bluuebunny/crossref_metadata_2025 huggingface dataset:
Participation of BTK in MYD88 signaling in malignant cells expressing the L265P mutation in Waldenstrom’s macroglobulinemia, and effect on tumor cells with BTK-inhibitor PCI-32765 in combination with MYD88 pathway inhibitors.
Authors: Yang Guang , Xu Lian , Zhou Yangsheng , Liu Xia , Cao Yang , Tripsas Christina , Patterson Christopher J , Hunter Zachary R , Tai Yu-Zu , Anderson Kenneth Carl , Treon Steven P.
Published: March 2020

8106

Background: Bruton’s tyrosine kinase (BTK) promotes B-cell receptor signaling along with B-cell expansion and survival through NF-κB and MAPK. MYD88 L265P is a widely expressed somatic mutation in tumor cells from WM patients. MYD88 L265P promotes enhanced tumor cell survival through IRAK 1/4 mediated NF-κB and MAPK signaling. We therefore sought to clarify the role of BTK signaling in MYD88 L265P expressing WM cells, and the impact of BTK and MYD88/IRAK inhibition on WM cell signaling and survival. Methods: Western blot analysis was performed using total and phospho-specific BTK antibodies in MYD88 L265P expressing primary WM patient cells, BCWM.1 and MCWL-1 WM cell lines following MYD88 knockdown by lentiviral transduction, and/or use of MYD88 or IRAK signal inhibitors. Cells were also treated with the BTK inhibitor PCI-32765, in the presence or absence of MYD88 homodimerization or IRAK1/4 inhibitors. Annexin V / PI staining was used to assess cell survival, and synergism assessed with CalcuSyn software. Results: BTK was phosphorylated in MYD88 L265P expressing WM cells. Knockdown of MYD88 by lentiviral transduction, and/or use of MYD88 or IRAK 1/4 kinase inhibitors led to decreased BTK phosphorylation. Phosphorylation of BTK, TIRAP, a major TLR adapter protein for MYD88 signaling, IRAK1, IKBα, ERK1/2 and STAT3 were significantly reduced following treatment with PCI-32765. Treatment with PCI-32765 also induced apoptosis of MYD88 L265P expressing WM cells, and showed synergistic tumor cell killing in the presence of either MYD88 homodimerization or IRAK 1/4 kinase inhibitors. Conclusions: BTK activation is facilitated by MYD88 pathway signaling in L265P expressing WM cells, and participates in MYD88 downstream signaling. Inhibition of BTK by PCI-327625 led to robust tumor cell killing of MYD88 L265P expressing WM,cells, which was potentiated by MYD88 pathway inhibitors. These studies provide the framework for the investigation of BTK inhibitors in WM, as single agents and in combination with MYD88 pathway inhibitors.
Phase II randomized study of high-dose interferon alfa-2b (HDI) versus chemotherapy as adjuvant therapy in patients with resected mucosal melanoma.
Authors: Lian Bin , Mao Li Li , Cui Chuan Liang , Chi Zhi Hong , Si Lu , Sheng Xi Nan , Li Si Ming , Tang Bi Xia , Guo Jun
Published: March 2020

8506

Background: High-dose interferon alfa-2b regimen has been demonstrated as the standard of adjuvant therapy for resected melanoma. But the subgroup of mucosal melanoma seems more aggressive and insensitive to immunotherapy. So we conducted a phase II study (ChiCTR-TRC-11001798) to compare Interferon regimen with chemotherapy as adjuvant therapy for this particular subgroup pts. Methods: Resected mucosal melanoma pts were randomized to observation (Group A) or receive postoperative adjuvant Interferon (IFN) alfa2b 15 MU/m2/day for 5 days/week X 4 weeks followed by 9 MU/m2 three times each week for 48 weeks (Group B), or chemotherapy with temozolomide 200 mg/m2 d1-5 + cisplatin 25 mg/m2 d1-3, repeated every 3 Weeks X 6 cycles (Group C). Results: 189 patients were enrolled and 184 patients were eligible for survival analysis. With a median follow-up of 26.8 months, the median RFS for Group A, B and C were 5.4, 9.4 and 20.8 months, respectively (P<0.001). Estimated median OS for Group A, B and C were 21.2, 41.1 and 49.6 months (P<0.001), respectively. Toxicities were generally mild to moderate. Conclusions: Chemotherapy significantly improved RFS and OS as adjuvant therapy for mucosal melanoma pts over HDI regimen or observation. This trial suggests that different subgroup of melanoma may need different adjuvant therapy.
Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma.
Authors: Patel Sapna Pradyuman , Hwu Wen-Jen , Kim Kevin B. , Papadopoulos Nicholas E. , Hwu Patrick , Radvanyi Laszlo George , Mahoney Sandy , Deburr Tawania L , Liu Ping , Bedikian Agop Y.
Published: March 2020

8514

Background: Ipilimumab (Ipi) alters the immune system balance by inhibiting the suppression of T-cell function. In two phase III trials, Ipi has shown an overall survival benefit alone and in combination with dacarbazine in previously treated and treatment-naïve patients (pts) with metastatic melanoma (MM), respectively. We performed a single-institution, phase II clinical trial of Ipi plus temozolomide (Tem) in pts with MM. Methods: Pts between the ages of 18 and 75 with previously untreated unresectable stage III or stage IV MM and an ECOG Performance Status of 0 to 1 were enrolled in a phase II trial of Ipi plus Tem. Induction phase consisted of Ipi 10mg/kg intravenous on Day 1 and oral Tem 200 mg/m2 on Days 1 – 4 every 3 weeks for 4 doses. Maintenance consisted of Ipi 10 mg/kg intravenous on Day 1 starting week 12 and repeated every 12 weeks and oral Tem 200 mg/m2 on Days 1 – 5 starting week 12 and repeated every 4 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS) rate at 6 months. Responses were evaluated using immune-related response criteria. Results: Sixty-four pts were enrolled and received at least one dose of study drug. All pts were included in the analysis. With a median follow-up of 8.5 months, the PFS rate at 6 months was 43%, exceeding the proposed rate of 30%, and the median PFS was 5.1 months. There were 10 (15.6%) confirmed complete responses and 8 (12.5%) confirmed partial responses. At the time of this analysis, median overall survival has not been reached. Immune-related adverse events (irAEs) were experienced by 88% of pts, most commonly pruritus (88%), rash (83%), diarrhea (56%), transaminitis (45%), and colitis (11%). Grade 3/4 irAEs seen in more than one patient were skin rash (11%), diarrhea (9%), pruritus (6%), and transaminitis (5%). Constipation occurred in 70% of pts and was the most common gastrointestinal (GI) toxicity. There were no GI perforations or deaths on study due to treatment. Conclusions: At a median follow-up of 8.5 months, the best overall response rate in this study is 28%. Ipi at 10 mg/kg in combination with Tem given in an induction followed by maintenance fashion is safe, well-tolerated, and efficacious in MM.
Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.
Authors: Meier Friedegund Elke , Forschner Andrea , Klumpp Bernhard , Flaherty Keith T. , Honegger Juergen Bernd , Witte Maria , Bornemann Antje , Dummer Reinhard , Bauer Juergen , Tabatabai Ghazaleh , Weide Benjamin , Eigentler Thomas K. , Schadendorf Dirk , Quintanilla-Fend Leticia , Niessner Heike , Garbe Claus
Published: March 2020

8526

Background: Brain metastases are a major contributor to mortality in stage IV melanoma patients. In melanoma, the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways play a major role in tumor progression and therapy resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib recently gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, ongoing clinical studies suggest short-lived responses to BRAF inhibitors in melanoma brain metastases. Methods: We observed in several melanoma patients that chemotherapeutics or BRAF inhibitors yielded a significant regression of extracerebral metastases while brain metastases progressed or newly occurred. We therefore aimed at identifying factors that may contribute to treatment resistance of brain metastases. Results: Immunohistochemistry of matched brain and extracerebral melanoma metastases demonstrated an identical pattern of ERK, p-ERK and AKT staining but a different pattern of p-AKT and PTEN staining with hyperactivation of AKT and loss of PTEN expression in brain metastases. Mutation analysis revealed no difference in BRAF, NRAS or KIT mutation status in matched brain and extracerebral metastases. By contrast, in monolayer culture expression of ERK, p-ERK, AKT, p-AKT and PTEN was identical in cell lines derived from brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed hyperactivation of AKT compared to melanoma cells stimulated by fibroblast-conditioned medium. When inhibiting the MAPK and AKT signaling pathways at different levels in cells freshly isolated from melanoma brain metastases, growth inhibition and apoptosis induction was most pronounced with novel PI3K inhibitors such as BKM120 and BEZ235. Conclusions: These data suggest that 1) hyperactivation of the AKT survival pathway is brain environment-induced and relevant for the survival of melanoma cells in the brain parenchyma and that 2) inhibition of AKT signaling may be a suitable strategy to enhance and/or prolong the antitumor effect of chemotherapeutics or BRAF inhibitors in melanoma brain metastases.
CNS metastases as a site of progression on SWOG intergroup study S0008: A phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 (BCT) versus high-dose interferon (HDI) in patients with high-risk melanoma.
Authors: Samlowski Wolfram E. , Moon James , Witter Merle , Atkins Michael B. , Kirkwood John M. , Othus Megan , Ribas Antoni , Sondak Vernon K. , Flaherty Lawrence E.
Published: March 2020

8527

Background: Central nervous system (CNS) metastases (mets) are common in stage IV melanoma patients (pts). However, the incidence of CNS mets in pts with high-risk regional melanoma (HRM; stages IIIA-N2a thru IIIC N3) is not well described. A recent large prospective S0008 trial provided an opportunity to evaluate the contribution of CNS mets to treatment failure and survival. Methods: All pts had HRM treated with wide excision and full regional lymphadenectomy. Pts were then randomized to receive treatment with either BCT or HDI. All eligible pts were included in the analysis. Relapse/progression in the CNS (PCNS) was retrospectively identified only if clearly documented in case report forms. The cumulative incidence of PCNS in the presence of the competing hazard of death was estimated and potential risk factors were explored using the methods of Fine and Gray. Survival from PCNS was measured from date of PCNS to date of death. Results: 402 patients were evaluated (BCT: 200, HDI: 202), with median follow (if alive) of 6 years. The site of progression was identified in 162 (78 %) of 208 pts relapsing on study. Clearly documented PCNS occurred in 53/402 pts (13%). PCNS as a component of initial relapse/progression occurred in 34 patients (8%) and an additional 19 patients (5%) had delayed PCNS following initial systemic relapse. Most PCNS (85%) occurred within 3 years of initial surgery. Differences between arms were not significant (22 on BCT, and 31 on HDI)(p=0.21). Lymph node macromets demonstrated a strong correlation with development of PCNS (p=0.01). Neither primary tumor ulceration nor head and neck primary site were significant risk factors. Survival from diagnosis of brain mets was short (median 6 mo BCS, 5 mo HDI, p=0.93). Conclusions: Although the S0008 trial was not specifically designed to evaluate PCNS, a retrospective analysis identified a high CNS failure rate (at least 13%) in HRM pts, including 8% as the initial site of relapse. Further studies are needed to evaluate if screening for CNS mets in high-risk pts is useful and whether early treatment improves survival.
Neoadjuvant ipilimumab in locally/regionally advanced melanoma: Clinical outcome and immune monitoring.
Authors: Tarhini Ahmad A. , Edington Howard , Butterfield Lisa H. , Tawbi Hussein , Moschos Stergios J. , Shuai Yongli , Lin Yan , Horak Mary , Sarkisian Saro , Shipe-Spotloe Janice , Milburn Christy , Sander Cindy , Johnson Jonas Talmadge , Kirkwood John M. ,   University of Pittsburgh Cancer Institute
Published: March 2020

8533

Background: Neoadjuvant ipilimumab (ipi) for stage IIIB-C melanoma may improve the clinical outcomes and provide access to pre/post ipi blood and tumor to gain insight into host effector and suppressor immune response mechanisms. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks x 4doses total) bracketing definitive surgery. Tissue samples were obtained at baseline and at definitive surgery (week ≥ 6) and serum/PBMC collected at baseline, 6 weeks, then at 3, 6, 9, 12 months and/or progression. Flow cytometry was used to monitor the host effector and suppressor immune response in blood and evaluable tumor. Results: Thirty pts (21 male, 9 female), age 40-87 were enrolled (25 cutaneous primary, 1 unknown, 4 mucosal). Six had AJCC stage IIIB (N2b, N2c) and 24 IIIC (N3) melanoma. Ninety-three cycles have been delivered (median 4). Worst toxicities included grade 3 diarrhea/colitis (5 patients; 17%), hepatic enzyme elevations (2; 7%), rash (2; 7%), lipase (1; 3%), all manageable. Median follow up is 14 months: among 29 evaluable pts 15 (52%) continue disease free. Median PFS is 15.5 months, 95% CI = (8.1,-). The probability of 6 and 12 month PFS is 82.4% (95% CI=0.63, 0.92) and 53% (95% CI=0.31, 0.70) respectively. Peripherally, a significant increase in frequency of circulating T-regs (CD4+CD25hi+ Foxp3+; p=0.02 CD4+CD25hi+CD39+; p=0.001) from baseline to 6 weeks was observed. Greater increases in T-regs were associated with improved PFS (p=0.045; HR=0.54). Significant decreases in circulating MDSCs, were observed in monocytic HLA-DR+/low/CD14+ MDSC subtype (p<0.0001). Spontaneous in vivo cross presentation was observed resulting in Th1 CD4 and CD8 antigen specific T-cell immunity (gp-100, MART-1, NY-ESO-1 peptides) with increase in frequency after ipi. Activated TIL in tumor increased after ipi (CD3+/CD4+/CD69+;p=0.06 and CD3+/CD8+/CD69+) with significant induction/potentiation of T-cell memory (CD8+/CD45RO+/TNF-α+;p=0.03). Conclusions: Neoadjuvant ipi exhibits promising clinical activity and significantly modulates the host effector and suppressor immune response. Full analysis of this completed trial and its correlates will be presented. Support: BMS, P30CA047904 and P50CA121973.
Suppression of apoptosis by BRAF inhibitors through off-target inhibition of JNK signaling.
Authors: Tsai Kenneth Yee , Vin Harina , Leung Marco , Chitsazzadeh Vida , Ojeda Sandra , Dwyer David , Richards Kristen , Stewart Larissa , Curry Jonathan , Kim Kevin B. , Ciurea Ana , Duvic Madeleine , Prieto Victor , Ullrich Stephen , Flores Elsa
Published: March 2020

8537

Background: The advent of targeted therapy has revolutionized the treatment of cancer. The mutant BRAFV600E protein is found in over 50% of melanomas and thyroid carcinomas, resulting in elevated kinase activity, increased mitogen-activated protein kinase (MAPK) pathway signaling, and cell proliferation. Vemurafenib and PLX4720 were designed to selectively inhibit the BRAF kinase, and clinical trials of vemurafenib in metastatic melanoma have demonstrated a response rate of over 50% and an overall survival advantage over standard dacarbazine therapy. Approximately 20-30% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) highlighting the importance of understanding toxicities associated with this drug. Paradoxical ERK activation in BRAF wild-type, RAS-mutant cells is thought to be the major mechanism by which this occurs, as evidenced by the presence of RAS mutations in 60% of such lesions. Methods: Using a combination of BRAF-wild-type cSCC cell lines, primary human keratinocytes, as well as a UV mouse model of cSCC and human cSCC samples, we identified novel effects of BRAFi on apoptosis. Results: Here we show an unexpected and novel effect of vemurafenib and PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases. JNK signaling and apoptosis are suppressed in cSCC lesions arising in vemurafenib-treated patients as well as in irradiated mouse skin. This occurs independently of paradoxical ERK signaling and in the presence of MEK inhibitor. Treatment with PLX4720 greatly accelerates the development of UV-induced cSCC in mice without Ras mutations. Kinome screening identified ZAK and MKK4 (MEK4 / MAP2K4) kinases as inhibited by vemurafenib, leading to suppression of MKK4 and MKK7 (MAP2K7) phosphorylation. Knockdown of inhibited off-target kinases recapitulates these anti-apoptotic effects of vemurafenib. Conclusions: Our results implicate suppression of JNK signaling, independent of ERK activation, as an additional, complementary mechanism of adverse effects of vemurafenib. This has broad implications for combination therapies with other modalities that induce apoptosis and for the long-term use of vemurafenib in the adjuvant setting.
Early alterations of microRNA expression to predict and modulate melanoma metastasis.
Authors: Hernando Eva , Hanniford Douglas , Shang Shulian , Segura Miguel F. , Pavlick Anna C. , Berman Russell S. , Shapiro Richard L. , Darvishian Farbod , Osman Iman , Shao Yongzhao
Published: March 2020

8550

Background: Melanoma is curable for most patients whose tumors are surgically removed early in disease progression; however, many primary melanomas recur and progress to metastasis. Clinical staging is insufficient to robustly classify patients at highest risk of recurrence, and prognostic molecular biomarkers have not yet been identified. Methods: We performed miRNA profiling of 92 FFPE primary melanomas to discover metastasis relevant miRNAs and develop predictive models of recurrence, which were then validated in an independent cohort. We identified miRNAs differentially expressed between primary tumors that did and did not recur (3-year minimum follow-up) and between thick and thin lesions. We selected candidate miRs for screening in a fluorescence-based in vitro invasion assay, and prioritized a subset for in vivo testing. Potential downstream mediators of these miRNAs were selected by mRNA array analysis and tested in a secondary invasion screen. mRNA candidates that mimicked the miR’s invasion-suppressive effect were tested in 3’UTR reporter assays to confirm them as direct targets. Results: Using the discovery cohort we identified a 20 miRNA signature that can distinguish Stage I/II primary tumors (n=70) that did from those did not recur with 3-year minimum follow-up with an AUC=94%, 95% CI: (0.88, 0.99). Applying this model to predict risk for recurrence in the independent validation cohort yielded an AUC = 96%, 95% CI: (0.90, 1) in discriminating recurrent versus non-recurrent stages I/ II patients (n=45). From the discovery cohort, 40 candidates were selected for invasion assay screening, of which 5 miRNAs robustly inhibit in vitro invasion in 5 melanoma cell lines. Three miRs (miR-382, miR-516b, and miR-7) strongly suppressed metastasis in a mouse model. Moreover, multiple mRNAs tested as potential mediators mimicked the invasion-suppressive effects of candidate miRs. Of those, NCAPG2 and CDC42 were identified as miR-516b targets, CTTN as a miR-382 target, and PIK3CD as a miR-7 target. These genes have been linked to metastasis in melanoma or other tumors. Conclusions: Our data demonstrate that aberrant expression of specific miRNAs at diagnosis is predictive of and functionally impacts melanoma progression.
Analysis of KIT expression and mutations in sinonasal, genital, and acrolentiginous melanomas.
Authors: Bull Christian R F , Schoenewolf Nicola L , Belloni Benedetta , Holzmann David , Tonolla Sabina , Lang Roland , Mihic Daniela , Andres Christian , Dummer Reinhard
Published: March 2020

8563

Background: Melanoma is subdivided into molecular defined groups. One major subtype is characterized by a mutation in the BRAF gene. BRAF is less commonly mutated in acrolentiginous (ALM) and mucosal (MM) melanomas, instead these subtypes predominantly show aberrations in the KIT/CD117 gene. KIT aberrations predict the outcome of targeted therapies in ALM and MM patients, however the particular role of KIT expression in these melanoma subtypes remains controversial. To explore the relationship between KIT expression, mutation, and tumor stages, we investigated immunohistochemical KIT expression and mutation status in primary ALM/MM lesions and their metastases. We also compared the frequency of KIT mutations of MM in different anatomic locations. Methods: KIT immunoreactivity and mutation status was assessed in 41 ALM and 25 MM patients, using polyclonal rabbit anti-human KIT/CD117 antibody, and PCR was performed for KIT gene exons 9,11,13,17 and 18. Of these, 19 ALM and 15 MM patients had matched primary and metastatic lesions. Phosphorylated extracellular regulated kinase (P-ERK) was investigated in a subset of 8 ALM and 8 MM matched primary/metastatic pairs by immunohistochemistry. Results: Heterogeneous KIT immunoreactivity was observed in both primary and metastatic lesions. Mutations were present in four of 41 ALM (10%) and five of 25 MM (20%) patients. Only vulvar mucosal samples carried KIT mutations in contrast to sinonasal lesions (p= 0.0109). In KIT-mutated tumors, the mutations were present in KIT expressing as well as KIT negative cells, as shown by Laser Capture Microdissection (LCM). P-ERK expression was preferentially found in metastases. Conclusions: KIT expression is heterogeneous and shows no relationship with disease progression and mutation status, therefore KIT immunoreactivity is not a valuable marker for treatment decisions. In mucosal melanoma patients, KIT mutation frequency is significantly associated with anatomic location. Vulvar melanoma patients are prone to carry activating KIT mutations and thus may be more likely to benefit from KIT-targeted therapies than other subtypes. Therefore, especially vulvar melanoma patients should be screened for activating KIT mutations.
MicroRNA alterations associated with BRAF status in melanoma.
Authors: Ma Michelle W. , Farhadian Joshua Andrew , Friedman Erica Brooke , Vega-Saenz de Miera Eleazar , Hanniford Douglas , Segura Miguel F. , Berman Russell S. , Shapiro Richard L. , Pavlick Anna C. , Zavadil Jiri , Hernando Eva , Osman Iman
Published: March 2020

8565

Background: We hypothesize that BRAF mutations result in microRNA (miRNA) alterations which contribute to orchestrating the mutant BRAF’s oncogenic effects in melanoma. Our study is the first to examine the association between the BRAF mutation status in primary melanomas and the expression of miRNAs that target known tumor suppressors. Methods: 84 prospectively accrued melanoma patients at New York University Langone Medical Center were studied. DNA and total RNA were extracted from consecutive sections of formalin-fixed paraffin-embedded primary tissues. BRAF mutation status was determined by DNA sequencing. RNA was hybridized to miRCURY miRNA microarrays containing 1314 probes. Normalized miRNA data were analyzed using the t-test (p<0.05) to identify differentially expressed miRNAs between BRAFmut vs. BRAFwt cases. Those with an average fold change (FC) > 2 were selected for predicted (TargetScan, PicTar) and validated (miRWalk) gene target analysis, and overlapping genes targeted by ≥ 2 miRNAs were analyzed using pathway-mapping algorithms (KEGG, BioCarta, PANTHER). Results: 48 (57%) primaries were BRAFwt and 36 (43%) were BRAFmut (26 V600E, 4 V600K, 1 V600R, 1 V600D, 4 other). 30 miRNAs met the criteria for statistically significant differential expression and FC thresholding: let-7i, miR-23c, -26a/b, -27b, -34a, -98, -126*, -141, -148a, -181b, -195, -199a-3p, -199a/b-5p, -200a/b/c, -203, -205, -455-3p, -491-3p, -606, -641, -646, -1297, -4301; miRPlus-C1070, -C1110, -G1246-3p (average FC: 2.3-3.5, all increased in BRAFmut vs. BRAFwt). Predicted and validated target gene analysis revealed 317 genes, of which 110 (35%) were convergent targets of ≥ 2 miRNAs. Pathway analyses of the predicted, validated, and convergent target genes pointed to the potential impact of BRAFmut-associated miRNAs on known tumor suppressors FAS, PTEN, and TNF and the p53 pathway. Conclusions: Differentially expressed miRNAs in BRAFmut vs. BRAFwt primaries target genes with known roles in melanoma biology and/or treatment response. These miRNAs warrant further study as potential effectors of the BRAFmut oncogenic program.
Immunological and biological changes during ipilimumab (Ipi) treatment and their correlation with clinical response and survival.
Authors: Simeone Ester , Gentilcore Giusy , Romano Anna , Daponte Antonio , Caraco Corrado , Grimaldi Antonio M , Curvietto Marcello , Esposito Assunta , Queirolo Paola , Mozzillo Nicola , Ascierto Paolo Antonio
Published: March 2020

8573

Background: Ipilimumab (Ipi) is approved in the US as first and second line therapy in patients with metastatic melanoma (MM) and in MM patients with previous therapy in the EU, based on an overall survival benefit shown in a phase III study (Hodi, NEJM 2010). To date, no clinical parameter has been found to be predictive for response to treatment and only few immunologic changes have been identified as potential candidates. Methods: From June 2010 to November 2011 we treated in the Expanded Access Program with Ipi at 3 mg/kg, 95 pre-treated metastatic melanoma patients. The median age was 58 yrs (range 17-84); 10 pts (10,5%) were stage IIIc inoperable, 2 pts (2,1%) stage M1a, 4 pts (4,2%) stage M1b, and 79 pts (83,2%) stage M1c. 30/95 pts had brain metastases and 1/95 spinal cord metastases. All 95 patients were evaluable for response (DCR = CR+PR+SD according the irRC), overall survival, safety, including changes in LDH, CRP (C-reactive protein) and lymphocyte populations (CD4+,CD4CD25+,FOXP3/T-Reg cells). PBMC and sera were collected at week 0, 4, 7, 10 and 12. Results: We found a statistical significant decrease of LDH, CRP and FOXP3/T-Reg cells (p<0.0001; χ2 and Mann-Whitney), and an increase of lymphocyte count (p<.0001) in the responders group. These differences were also correlated to survival (log-rank test). No differences were observed for CD4+ and CD4+CD25+ between responders and non-responders (p=0.39;p=0.83; Mann-Whitney). An ORR of 22.1% (1CR+20PR; 95% CI 13.8-30.4) and a DCR at week 24 of 37.9% (36/95; 28.1-47.6, 95% CI) were observed. Median overall survival was estimated of 7.8 months (95%CI:5.0-10.6), with a p value not evaluable at the moment of the analysis due to insufficient follow-up because of long-term survival. Adverse events were registered in 40% (38/95) of patients and the most frequent were of grade 1 and 2 (pruritus 57.9%; rash 5.3%; thyroditis 5.3%). Conclusions: The decrease of LDH, CRP and T-Reg cells during Ipi treatment suggest these parameters should be further explored as potential predictive markers for response and survival. Given the potential clinical utility of these findings, these data warrants further prospective validation in a randomized trial.
Metastatic basal cell carcinoma: Differences in survival by site of spread.
Authors: McCusker Margaret Elizabeth , Hou Jeannie , Wang Lisa , Yue Huibin , Hauschild Axel
Published: March 2020

8585

Background: Basal cell carcinoma (BCC), the most common skin cancer, rarely metastasizes. Consequently, the epidemiology of metastatic BCC (mBCC) is poorly characterized. The largest published mBCC review includes 170 cases reported from 1894–1980 (von Domarus H, Stevens P. J Am Acad Dermatol 1984;10:1043-60). Targeted therapies with hedgehog signaling pathway inhibitors, such as vismodegib, are currently being developed to treat this rare disease. The objective of the current analysis was to provide an updated description of the epidemiology and survival outcomes for mBCC. Methods: A PubMed literature search was conducted for mBCC case reports published in English during 1981–2011. mBCC cases that met the following criteria were evaluated: primary BCC located on skin; primary tumor and metastasis confirmed by pathology, and metastasis was not the result of direct tumor spread. Only cases with survival data giving dates (month and year) or durations were included in the analysis. Differences between groups were assessed with t tests and χ2 tests as appropriate. Survival was assessed with Kaplan–Meier (K-M) methods. Results: We identified 101 mBCC cases that met the selection criteria; 38 patients (38%) had lymph node-only disease (LD) and 63 (62%) had distant metastases (DM). In both groups, males predominated. DM patients were younger at mBCC diagnosis (mean 59 vs 66 y for LD). Among 96 cases with treatment data for metastatic disease, more DM patients received chemotherapy (25% vs 9% for LD), but more LD patients underwent surgery (85% vs 52% for DM). Survival duration ranged from 0 to 120+ months in all patients. The overall 1-y probability of survival after mBCC diagnosis was 75.7% (95% CI 67.2–84.2%), with lower survival in DM patients (69.1%; 95% CI 57.5–80.7%) vs LD patients (86.5%; 95% CI 75.5–97.5%). Conclusions: Patients with LD and DM mBCC may have different clinical courses and outcomes. Based on published case reports, DM patients were younger at mBCC diagnosis and had a lower 1-y survival probability vs LD patients. To our knowledge, these are the first K-M survival estimates reported for an mBCC case series of this size. These data help to provide a historical context for novel mBCC therapies under development, such as vismodegib.
Clinical experience with atypical spitzoid tumors in patients younger than age 18: Does fluorescence in situ hybridization predict lymph node metastasis?
Authors: Stanelle Eric J. , Busam Klaus J. , Rich Barrie S. , Coit Daniel G. , La Quaglia Michael P.
Published: March 2020

8586

Background: Determining the malignant potential of atypical spitzoid melanocytic proliferations can be diagnostically challenging, and many patients are therefore managed as if they had melanoma. However, few studies focus specifically on atypical spitzoid tumors (AST). Further, cytogenetic analysis using fluorescence in situ hybridization (FISH) has been used to determine malignant potential. We reviewed our institutional experience to determine staging and clinical outcomes, and the correlation between FISH findings and regional nodal positivity in patients with AST. Methods: With IRB approval, we retrospectively reviewed all patients aged <18 years treated for AST from 1981-2011 to determine staging variables, outcome, and the results of 4-probe FISH assay. A total of 44 patients with a median age of 11.5 years were identified. All pathology was re-reviewed by a single dermatopathologist. Staging was based on 2010 AJCC criteria. Correlations were determined using either the Pearson or Spearman correlation coefficient. Results: Median lesion thickness was 2.8 mm (range: 0.55-12) and eight (18%) lesions met spitzoid melanoma criteria. Median followup was 4.1 years for all patients (5.5 years for spitzoid melanomas). Thirty-nine patients (89%) underwent sentinel lymph node biopsies (SLNB) and 15 (38%) were positive. Lymph node (LN) positivity correlated with tumor thickness (p=0.002), stage (p=0.001), and mitotic rate (p=0.05). FISH was available for 17/39 patients who had SLNB; sensitivity and specificity for LN metastases were 50% and 54%, respectively. Of 15 patients with a positive SLNB, 12 underwent completion LN dissection, three of which were positive for 1, 2, and 3 additional nodes, respectively. There were no recurrences or disease-related deaths. Conclusions: Traditional indicators of thickness and stage predicted nodal involvement in pediatric patients with AST. However, FISH results did not predict nodal status and should not be used to guide management. With 100% disease specific survival and no recurrences, AST should be considered a separate entity from melanoma and complete excision may be sufficient therapy.
A phase II, multicenter, open-label study of YM155 plus docetaxel in subjects with stage III (unresectable) or stage IV melanoma.
Authors: Steinberg Joyce Leta , Bedikian Agop Y. , Ernst D. Scott , Chmielowski Bartosz , Redman Bruce , Keating Anne Therese , Jie Fei , Chen Caroline , Weber Jeffrey S. , Kudchadkar Ragini Reiney ,   YM155-CL-034 Study Group
Published: March 2020

8587

Background: Survivin is a microtubule-associated protein implicated in both preservation of cell viability and regulation of mitosis in tumor cells. It is over-expressed in melanoma, breast, and non-Hodgkin’s lymphoma. YM155 is a first in class survivin inhibitor. Methods: The study had 2 parts: Part 1 established the dose of docetaxel that was tolerable in combination withYM155 at 5 mg/m2/day continuous infusion over 168 hours q 3 weeks. Part 2 utilized the dose of docetaxel established in Part 1 to further evaluate the tolerability and activity of the combination. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were overall response rate, 1-year overall survival (OS), time from first response to progression, clinical benefit rate, time to response, and safety. Results: 64 patients with metastatic melanoma were treated with docetaxel followed by continuous infusion YM155. 7 patients were treated with 100mg/m2 of docetaxel and 57 patients were treated with 75mg/m2 of docetaxel. Median age was 59, with 44 men and 20 women treated. 6-month PFS per Independent Review Committee (IRC) was 34.8% (95% CI 21.3 – 48.6%). Overall objective response rate per IRC was 12.5%, with no complete responses (CR) and 8 patients with partial responses (PR). The Stable disease (SD) rate was 51.6%, leading to a clinical benefit rate (CR + PR + SD) of 64.1%. Estimated 1-year overall survival is 50.5%. 87.5% of patients experienced a Grade 3 (G3) or Grade 4 (G4) event attributable to either YM155 or docetaxel. The clinically pertinent G3 or 4 toxicities occurring in greater than 5% of patients treated included neutropenia (59.4%), febrile neutropenia (12.5%), mucositis (9.4%), fatigue (7.8%), diarrhea (6.3%), and dehydration (6.3%). There were 3 deaths on study, all attributable to disease progression. Conclusions: YM155 is a novel agent that shows modest activity when combined with docetaxel in patients with melanoma. YM155 was generally well tolerated, but the pre-determined primary endpoint for efficacy was not achieved.
Pharmacodynamic activity of selumetinib to predict radiographic response in advanced uveal melanoma.
Authors: Carvajal Richard D. , Ambrosini Grazia , Wolchok Jedd D. , Chapman Paul B. , Dickson Mark Andrew , D'Angelo Sandra P. , Bluth Mark J. , Paucar Daniel , Fusco Anne , Bohr David , Roman Ruth Ann , Montefusco Mary , Doyle L. Austin , Marr Brian , Abramson David H. , Chou Joanne F. , Panageas Katherine , Schwartz Gary K.
Published: March 2020

8598

Background: Functionally activating mutations (mut) in Gnaq or Gna11, genes that encode for widely expressed G-protein alpha subunits, are early oncogenic events in uveal melanoma (UM) development and result in activation of the MAPK pathway. We previously demonstrated effective pathway inhibition with selumetinib (AZD6244, ARRY-142866) in UM cell lines, with decreased viability associated with pERK and cyclinD1 suppression (Ambrosini, AACR 2010). Methods: Using paired metastatic tumor biopsies from patients (pts) with radiographically progressing UM treated with selumetinib 75 mg BID on a phase II trial (NCT01143402), we correlated MAPK pathway inhibition with radiographic tumor regression and clinical benefit. Biopsies were performed at baseline and after 14 +/-1 days of treatment. Western blotting was performed for pERK and cyclinD1, and quantitated by densitometry. Response (RECIST 1.1) was assessed at baseline, week (wk) 4, wk 8, and q8wks subsequently. Radiographic regression was defined as greatest percentage shrinkage from baseline. Clinical benefit was defined as RECIST response or stable disease ≥16wks. Results: Paired tumor biopsies were assayed from 18 pts: median age 60 (range 47-81), M:F 11:7, median 1 prior therapy (range 0-2), 17 with liver involvement, Gnaq mut:Gna11 mut:wild-type 8:9:1. Radiographic regression was observed in 5 pts, with 2 achieving partial responses. 4 pts were on study ≥16wks (16+, 20, 25, 31 wks), with one currently on study at 11+ wks. Median pERK and cyclinD1 as measured by densitometry decreased by 48% (p=.03) and 76% (p=.03), respectively. Radiographic regression correlated with suppression of pERK (Spearmen’s rank correlation; p=0.04) but not cyclinD1 (p=0.38). A trend towards pERK suppression correlating with clinical benefit was observed (p=.07) with each of the 5 pts achieving PR or SD ≥16wks having a decrease of ≥30% in pERK from baseline. Conclusions: Selumetinib can inhibit pERK and cyclinD1 in UM and can result in tumor shrinkage. Sustained inhibition of pERK inhibition at day 14 may be predictive of benefit. Further evaluation of MEK inhibition in this disease is warranted.
Exhibition of a stem-cell like phenotype with the expression of CD271 in drug-resistant melanoma cells.
Authors: Lieser Elizabeth Ann Teresa , Leontovich Alexey A , Holtan Shernan G. , Nevala Wendy Kay , Markovic Svetomir
Published: March 2020

8599

Background: Chemotherapy resistance is a common, difficult problem for melanoma patients needing long term care and those suffering from recurrence. Neural growth factor receptor (NGFR), also known as CD271, is commonly expressed on mesenchymal stem cells and is important for development, survival and differentiation of cells. This has previously shown to be expressed on melanoma stem cells. We hypothesized that treatment with carboplatin enriches the population of tumor cells for cancer stem cells (CSC) as a mechanism of chemotherapy resistance. Methods: Core tumor samples from 118 patients with metastatic melanoma were obtained from formalin-fixed paraffin embedded specimens. Slides were stained using an anti-CD271 antibody for IHC. A375 melanoma cells were treated with increasing concentrations of carboplatin for approximately 1 year. WT, 6 mg/mL and 10 mg/mL resistant cells were tagged with CD271-PE antibody and run on a flow cytometer. These cells were then tested for gene expression by microarray using an Affymetrix human 133 plus 2.0 chip, and analyzed on Partek software. Pathway analysis of these carboplatin resistant cells was preformed using Ingenuity. Results: Virtually all melanoma tumor samples stained positively for CD271 by IHC, with a median of 50% cells within tumor samples expressing the cytoplasmic marker. Flow cytometry demonstrated an increase in the percentage of cells expressing CD271 as resistance to carboplatin increased. Wild type A375 cells contained 30% positive CD271, A375 6mg/mL resistant contained 42% positive and A375 10mg/mL resistant showed 66% positive. Microarray also exhibited a direct correlation between CD271 gene expression with increasing carboplatin resistance. Functional ontology enrichment revealed development and regulation of the EMT pathway as an important process impacted by our resistant cell line. Conclusions: The data suggests that as melanoma cells become resistant to certain chemotherapy drugs they essentially loose their differentiated phenotype and become more stem cell-like. Monitoring melanoma expression of CD271 could help individualize therapy and anticipate chemotherapeutic resistance in this high-risk group of patients.
Post diagnosis weight gain and the role of exercise in breast cancer survivors.
Authors: Sanft Tara Beth , Alvarez-Reeves Marty , Irwin Melinda
Published: March 2020

9007

Background: Obesity is linked to poor breast cancer (Br Ca) outcomes including higher risk of recurrence and death. No study has examined if post-diagnosis weight (wt) gain modifies the effect of exercise interventions on body composition. We examined wt change from diagnosis (diag) to enrollment (enroll) into a 6-mo randomized trial of exercise v. usual care to explore if post-diagnosis wt gain modified the effect of exercise on body wt, body fat, lean body mass (LBM) and bone mineral density (BMD) in breast cancer survivors. Methods: 75 inactive Br Ca survivors were recruited and randomized to exercise (n = 37) or usual care (UC) (n = 38). At baseline, women completed a questionnaire assessing self-report wt at diag and at the time of enroll into the study (~3 yr). The exercise group participated in 150 min/wk of supervised exercise. The UC group maintained their physical activity level. Body composition was assessed at enroll and 6-mo via dual-energy X-ray absorptiometry (DXA) by one radiologist blinded to intervention group. Results: Wt and DXA data were available for 68 / 75 participants. On average, women gained 3.3±8.2 kg from diag to enroll, with 53% gaining wt (mean = 8.9 ± 6.8 kg) and 47% maintaining or losing wt (mean change = -2.9 ±3.9 kg). The majority of wt gain occurred among women who were non-obese at diag (BMI < 30), with 60% of non-obese women gaining wt (mean = 8.0 ± 6.8 kg) compared with 38% of obese women gaining wt (mean = 12.2 ± 6.4 kg). Those randomized to exercise lost body fat including women who gained wt since diag (mean % fat loss for exercisers (-0.92 ± 0.31) vs. UC (0.36 ±0.30), p = .0063) and women who did not gain wt since diag (mean % fat loss for exercisers (-0.65 ± 0.39) vs. UC (0.45±0.47), p = .08) even after adjusting for obesity status at diag. Similar improvements in LBM and BMD were observed with exercise in women who did or did not gain wt since diag. Conclusions: Wt gain in Br Ca survivors is common, the majority of weight gain in this study occurred among women who were not obese at diag. Exercise led to body fat loss and other favorable body composition changes among both non-obese and obese women. Exercise and other wt management programs should be offered to all Br Ca survivors regardless of BMI at diagnosis as a strategy towards prevention of wt gain.
Falls, physical performance deficits, and functional losses in cancer survivors with chemotherapy-induced neuropathy (CIPN): A University of Rochester CCOP study.
Authors: Mohile Supriya Gupta , Fan Lin , Gewandter Jennifer S. , Mustian Karen Michelle , Peppone Luke Joseph , Heckler Charles E , Hopkins Judith O. , Dakhil Shaker R. , Miller Jessica , Morrow Gary R.
Published: March 2020

9014

Background: CIPN impairs quality of life in cancer survivors. Little is known about the prevalence of falls, physical performance (PP) deficits, and functional losses or their association with CIPN toxicities in cancer survivors. Methods: We conducted an analysis of baseline assessments from a phase III randomized clinical trial in cancer survivors with CIPN self reported pain scores of > 4 reflecting leg and foot pain from neuropathy over the past 24 hours on a scale from 0 (“no pain”) to 10 (“pain as bad as you can imagine”). Patients also completed EORTC QLQ-CIPN-20 sensory and motor scales for neuropathy toxicities and self reported falls in the previous 3 months. A PP deficit was defined as “a lot of difficulty” or “unable to do” any of 6 physical tasks (e.g., lifting objects, walking a quarter of a mile). Functional losses were defined as “a lot of difficulty” or “unable to do” any of 5 functional tasks (e.g., managing money, bathing). We examined the association of baseline characteristics and CIPN toxicities with falls, PP deficits and functional losses using logistic regression. Results: Of 421 patients, 11.9% experienced recent falls, 58.6% reported a PP deficit, and 26.6% reported a functional loss. Patients with falls and/or PP deficits were more likely to be older (mean age 60.9 vs 58.9, p=0.02), female (75.3% vs 65.2%, p=0.03) and have less education (<high school: 7.1% vs 0.6%, p<.01). Cancer and chemotherapy history were not different between groups. Patients with falls and/or PP deficits reported higher severity of CIPN toxicities: pain (6.82 vs 6.05, p<0.01), sensory (23.3 vs 19.6, p<0.01), and motor (17.4 vs 12.7, p<0.01). In multivariable analysis, factors associated with having a fall and/or PP deficit included: older age (OR 1.03, p=0.04), low education (OR 9.34, p=0.04), and motor toxicity (OR 1.21, p<0.01). Factors associated with functional losses included: non-white race (OR 3.16, p=0.01), Hispanic ethnicity (OR 5.32, p=0.05), motor toxicity (OR 1.19, p<0.01), and PP deficit (OR 4.94, p<.01). Conclusions: CIPN toxicities, primarily motor, are significantly associated with falls, physical performance deficits, and functional losses.
A prospective study to evaluate the efficacy and safety of oral acetyl-L-carnitine (ALC) in treatment of chemotherapy-induced peripheral neuropathy (CPIN).
Authors: Sun Yuanjue , Liu Baorui , Liu Ping , Wu Changping , Zheng Rongsheng , Zhang Xiaohua , Zhuang Zhixiang , Deng Yongchuan , Zheng Leizhen , Xu Qing , Jiang Bin , Ouyang Xuenong , Gao Jianfei , Jiang Su , Zheng Wei , Li Benjamin Xiaoyi , Shu Yongqian , Yao Yang
Published: March 2020

9017

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of many commonly used chemotherapeutic. This side effect of chemotherapy can be debilitating and effective treatment for CIPN remains elusive. Previous studies demonstrated that Acetyl-L-Carnitine (ALC) is effective in attenuating CIPN, controlled study is needed to substantiate ALC’s effect in treatment of CIPN. Methods: This study was designed to evaluate the efficacy and safety of Acetyl-L-Carnitine (ALC) Hydrochloride Enteric-coated Tablet (oral administration) in the treatment of CIPN. It was a prospective, randomized, double-blinded, placebo-controlled and paralleled clinical study (registration No. 2007L03540). Of 239 subjects enrolled in the study (NCI grade 2 or above), 118 subjects received 3g/day ALC orally for 8 weeks and 121 received placebo. Primary endpoint was set as improvement of peripheral neuropathy at least 1 grade and assessment was made in week 4, 8 and 12 after enrollment. Results: In full analyses set (FAS) and per-proposal set (PPS), the peripheral sensory neuropathy was significantly ameliorated in ALC group with 50.5% and 51.6% patients meeting the primary endpoint at week 8 and 12 respectively while only 24.1% and 23.1% of patients in the placebo group at week 8 and 12 respectively (p<0.001 in both sets). Secondary endpoint such as nerve electrophysiological test and Physical Condition Score (Karnofsky performance status, KPS) were also significantly improved in patients with ALC treatment (in FAS, P=0.0463 and P=0.022; in PPS, P=0.0076and P=0.0064, respectively). Cancer-related fatigue was significantly alleviated after ALC treatment in PPS (P=0.0135). Safety: 236 subjects were included in safety assessment and 41 patients experienced 62 adverse events during the course of study. There was no significant difference in AE/SAE incidence between the two groups (P=0.3903). Conclusions: Oral administration of ALC is effective in attenuating CIPN as well as in reducing cancer-related fatigue and improving physical conditions in cancer patients. The treatment of oral ALC is safe and well tolerated.