bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term (LT) disease-free survival (DFS) of melanoma (MM) and renal cell cancer (RCC) patients following high-dose interleukin-2 (HD IL2).
Authors: Clark Joseph , Curti Brendan D. , Davis Elizabeth J. , Kaufman Howard , Amin Asim , Alva Ajjai Shivaram , Johnson Douglas Buckner , White Richard L. , Wiernik Peter H. , Dutcher Janice P.
Published: September 2018

e21005

Background: HD IL2 treatment (Tx) produces durable complete responses (CRs) and surgical CRs. Patients (pts) achieving partial response (PR) and stable disease (SD) demonstrate improved survival compared with pts who progress. Methods: 7 HD IL2 Tx centers identified pts with survival > 5 years (yrs) after HD IL2. DFS was from end of IL2 to January 2017. Tx courses generally consisted of 2 1-week cycles of HD IL2, 600,000-720,000 U/kg IV every 8 hours. We collected data on pts Tx with HD IL2 alone, or HD IL2 plus local Tx (surgery or radiation (SRS) leading to CR) with survival > 5 yrs after HD IL2 Tx. Results: 72 pts are reported: 29 RCC (male 22, female 7) and 43 mm (male 26, female 17). Median age at Tx of RCC is 54 yrs (range, 47-67 yrs) and of mm is 50 yrs (range, 24-72 yrs). Sites of metastatic disease for 26 mm pts were lymph nodes (LN) -18, lungs-12, bone-6, liver-9, brain-3, other organs-10 and for 22 RCC pts were lung-17, LN-5, adrenal-4, bone-3, other organs-8. Number of IL2 courses received: 1-10 pts, 1.5-4 pts, 2-28 pts, 2.5-5 pts, 3-24 pts, 4-one pt. Among the 29 RCC pts, there are 24 CRs, 3 surgical CRs and 2 PRs with no further Tx. Among 43 mm pts, there are 34 CRs, 2 near CRs, and 7 Surgical/SRS CRs. DFS in these pts after HD IL2 Tx ranges from 5+ yrs to 30+ yrs, median 10.5+ yrs. 10 RCC and 16 mm are alive > 5 - < 10 yrs after IL2, and 19 RCC and 27 mm are alive > 10 yrs after IL2. LT toxicity among these 72 pts includes hypothyroidism-5 pts, arthralgias/arthritis-5 pts, vitiligo-3 pts, and 1 pt each: neuropathy, PVCs, and normal pressure hydrocephalus. Additional pts may be added as records become available. Conclusions: We document LT DFS ( > 5 yrs) after CR or PR from HD IL2 alone. Surgical or SRS conversion of PR to CR can produce durable CRs. LT DFS was observed in pts with visceral and bone metastases, not only those with LN or lung sites. Neither age, sex, nor number of courses of IL2 predicted LT DFS. Chronic toxicity due to IL2 is uncommon in LT survivors.
The management of BRAF mutant melanoma brain metastases upon tyrosine kinase failure.
Authors: Ladwa Rahul , Atkinson Victoria
Published: September 2018

e21020

Background: Brain metastases (BM) failure on tyrosine kinase inhibitor (TKI) is a frequent complication in patients with BRAF mutant metastatic melanoma (MM) and is associated with a poor prognosis. We aimed to explore the outcome of these patients with modern therapeutic options. Methods: We retrospectively analysed 55 patients with treated BRAF mutant mm diagnosed with BM on TKI at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 53 (17-82) years, presence of seizures (N = 7), LDH > 250 (N = 23) and presence of systemic disease (N = 54). BM were categorised as solitary (N = 8), 2-6 (N = 23), more than 6 (N = 13) and leptomeningeal disease (N = 11). Management of BM included surgical resection (N = 6), stereotactic radiosurgery (SRS) (N = 14), whole brain radiotherapy (N = 13) and best supportive care (N = 16). BRAF use post progression with BM was used (N = 10). Immunotherapy with Ipilimumab (N = 17) and PD1 inhibitor (N = 24) was used. With a median follow up of 5 months, 47 (85%) patients had died from MM. Death occurred due to progressive disease in the brain (N = 24), systemically (N = 5) or both (N = 18). The number of patients surviving over 6 months (N = 27) were associated with < 6 BM, use of radiotherapy, use of anti PD1 antibodies and the use of ablative therapies with immunotherapy. Statistically improved overall survival (OS) were found with < 6 BM, SRS use and PD1 inhibitor use. Ablative treatments (resection or SRS) with subsequent immunotherapy confers a median OS of 13 months in select patients. Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BRAF mutant mm on TKI who develop BM remains poor. Death is frequently due to PD within the brain. The use of ablative techniques and immunotherapy are optimal treatment options in this poor prognostic group.
CTLA4 and CD47 combinational therapy to extend survival in melanoma.
Authors: Schwartz Anthony L. , Nath Pulak , Lessey-Morillon Elizabeth , Ridnour Lisa , Allgaeuer Michael , Roberts David
Published: September 2018

e21025

Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x106B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response.
Accelerated melanoma mortality rates among middle-aged white males with tumors of all thicknesses.
Authors: Berk-Krauss Juliana , Polsky David , Stein Jennifer , Geller Alan
Published: September 2018

e21029

Background: Effective early detection of melanoma remains one of the most crucial strategies in improving patient prognosis, due to the inverse relationship between primary tumor thickness and survival time. However, recent studies have demonstrated the mortality burden of thin melanomas is at least as severe as that of thicker melanomas. Recognizing specific mortality trends among men and women by age and thickness is essential for establishing targeted melanoma screening efforts. Methods: We evaluated Surveillance, Epidemiology and End Results (SEER) data from 2009-2013. Melanoma thickness was divided into four standard categories: 0.01-1.00mm, 1.01-2.00mm, 2.01-4.00mm and > 4.01 mm. Melanoma mortalities were calculated among white men and women by age and thickness. We used a Bayesian analysis to calculate the probability of an individual dying from a melanoma of a given gender, age, and thickness. We then compared these probabilities between men and women. Results: Among white men, the largest increases in mortality rates occurred in the jump from the 45-49 to 50-54 age group at an increase of 68% for 0.01-1.00mm tumors, and from the 50-54 to 55-59 age group at an increase of 91% for 1.01-2.00mm tumors, 71% 2.01-4.00mm tumors and 80% for > 4.01mm tumors. In white women, mortality rates regardless of thickness increased at a slow incremental pace, across all age groups at an average overall rate of 36%. Mortality rates for white men with < 1mm and 1.01-2mm melanomas were comparable within the age groups less than 64 years, as was the case for white women with tumors of these thicknesses. The probability of a man dying was greater than of a woman for any age or thickness category. Conclusions: Melanoma mortality rate trends are nuanced and can vary significantly by age, thickness, and gender. In white men, mortality rates begin to accelerate sharply around the mid-50s age group. Screening efforts should therefore target detecting melanoma in middle-aged males in the in situ or earliest stage.
Immune cell profiling of melanoma metastases from patients treated with TriMixDC-MEL dendritic cell therapy in combination with ipilimumab.
Authors: Schats Kelly , Van Vre Emily A. , Debyser Isolde , Vandenbroeck Arno , Jansen Yanina , Seremet Teofila , Marien Koen , Fransen Erik , Schrijvers Dorien , Van Criekinge Wim , Thielemans Kris , Neyns Bart , De Meester Ingrid , Kockx Mark
Published: September 2018

e21030

Background: Ipilimumab has proven clinical benefit in a subset of melanoma patients. Previously a high rate of durable complete response was shown with the combination of ipilumumab and TriMixDC-MEL therapy (Wilgenhof et al. JCO 2016). Methods: Melanoma metastases were collected from patients, before initiation of combined ipilimumab and dendritic cell (TrimixDC-MEL) therapy [NCT01302496]. Formalin-fixed, paraffin-embedded samples were available from 24 patients of which 6 had durable benefit (DB) and 18 had no clinical benefit (NB). Serial 4µm slides were stained with immunohistochemistry (IHC) for immune response markers. Semi-automated analysis (Definiens software) was applied to estimate the tumor area stained for CD8, CD20, CD163, OX40, ICOS and LAG3, % of FOXP3 positive T-cells and IRF1-positive tumor nuclei. H-scores were calculated for IDO, STING and MHC-I on tumor cells (TC). A qualified pathologist scored the % PD-L1 on TC and immune cells (IC). In addition, RNA was extracted (n = 19) and analyzed using the NanoString nCounter Pan Cancer immune profiling panel. Results: The IHC and NanoString variables were tested for predictive response, as single marker using logistic regression and the area under the curve (AUC) values. The top 15 biomarkers for either IHC or NanoString are listed in the table below (AUC in descending order). Gene Ontology analysis (GOstat) of Nanostring markers revealed over-representation of genes involved in the response to other organisms (GO: 0051707) and viruses (GO: 0009615) in DB patients. Conclusions: This study identified a set of potentially new predictive biomarkers, including virus response related genes, for DB following ipilimumab plus TriMixDC-MEL therapy. Further prospective validation is warranted. [Table: see text]
Coupling a phenotypic assay-based platform, multi-plex IHC and quantitative pathology to predict anti-tumor efficacy to immune checkpoint blockade in melanoma.
Authors: Radhakrishnan Padhma , Biswas Manjusha , Smalley Munisha , Majumder Biswanath , Berger Raanan , Goldman Aaron
Published: September 2018

e21041

Background: Emerging clinical evidence using immunotherapy suggests there is extraordinary antitumor potential by releasing the brakes on the immune system. However, clinical responses vary widely among patients, and a majority do not experience positive response. There is a huge unmet need to understand these disparities at the individual patient level. Methods: Here, we describe a quantitative approach to predict the antitumor effect of immune checkpoint blockade using a live-tissue ex-vivoplatform technology, CANscript™, which captures the native 3D tumor microenvironment. Utilizing fresh melanoma resections we interrogated phenotypic changes to the tumor-immune contexture in response to PD-1 and PD-L1 inhibitors in combination and as single agents. To do this, we used a multi-plexed immunohistochemistry (primarily CD8, CD45, FOXP3, CXCR4, CD68, PDL1, PD1, ERK-phosphorylation), and quantification of immune cell migratory potential, which were correlated to antitumor indications such as tumor cell proliferation, and cell death. Results: The data confirmed that CANScript™ preserves the tumor-immune contexture and native heterogeneity across different patients. Importantly, we observed that PD-1 and PD-L1 blockade resulted in patient-specific therapeutic response, which was characterized by differential, quantitatively distinct distribution and infiltration of immune cells, distinct patterning of cytokines linked to functional dysregulation, and changes in tumor proliferation and apoptosis. Interestingly, the data demonstrated unique immune signatures associated with single agent vs. combination therapy, inducing functionally distinct mechanisms in the tumor immune compartment, and disparate antitumor effects within an individual patient tumor. Conclusions: Together, these findings demonstrate that quantitative pathology can help predict therapeutic response of immune checkpoint inhibitors at the individual patient level. Such information can re-shape our understanding of patient selection and rational combinations for novel immune checkpoint inhibitors.
Mutation analysis of mucosal and cutaneous melanomas during progression.
Authors: Palmieri Giuseppe , Colombino Maria , Casula Milena , Lissia Amelia , Botti Gerardo , Scognamiglio Giosuè , Caraco Corrado , Ascierto Paolo Antonio , Fraggetta Filippo , Paliogiannis Panagiotis , Manca Antonella , Sini MariaCristina , Doneddu Valentina , Cossu Antonio
Published: September 2018

e21047

Background: The prevalence of mutations in driver genes during progression in cutaneous and mucosal melanomas remains inconclusive. We investigated the prevalence and distribution of mutations in main candidate genes involved in melanomagenesis among different melanoma tissues using a next-generation sequencing (NGS) approach. Methods: Forty-eight tumor samples from 36 patients with mucosal melanoma (MM) and fifty-two tumor samples from 34 patients with cutaneous melanoma (CM) were collected, after obtaining patients’ written informed consent for tissue sampling. Genomic DNA was isolated from macrodissected tumor tissues containing at least 80% neoplastic cells and analyzed for mutations in 25 most common melanoma-associated oncogenes and tumor suppressor genes, using the IMI Diagnostic Melanoma Panel on the Ion Torrent platform (Life Technologies, USA). Results: A total of 100 tumor tissues from 70 melanoma patients were analyzed. BRAF mutations were detected in 21/34 (62%) CM patients and 13/36 (36%) mm patients. The second most prevalent mutations were found in K-/N-RAS (6/34; 18%) and cKIT (6/36; 17%) genes among CM and mm patients, respectively. No concomitant mutations of BRAF, RAS, and cKIT genes were detected. Among others, mutations were more frequently found in CCND1 (20%), ARID2 (16%), and NF1(12%) genes, considering the entire series of patients. Vast majority of patients who had paired samples of primary and secondary melanomas showed consistent mutation patterns between primary tumors and metastatic lesions. Similar frequencies of mutations in driver genes were seen across metastatic sites. Conclusions: In the era of targeted therapies, assessment of the spectrum and distribution of mutations in main molecular targets among patients with melanoma is needed. Our findings about the prevalence of mutations in driver genes in paired tumor lesions from patients with cutaneous and mucosal melanoma may be useful in the management of such diseases. The Italian Melanoma Intergroup (IMI) includes the following additional members who participated as investigators in this study: Mario Mandalà, Paola Queirolo, Ignazio Stanganelli, Vanna Chiarion Sileni, Pietro Quaglino, Anna Maria Di Giacomo.
Influence of job assignment on melanoma (MEL) incidence in commercial aircrew.
Authors: Cranmer Lee D.
Published: September 2018

e21058

Background: Commercial cabin and cockpit aircrews are at increased cutaneous MEL risk. Occupational and social factors have been invoked to explain this. However, the two groups work in on-board environments with different types/levels of potential exposures. Meta-analysis is conducted to address the hypothesis that differences exist in aircrew MEL risk based on location of in-aircraft job assignment, reflecting differential etiologic occupational exposures. Methods: Medline was searched with the keywords “Cancer,” “Aviation,” and “Melanoma.” Included studies: (1) primarily focused on cutaneous MEL; (2) were in commercial aircrew; (3) measured risk vs a general population; (4) measured risk by Standardized Incidence Ratio (SIR) with 95% confidence intervals (CI); (5) defined the gender distribution; and (7) defined cabin vs cockpit job assignment. Summary SIRs and CIs were calculated using maximum-likelihood, random effects meta-analysis. Values obtained were compared to one another using a z-test, with p < 0.05 pre-specified for null hypothesis rejection. Results: 6 primary studies were identified in the initial search. These were screened for other pertinent references. The secondary search yielded an additional 9 primary studies. For cabin crew, 10 study groups from 6 studies were included. 411,561 person-years of follow-up among 28,093 subjects (86% female) were included (SIR 2.18, 95% CI 1.83-2.60). For cockpit crew, data from 9 studies representing 830,670 person-years of follow-up among 45,986 subjects (1% female) were included (SIR 2.44, 95% CI 1.94-3.08). z-test for the difference indicated that the two SIR values were not statistically different ( z= 0.77, p = 0.441). Conclusions: Though cockpit crew demonstrate an increased SIR vs cabin crew, this is not statistically significant. These results suggest that occupational exposures in different locations within commercial aircraft does not influence MEL risk. Other factors, such as cosmic radiation, non-aircraft occupational exposures and avocational exposures, should be the targets of further assessment.
Effect of very small tumor size on cancer-specific mortality in node-positive melanoma.
Authors: Liu Xinyang , Wang Zhichao , Li Qingfeng
Published: September 2018

e21059

Background: Traditionally, larger tumor size and lymph node (LN) involvement have been considered independent predictors of mortality in melanoma. We aimed to characterize the interaction between tumor size and LN involvement in melanoma specific mortality. In particular, we evaluated whether very small tumor size represented a particularly aggressive disease variant compared with larger LN-positive melanoma. Methods: Using Surveillance, Epidemiology and End Results registry data, we identified 57,223 patients (aged 18-85 years) diagnosed between 1998 and 2012 with histologically confirmed nonmetastatic melanoma treated with surgery. Primary study variables were tumor size, LN involvement, and their corresponding interaction term. Kaplan-Meier methods, adjusted Cox proportional hazards models with interaction terms were performed. Potential confounders included age, sex, year of diagnosis, marital status and number of LN dissected. Results: Median follow-up was 48 months. In multivariable analysis, there was significant interaction between tumor size and LN involvement ( P < 0.0001) using the likelihood ratio test and Wald test. In the absence of LN involvement (n = 54,922), the hazard ratio (HR) increased monotonically with increasing tumor size. Among patients with LN involvement (n = 2,301), using the smallest tumors as the reference group, hazard ratio of cancer specific mortality decreased unexpectedly in 0.01-1.00mm tumors (HR 0.61, p = 0.022) and 1.01-2.00mm tumors (HR 0.58, p = 0.007), and reached to a similar level in tumors sized 2.01-4.00mm (HR 0.81, p = 0.280), and subsequently increased in tumors sized larger than 4.00mm (HR 1.57, p = 0.016). Conclusions: In LN positive melanoma, very small tumors may predict for higher mortality compared with larger tumors. These results should be validated in future database studies. Table. Effect of tumor size in LN positive and LN negative melanoma. [Table: see text]
Non-classical BRAF melanoma: A retrospective review of disease characteristics and prognostic implications.
Authors: Parmar Ambika , Feilotter Harriet , Baetz Tara D.
Published: September 2018

e21060

Background: Activating mutations in the BRAF gene occur in 40-60% of melanomas with the majority of mutations resulting in V600E/K. Previous cohort studies have identified rates of non-V600E/K BRAF mutations to occur in 5-12% of patients. Despite this, there remains limited evidence characterizing the disease characteristics and outcomes of patients who harbor the non-classical BRAF mutation. Methods: Retrospective review of all melanoma patients treated at a tertiary cancer center that had BRAF mutation testing through targeted sequencing. Three groups of patients were identified and compared with respect to patient and disease characteristics: a) BRAF negative; b) BRAF V600E/K positive; c) BRAF non-V600E/K positive. Results: BRAF testing was performed in 168 melanoma patients of which 101 (60%) were BRAF negative; 55 (33%) were BRAF V600E/K positive; 12 (7%) were BRAF non-V600E/K positive (2 G466E, 1 of each G469E, K601N, K601E, L597Q, L597S, V741I, N594G, D594N, V600R and 1 with both K601N & V600E). Of these, 147 patients had baseline demographic and treatment data available for analysis. BRAF mutations were more common among males (45.6% of men vs. 22.7% of women, p = 0.03). No significant differences between other baseline patient demographics noted. Pathological characteristics revealed a non-significant trend toward poorer prognostic factors with BRAF non-V600E/K patients having increased Breslow depth (7.0 mm vs. 5.0 mm BRAF negative, 4.3 mm BRAF V600E/K) and higher rates of ulceration (71% vs. 44% BRAF negative, 30% BRAF V600E/K). BRAF non-V600E/K patients displayed a non-significant trend toward poorer overall survival (71 months vs. 215 months BRAF negative, 125 months BRAF V600E/K). Conclusions: Non-V600E/K BRAF positive patients appear to display less favorable disease characteristics and outcomes as compared to BRAF negative and BRAF V600E/K positive patients. Non-V600E/K melanoma show limited response to BRAF targeted therapy; however, evidence suggests the presence of non-classical mutations may confer susceptibility to MEK inhibition. Further characterization of non-V600E/K BRAF melanoma may allow for more refined prognostication and treatment decisions.
Role of testosterone synthesized by skin melanocytes in preventing malignant transformation of nevi.
Authors: Frantsiyants Elena Mikhaylovna , Bandovkina Valeria , Pogorelova Yulia A. , Kaplieva Irina V. , Cheryarina Natalia D. , Maksimova Natalia A. , Maksimova Maria I. , Neskubina Irina Valerevna , Trepitaki Lidia K. , Kit Oleg I.
Published: September 2018

e21066

Background: Melanocytes are involved into the synthesis and metabolism of steroid hormones in the skin. Cutaneous melanoma in 75% of cases occurs in congenital or acquired pigmented nevi. There are no studies comparing local hormonogenesis in nevi and melanomas. The purpose of the study was a comparative analysis of hormone levels in tissues of dysplastic nevi and cutaneous melanoma (pТ1-2N0M0). Methods: Levels of prolactin (PRL), progesterone (P4), total and free testosterone (T and fT), estrone (E1) and estriol (E3) and sex steroid-binding globulin (SSBG) were studied by ELISA in 17 samples of рТ1-2N0M0 melanoma and in 23 samples of dysplastic nevi. Intact tissues (n = 15) obtained from non-cancer patients during surgical treatment was used as the control. Results: Levels of T in nevi, compared to intact tissues, were 1.4 times higher, fT – 8.7 times higher, while SSBG content was 1.9 times lower; E3 was 1.6 times higher, PRL – 1.4 times lower, and levels of E1 in nevi were similar to the values in intact tissues. рТ1-2N0M0 melanomas, compared to intact tissues, demonstrated local androgen imbalance: T levels were decreased by 1.8 times, while fT exceeded the norm by 1.8 times, and SSBG – by 6 times. E1 content increased by 1.6 times, E3 decreased by 2.8 times. The E1/E3 ratio in nevi was reduced by 1.6 times, while in melanoma it was increased by 4.4 times. The T/E1 ratio in nevi was increased by 1.4 times, and in melanoma it was decreased by 2.8 times. Levels of PRL and P4 in melanomas, nevi and in intact tissues did not differ significantly. Conclusions: Melanoma was characterized by hyperestrogenia due to increased levels of E1 and low E3 concentrations which caused malignant transformation of melanocytes. Most likely, in melanoma spent SVT estrone synthesis, as evidenced by increase in the E1 / E3 and decrease T / E1.Apparently, fT in melanoma is used for estrogen synthesis, as indicated by the E1/E3 increase and decrease in the T/E1 ratio. Increased E1 synthesis can contribute to the realization of estrogen genotoxic effects. These mechanisms are absent in tissues of nevi. Hyperandrogenism in nevi probably prevents malignant transformation due to low aromatase activity.
Impact of the epigenetic modulator BORIS on sensitivity of melanoma cells to UV-induced DNA damage.
Authors: Janssen Sanne , Van Kempen Leon , Elchebly Mounib , M'Boutchou Marie-Noel , Spatz Alan
Published: September 2018

e21077

Background: Cutaneous melanomas display considerably higher mutational load compared to other solid tumors, mainly due to DNA damage and absent/defective repair. Chromatin organization plays an important role in these processes, with open chromatin conferring a higher sensitivity to DNA damage. BORIS is an epigenetic modifier that is correlated with open chromatin and is abnormally expressed in primary and metastatic melanoma. Here we set out to obtain a better understanding of BORIS’s role in chromatin organization and DNA damage in melanoma. Methods: A panel of melanoma cell lines was selected and BORIS mRNA expression was determined using qPCR. Cellular localization of BORIS was assessed by immunofluorescence. Ectopic BORIS expression was established exploiting a doxycycline inducible expression vector and proliferation was assessed using crystal violet and Hoechst staining. DNA damage was induced by exposure to 60 J/m2 UVC followed by apoptosis and cell cycle analysis using flow cytometry. Results: We confirmed aberrant BORIS expression in 61% of our melanoma cell line panel and observed nuclear BORIS localization in areas of low chromatin density. Forced expression of BORIS in BORIS low/intermediate cell lines resulted in a significant reduction in cell growth and increased cell death. Interestingly, BORIS overexpressing cells exposed to UV irradiation displayed a higher degree of cell cycle alterations and increased level of apoptosis compared to BORIS low/intermediate cells. Conclusions: Our results demonstrate that BORIS is increased in melanoma, localized in areas of open chromatin, and increased sensitivity to UV-induced DNA damage. Taken together, this indicates a role for BORIS in directing the chromatin state into a more open conformation, allowing increased sensitivity to DNA damage. Currently, we are analyzing DNA damage in BORIS overexpressing cells and are further investigating BORIS’s role in directing chromatin state by exploiting ATAC-seq and ChIP-seq for various epigenetic marks.
Effect of some cytokine combinations on growth and metastasis of experimental melanoma.
Authors: Zlatnik Elena Yurievna , Zolotareva Ekaterina I. , Nepomnyashchaya Evgeniya M. , Shulgina Oksana G. , Novikova Inna Arnoldovna , Przhedetskiy Yury Valentinovich , Pozdnyakova Victoria V. , Kochuev Sergey , Przhedetskaya Viktoria
Published: September 2018

e21081

Background: The purpose of the study was development and experimental validation of new methods of melanoma immunotherapy involving cytokines. Methods: The study included 30 С57Bl/6 mice with transplantable B16 melanoma. Dynamics of tumor growth, melanoma metastases to the lungs and spleen, morphology of melanoma, spleen and thymus and lymphocyte subsets in the blood and spleen after injected combinations of immunomodulators based on recombinant cytokines – IL-2 (Roncoleukin), IFN-γ (Ingaron) and TNF-α with thymosin (Refnot) – were studied. Results: Roncoleukin+Ingaron was the most effective combination that inhibited tumor growth during the therapy and after it by 30-38% and had a marked antimetastatic effect, up to complete absence of metastases in all animals. Morphological study demonstrated that thymus was the most active in this group of mice (a well-developed cortex with densely packed thymocytes); apparently, it was the cause for the increased levels of T-cells in the blood and Th (CD3e+CD4+) in the spleen of tumor-bearing mice compared to controls. The spleen of the mice showed a well-developed white pulp with large follicles, and Th level was the maximal – 47.9±1.5%, while in other groups it ranged from 15 to 35%. Morphological study of tumors revealed extensive necrosis (up to 2/3 of the tumor area), leukocyte infiltration, bleeds, blood clots in the vessel lumen and degenerative changes in tumor cells in all combinations of immunomodulators. Melanoma structure in the control group was typical, and most mice developed small and large metastases, sometimes multiple ones with extensive lung lesions; spleen metastases were observed in some mice. Conclusions: The study demonstrated the benefits of a search for optimal combinations of cytokine-based immune drugs to influence effectively an experimental transplantable tumor.
Clinical features and factors associated with survival in mucosal melanoma.
Authors: Aliaga Llerena Karina Mayra , Muñiz Johana , Gomez Henry Leonidas , Neciosup Silvia P.
Published: September 2018

e21082

Background: Mucosal melanoma (MM) is a rare, aggressive and poorly prognostic neoplasm compared to cutaneous melanoma (MC), probably due to the lack of knowledge about its pathogenesis, biology, risk factors, staging and treatment not yet well established. Our objective is to identify the epidemiological, clinical and pathological characteristics of mm and ocular melanoma (OM) as well as its relation with survival. Methods: Observational, descriptive and retrospective study. We analyzed data from 219 patients who met the selection criteria. Overall survival (OS) was estimated using the Kaplan-Meier method and the differences were assessed using the log rank test. In the statistical analysis SPSS 19 software was used and a p < 0.05 was considered statistically significant. Results: The mm represented 0.2% (219/98361) of the total number of patients diagnosed with cancer. MC represented 89% (N = 1598), mm 10% (N = 195) and MO only 1% (N = 24). mm predominated in females (N = 118 60%) with a median age of 63 years for both sexes. The most frequent sites were head and neck (N = 91 46.7%), anorectal (N = 68 34.9%) and vulva-vagina (N = 20 10.2%). The 5-year OS was 19.6% with a median of 21 months in the mm and 49.6%, with a median of 38 months in OM. Breslow > 4mm (p = 0.004), location (p = 0.019), distant disease (p = 0.004) and treatment type (p = 0.003) were considered as factors associated with survival. Conclusions: The MM, in the era of immunotherapy, is still considered one of the neoplasias with poor prognosis and poorly studied. It is vital to incorporate these patients into clinical trials in order to obtain real information on treatment efficacy, given the limited data available at the time.
Palliative care referrals and related outcomes among advanced cancer patients: A study revealing our institutional shortcomings.
Authors: Sedhom Ramy , Barile David
Published: September 2018

e21506

Background: Palliative care (PC) has an important role in the care of cancer patients at the end of life. Unfortunately, referral occurs very late in the illness trajectory, often within days of patient death. We examined palliative care referral among advanced cancer patients and associated outcomes during their final 2 weeks of life at our academic medical center. Methods: We reviewed the medical records of 269 cancer inpatients with solid malignancies that died in the past three years at our institution. We retrospectively compared patients who accessed palliative care services with those who did not. A multivariate logistic regression model including age, gender, type of cancer and metastatic status was conducted. Results: 74/269 patients (28%) had a palliative care consult prior to death. The most common cancer types were respiratory (26%) and gastrointestinal (21%). Patients with breast and gynecologic malignancies had significantly greater referral to palliative care services. The overall aggressiveness of care for the last year was significantly less (p = 0.003) for patients who were referred to palliative care. Patients referred to PC received less chemotherapy in the last 2 weeks of life (8% versus 21%, p < 0.001). We found that patients who were not referred to palliative care services experienced death more frequently in the ICU (16% versus 2%, p < 0.001), and in the emergency room (12% versus 1%), p < 0.001). Conclusions: Despite increased awareness of the importance of palliative care, and their overall improvement in survival among cancer patients, there are still disparities regarding access to palliative care and location of death. Patients receiving palliative services receive less aggressive interventions during their 2 last weeks of life and are less likely to die in the intensive care unit or emergency room. Quality improvement projects are underway addressing our shortcomings to palliative care services for our patients with advanced malignancies.
Participation of elderly gynecological cancer patients in clinical trials.
Authors: Prieske Katharina , Trillsch Fabian , Oskay-Oezcelik Gulten , Chekerov Radoslav , Schoening Eva-Maria , Oliveira-Ferrer Leticia , Grimm Donata , Kuerti Sasha , Suling Anna , Schmalfeldt Barbara , Sehouli Jalid , Mahner Sven , Woelber Linn Lena
Published: September 2018

e21520

Background: Elderly patients (pts) are underrepresented in clinical trials in gynecological cancer, even though they are disproportionally often affected. This study aimed to evaluate disposition and apprehension of elderly pts towards study participation. Methods: 112 elderly gynecological cancer pts (median age 70; range 65-92) were surveyed in a multicenter cross-sectional study. Besides fitness, state of disease, education and domestic situation, questions aimed at the general willingness to participate in a clinical trial. Personal reasons for rejection and suspected advantages/disadvantages that might evolve from participation were inquired. Results: Willingness to participate in a study was generally high (66.1%, 74/112). 42/112 (37.5%) had given their consent to participation in a study before, 12.5% (6/48) refused even though they were offered participation. Reasons for potential study participation were: ‘better monitoring of the disease’ (51/112), ‘better medical care’ (35/112), ‘to help medical research’ (31/112), ‘better medication’ (27/112) and ‘because of my doctor’s recommendation’ (17/112). Reasons for potential refusal were: ‘too time consuming’ (19/112), ‘fear of side effects’ (17/112), ‘misuse as experimental animal’ (14/112), ‘long distance to clinic’ (11/112) and ‘too little or unclear information’ (7/112). 26.1% (29/112) of pts stated, that they had ‘no objection’ against study participation. The question if pts anticipated having a longer life due to study participation was answered with ‘yes’ or ‘rather yes’ in 33.9% (38/112), 23.2% answered ‘no’ or ‘rather no’ (23.2% undecided). No relation between willingness to participate in a study and general fitness (p = 0.311), education (p = 0.631) or domestic situation (p = 0.195) could be observed. However, with increasing age, willingness decreased (p = 0.029). Conclusions: Elderly pts are generally willing to participate in clinical studies regardless of their fitness or educational background. Benefits of participation seem to be unclear among a majority of potential study participants. Therefore it might be decisive to provide more general information regarding benefits and safety for the elderly pts in a clinical trial.
The association of comorbid conditions and BMI on overall survival in geriatric breast cancer patients.
Authors: Desai Meghna R. , Iqbal Muhammad , Manthri Sukesh , Robinson Kathy , Mocharnuk Robert S.
Published: September 2018

e21525

Background: Breast cancer is the most common cancer and the second leading cause of cancer death in women. More than one-half of all women diagnosed with breast cancer are older than 65 years, and the incidence increases with age. Geriatric cancer patients also have higher comorbidity than the general cancer population. Patients with 3 or more comorbid conditions had a 20-fold higher rate of mortality from causes other than breast cancer. The purpose of this study was to determine whether specific comorbidities associated with specific organ systems, in addition to increased BMI, resulted in decreased survival. Methods: In this retrospective analysis, 269 patients with histologically confirmed invasive or in-situ breast cancer and above 65 years of age at the time of diagnosis were eligible. Patient comorbidities were recorded by system, including cardiovascular, renal, pulmonary, endocrine, neurologic, psychiatric and other systems. Patient BMI was also recorded. The primary outcome was overall survival (OS). Survival analysis was conducted by Kaplan Meier estimation and Cox proportional hazards regression analysis. Results: Patients with renal comorbidities were found to have decreased OS, disease free and progression free survival compared with rest of the population (HR 2.65, p = 0.023; HR 2.71, p = 0.021; HR 27.5, p = 0.019). For patients with cardiovascular (HR 1.46, p = 0.479), pulmonary (HR 1.63, p = 0.176), endocrine (HR 0.99, p = 0.991), neurologic (HR 1.92, p = 0.15) and psychiatric (HR 1.68, p = 0.187) comorbidities, there was no significant difference in OS compared with their counterparts. Patients with 4 or more systemic comorbidities had decreased OS compared with patients with either 1 or 2 systemic comorbidities (HR 0.178, p = 0.012; HR 0.404, p = 0.038). There was no significant change in OS with increased BMI (HR 0.998, p = 0.871). Conclusions: In patients with newly diagnosed breast cancer age 65 or older, those with renal comorbidities were found to have decreased OS, DFS and PFS. Patients with 4 or more systemic comorbidities also had decreased OS compared with those who had 1 or 2 comorbidities. Other comorbidities and BMI did not affect OS in these patients.
Tumor biologic characteristics and clinical outcomes in geriatric patients with breast cancer.
Authors: Manthri Sukesh , Iqbal Muhammad , Robinson Kathy , Mocharnuk Robert S. , Desai Meghna R.
Published: September 2018

e21526

Background: The probability of dying from breast cancer increases from 0.2% to 2% annually for women once they reach 70 years of age. However there is limited age-related information available about tumor biologic characteristics (TBCs) and clinical outcomes among elderly patients (pts). The purpose of this study was to analyze the impact of TBCs on clinical outcomes in a single institution's geriatric breast cancer pts. Methods: An institutional database of a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis was reviewed in an IRB approved fashion. Tumors were assessed for Nottingham grade, stage, ER/PR status, HER-2 status, tumor histology, lymphovascular invasion and nodal status. Kaplan-Meyer and Cox proportional hazards methods were used to calculate overall survival (OS). Results: Breast cancer was seen equally in both breasts: left n = 130 (48.3%), right n = 132 (49.1%). Most tumors were located in the upper outer quadrant (n = 122, 45.35%). TNM clinical stage Tlc was identified in 79 pts (29.36%), Tlb in 55 pts (20.44%), T2 in 54 pts (20.07%) and no nodal involvement in 146 pts (54.27%). Nottingham Grade 2 (n = 120, 44.60%) and invasive ductal carcinomas (n = 152, 56.50%) were diagnosed most often. Tumors were more frequently ER+ (n = 237, 88.10%), PR+ (n = 210, 78.06%), and HER2-negative (n = 219, 81.41%). There was no statistically significant increase in OS based on location of tumor (P = 0.9796) and tumor histology (invasive ductal vs invasive lobular cancers, P = 0.1143). Node negative breast cancers were associated with increased OS (P = 0.0014). Grade 2 tumors were associated with increased OS compared to Grade 3 tumors (P = 0.0112). ER+ and PR-negative tumors were associated with decreased OS in both short term and long term follow up (P = 0.0083 & P = 0.0254). Conclusions: In pts 65 years of age or older with newly diagnosed breast cancer, lack of nodal involvement is associated with increased OS. Prognosis for ER+ and PR-negative tumors is worse compared to ER+ and PR+ tumors. Nottingham Grade 2 tumors have better OS compared to Grade 3 tumors. Location of tumor and tumor histology are not associated with increased OS.
Endoscopic ultrasound: A safe procedure for elderly oncology patients?
Authors: John Elizabeth S. , Razjouyan Hadi , Singhal Nakul , Chokhavatia Sita , Tilara Amy
Published: September 2018

e21531

Background: Endoscopic ultrasound (EUS) has many indications in the management of gastrointestinal tumors, and has become pivotal in guiding therapy. While studies show that surgery in the elderly with malignancy causes increased morbidity and costs, no studies exist to assess the safety of EUS in this group. Methods: A single center retrospective analysis of patients who underwent EUS by two advanced endoscopists from April 2015 to December 2015 was performed. Patient demographics, procedure indications, final diagnoses, procedure length, sedation type, ASA classification, and intra-procedural complications, peri-procedural (immediate) complications, and post-procedural (24 hours after) complications were collected. Statistical analysis was done with Chi-square and comparison of mean tests. Results: 111 patients were identified with either a confirmed or suspected gastrointestinal malignancy out of 200 total patients included in the study. These patients included 38 with suspected pancreatic adenocarcinoma, one of which revealed pancreatic gastrinoma; 27 with suspected gastric adenocarcinoma or for staging; 17 with suspicious esophageal masses or for staging of squamous cell carcinoma or adenocarcinoma; 9 duodenal masses, 3 colorectal masses, 2 mediastinal masses, 1 biliary mass, 3 potential metastatic lesions to the GI system, and 8 patients with abdominal lymphadenopathy suspicious for malignancy. Patients over 65 years tended to have a lower risk of intra-procedure complications compared to those under 65, irrespective of all other factors including gender, performing endoscopist, and length of procedure (8.3% vs. 18.3%, p = 0.09). No significant differences were found in peri- and post-procedural complications between the over age 65 and under age 65 groups (4.0% vs. 1.6%, p = 0.44; 5.9% vs. 15.2%, p = 0.19). Conclusions: Due to the poor performance status often seen in the elderly oncology population, complications often arise from invasive procedures leading to increased morbidity, mortality, and costs. EUS aids in diagnosis, staging, and therapeutic decision-making of patients with gastrointestinal malignancies, and as this study shows, can be performed in older patients without incurring increased risks.
Basal physical inactivity as an independent risk factor for early death in elderly cancer patients: A prospective Brazilian cohort study with 608 patients.
Authors: Telles O Lima Jurema , Mello Maria Julia Gonçalves , Bergmann Anke , Bezerra Mirella Rebello , Cavalcanti Zilda , Sales Letícia telles , Thuler Luiz Claudio Santos
Published: September 2018

e21534

Background:With the aging of the population, cancer in the elderly people is becoming an increasingly common and complex health problem, particularly in low-middle-income countries, where physical inactivity and obesity have also been challenging and correlated with cancer and aging. The aim of this study is to determine whether the baseline physical inactivity per International Physical Activity Questionnaire(IPAQ) is an independent factor of premature death in the first six months.Methods: prospective cohort study of elderly patients (≥ 60 years). Participants with a recent diagnosis of cancer were from eight community hospitals and one cancer center in Northeast Brazil and were recruited during their first medical appointment at the outpatient oncologic clinic. Sociodemographic and clinical variables were determined and baseline comprehensive geriatric assessment (CGA) was conducted including IPAQ and Time Up and Go test. Data were analyzed using multivariate Cox proportional hazards models, overall survival was estimated using the Kaplan–Meier method and survival curves were compared using the Log rank test. Results:From 2015-2016, 608 patients, mean age 71.9 (SD ±7.4; range 60-96), 50.7% male, were enrolled. Main diagnoses were prostate cancer (29.1%), digestive system cancer (25.5%) and breast cancer (16.0%). 40.3% were considered obese/overweight (BMI ≥ 27). 42.1% were considered physically inactive per IPAQ. The mean of the Time Up and Go test on the physically inactive group by IPAQ was of 13.11s (SD ± 6.5), and of 22.72s (SD± 16.7) on the physically active one. After adjustment for age, site of cancer and cancer stage, the multivariate regression Cox model showed that being physically inactive is an independent predictor for early death (HR = 2.35, 95% CI: 1.50‒ 3.66, p < 0.001).Conclusions:Physical inactivity at admission was identified as a significant predictor of risk for premature death in elderly cancer patients. The evaluation of the physical activity should be incorporated into regular geriatric assessment of elderly cancer patients.