alive. RESULTS: 15,052 people who met eligibility criteria for this analysis, including 1094 (7.27%) with pre-existing type 2 diabetes (271 metformin never users and 823 metformin users) and 13 958 people without diabetes assessed. During follow-up (mean follow-up time was 4.4 years, with range from 1 day to 17 years) there were 10,927 deaths including 8559 from colorectal cancer. Significantly lower risk in CS between diabetic and non-diabetic people with lower risk of cancer-specific mortality (HR 0.87, 95% CI 0.80-0.94) in diabetic patient population was seen. After adjustment for age, stage at diagnosis and metformin usage, significant difference in colorectal CS between metformin users in diabetic patient population compared to non-diabetics and metformin non-users in diabetic patient population was found (0.80 (0.72-0.89) vs 1.00 and vs 1.05 (0.91-1.23)). Overall survival (OS) was better for diabetic patients with significant difference in diabetic metformin users (HR 0.91, 95% CI 0.79-0.94). CONCLUSIONS: Colorectal cancer patients with T2DM treated with metformin as part of their diabetic therapy appear to have a superior OS and CS. However, prospective controlled studies are still needed to evaluate the efficacy of metformin as an anti-tumor agent.

Breast Cancer Screening Program in Lithuania: Interval Cancers and Program Sensitivity After 7 Years of Mammography Screening.

OBJECTIVE: Analysis of interval cancers is critical in determining the sensitivity of screening and represents an objective measure of the quality of mammography screening program (MSP). METHODS: Period analyzed: from 2006 to 2012. The rate of screen-detected, interval cancers and program sensitivity were measured. A comparison of screen-detected and interval cancers was performed. RESULTS: During the period of the study, 429 473 women were screened and 1297 were found to have cancer. The overall screen-detected cancer rate was 30.2 per 10 000 women screened. Four hundred thirty-one case of interval cancers have occurred during the period of the study. The interval cancer ratio (ICR) was 0.25. Overall sensitivity of MSP amounted to 75.1%. Slightly lower sensitivity was found among the youngest age-group, especially for those with lobular cancers. Interval cancers were bigger in size, more often with metastases in lymph nodes, than screen-detected cancers, but these differences were not statistically significant. CONCLUSIONS: Overall program sensitivity in Lithuania is about 75%, ICR is 0.25, and these parameters are comparable to other European countries.

Suicide risk among colorectal cancer patients in Lithuania.

PURPOSE: We aimed to estimate suicide risk among colorectal cancer patients in the country showing the highest suicide rates among developed countries. METHODS: Patients with colorectal cancer diagnosed between 1998 and 2012 were identified from the Lithuanian Cancer Registry. Standardised mortality ratios (SMRs) for suicide were calculated for patients diagnosed with cancer in Lithuania, relative to suicide rates in the general population. RESULTS: Twenty thousand seven hundred sixty-five primary colorectal cancer cases diagnosed between 1998 and 2012 were extracted from the database. Among 19,409 first primary colorectal cancer patients, we identified 67 suicides and the expected number of suicides calculated from general population was 41.4 in this cohort, resulting in an SMR of 1.62 for both sexes (95% CI, 1.27-2.06). A higher suicide risk was found for women (SMR 2.15; 95% CI 1.35-3.41), than for men (SMR 1.48; 95% CI 1.12-1.96). The suicide risk was almost twice higher in patients 60 and older, with highest increase in the oldest patients (SMR 2.12, 95% CI 1.01-4.46). The risk of suicide was not significantly elevated in colorectal cancer patients with localised tumours, but there was a fourfold increase in risk in patients with stage IV tumours. Compared with the general population, the risk of suicide among colorectal cancer patients was four times higher during the first 3 months after diagnosis and decreased thereafter. CONCLUSIONS: The patients with colorectal cancer have a higher rate of suicide compared with the general Lithuanian population. Sex, age, advanced rectal cancer and distant spread of disease were the main predictors of suicide among colorectal cancer patients.

Natural killer cell-based immunotherapy: a new fighter against melanoma?

Changes in the expression of proteins on cancer cell surface are a typical outcome of malignant transformation. Natural killers (NKs) utilize a set of activating and inhibitory receptors that enable them to recognize altered protein expression and then destroy 'stressed' cells such as cancer or virus-infected cells. Major histocompatibility complex class I polypeptide-related sequence A and B (MICA and MICB, respectively) are expressed by various human tumors and can be recognized by activating NK cell receptor NKG2D. However, cancer frequently escapes recognition by NK cells by proteolytic shedding of MICA and MICB proteins. A study carried out by Ferrari de Andrade and colleagues showed that monoclonal antibody targeting the site of proteolytic shedding of MICA and MICB reduced the progression of melanoma in immunocompromised and immune competent mice models by activation of NKG2D. This approach prevented the reduction of essential immunostimulatory ligands (MICA/MICB) and restored NK cell-driven anticancer immunity.