bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient human leukocyte antigen (HLA) genotype may predict response to anti-programmed death receptor 1 (anti-PD1) in advanced melanoma.
Authors: Oey Oliver , Khattak Muhammad Adnan , Abed Afaf , Meniawy Tarek , Reid Anna , Calapre Leslie , Millward Michael , Gray Elin
Published: June 2021

e21512

Background: Anti-PD-1 therapy has improved the outcome of advanced melanoma patients with a 5-year survival rate of about 40-45%. However, biomarkers predictive of response to immune checkpoint blockade therapy are lacking. There is limited data on the utility of host germline human leucocyte antigen (HLA) genotype as a predictor of response to anti-PD-1 therapy in advanced melanoma. Here, we investigate the prognostic value of HLA in predicting survival outcomes of patients with unresectable locally advanced, metastatic melanoma on anti-PD-1 therapy. Methods: Blood was collected from 113 metastatic melanoma patients who were treated with anti-PD-1 therapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and subsequently HLA-I and HLA-II typed using clinically validated assay. Univariate analyses were conducted using Cox regression model correlating homozygosity at HLA-I and HLA-II loci with overall survival (OS). HLA-A and HLA-B were classified into 12 supertypes and correlated with OS. Multivariate analyses were performed while controlling for age, gender, prior therapy, BRAF mutation status, ECOG performance status and presence of liver and brain metastases. Results: Homozygosity at HLA-I or HLA-II loci was not associated with OS. However, the absence of HLA-B62 supertype was associated with a trend towards improved OS (HR: 0.53 [95% CI:0.25-1.10]; P = 0.09) as reported previously. Notably, the absence of HLA-B27 supertype was associated with improved OS which was statistically significant (HR: 0.45 [95% CI:0.24-0.85]; P = 0.01). In multivariate analyses, the prognostic value of HLA-B27 supertype (HR: 0.38 [95% CI:0.19-0.76]; P = 0.006) was maintained, whereas the prognostic value of HLA-B62 supertype significantly improved (HR: 0.42 [95% CI:0.19-0.94]; P = 0.03). Conclusions: Our results suggest a limited role of HLA homozygosity in predicting survival of melanoma patients treated with anti-PD-1 therapy. However, we identified that the absence of HLA-B62 and HLA-B27 supertype is associated with improved survival benefit. Therefore, HLA-B27 and HLA-B62 supertype may be used as adjunct biomarkers of response to anti-PD-1 therapy in patients with melanoma in addition to PD-L1 status, pending validation in prospective randomised clinical trials.
Incidence of immune-related adverse events with pembrolizumab in advanced melanoma and correlation with treatment response: A single institution review of irAEs.
Authors: Myrdal Caitlyn N. , Mehta Paras , Smith Eric , Briones Kimberly , Albright Jason , Curiel-Lewandrowski Clara , McBride Ali , Sundararajan Srinath
Published: June 2021

e21519

Background: Anti-PD-1 therapy has become a mainstay of advanced melanoma treatment. However, associated irAEs are common and contribute to significant delays or cessation of treatment. In this retrospective cohort study, we aim to characterize the real-world irAE profile of pembrolizumab at our institution and its prognostic implications. Methods: We evaluated unresectable stage III-IV melanoma patients treated with pembrolizumab between 2011 and 2016 at the University of Arizona Cancer Center (UACC). Information regarding demographics, treatment, irAEs, and hospitalizations were recorded. Adverse events were graded using the common terminology criteria for adverse events v.4.0 (CTCAE). Results: Seventy-three patients were identified, 4 (5.5%) with unresectable stage III and 69 (94.5%) with stage IV melanoma. The median age was 68; 48 (65.8%) patients were male and 25 (34.2%) were female. Nineteen patients (26.0%) had a preexisting autoimmune disorder. 171 irAEs were identified in 58 of the patients. 141 (82.5%) were Grade 1, 24 (14.0%) were Grade 2, and 6 (3.5%) were Grade 3. Incidence and time to onset of significant events is displayed in Table. Eleven (15%) patients were hospitalized, and 8 patients (11.0%) stopped treatment due to an irAE. Sixteen (84.2%) patients with a preexisting autoimmune condition experienced an irAE versus 78% of patients without an autoimmune condition. Twelve patients (75%) had an exacerbation of their autoimmune condition. Response could be assessed in 67 patients . 30 patients of the 67 (45%) had a CR or a PR and 37 patients (55%) had progressive disease (PD). 58 of 67 (87%) experienced an irAE. 29 (50%) of the 58 irAE patients had PD, while 8 (88.9%) of the 9 non-irAE patients had PD. The relative risk of progression in patients who experienced an irAE versus who did not was 0.56 (95% CI: 0.39-0.79, p= 0.001). Conclusions: Experience with pembrolizumab at our institution suggests a similar irAE profile compared to landmark trials, though we observed a higher percentage of patients who required discontinuation of pembrolizumab (11% versus 5% in Phase III trials). In our retrospective study, the risk for progression was significantly higher in patients without irAE versus with any irAE, suggesting that development of irAE could be a positive prognostic sign.[Table: see text]
RECQL5 mutations as a potential efficacious predictor of immunotherapy in melanoma patients.
Authors: Zhao Yun , Fan Dandan , Huang Xiaochun , Huang Mengli , Chen Yaoxu , Bei Ting
Published: June 2021

e21547

Background: Gene mutations in DNA damage repair (DDR) pathway were reported to affect the clinical response to immune checkpoint inhibitors (ICIs) by driving mutagenicity. Previous studies showed that RECQL5 is involved in RAD51-mediated strand invasion for homologous recombination DNA damage repair (HR-DDR). RECQL5 encoding RecQ protein-like 5 (RECQL5) is a member of RecQ helicase family and was discovered to play a tumor-suppressive or oncogenic role in various cancers. However, the association between RECQL5 mutation and ICI efficacy has not been revealed. Methods: Data of nine publicly independent cohorts of NSCLC, melanoma, and pan-cancer were retrieved (Rizvi, MSKCC, OAK/POPLAR, Van Allen, Hugo, Synder, Miao and Samstein cohorts) to investigate the correlation between RECQL5 mutations and clinical events including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Wilcoxon test was used for comparing tumor mutational burden (TMB) between RECQL5-mutated patients and their wild-type counterparts. In addition, the correlation between infiltration of immune cells and RECQL5 mutation status was also analyzed by QUANTISEO using data of SKCM cohort (n=466) from TCGA database. Statistical significance was set at P = 0.05. Results: RECQL5 mutations were most commonly seen in melanoma patients and the detection rate was 4%-8% in melanoma patients from cohort Van Allen, Hugo, Synder, and Miao. RECQL5 mutation was not detected in other cancers except for one lung cancer case. In the three melanoma cohorts (Van Allen, Synder, Miao) with OS data available, the OS of the RECQL5-mutated patients was 2 to 3 times longer than that of the RECQL5-wt patients. In Synder cohort, the difference in OS between these two subsets was statistically significant (53.9 months vs 25.0 months, P = 0.045). In addition, the occurrence of RECQL5 mutations was correlated with higher CBR both in Miao ( P = 0.017) and Synder cohorts ( P = 0.011). No difference was observed in the PFS or ORR between these two subsets. Notably, RECQL5 mutations were associated with higher TMB levels both in Miao (32.6 mut/Mb vs 7.9 mut/Mb, P = 0.016) and Synder cohorts (1124 mut/Mb vs 358 mut/Mb, P = 0.033). Moreover, RECQL5 mutations were found to be correlated with increased infiltration of CD4+ T cells (no-regulatory) ( P = 0.037), B cells ( P = 0.13) and decreased infiltration of regulatory CD4+ T cells ( P = 0.02) in RECQL5-mutated tumors over RECQL5-wt tumors. Conclusions: RECQL5 mutations can serve as a potential predictor for a durable response to ICIs in melanoma. Moreover, the occurrence of RECQL5 mutations was correlated with higher TMB level as well as infiltration of immune cells, indicating the underlying mechanism of its predictive effect.
Effect of time to surgical intervention in stage 3 cutaneous melanoma.
Authors: Pairawan Seyed Saeed , Selleck Matthew J. , Caba Molina David , Solomon Naveenraj Livingstone , Reeves Mark Evan , Garberoglio Carlos A. , Namm Jukes P.
Published: June 2021

e21571

Background: Delay in surgical resection has been found to be associated with poorer overall survival (OS) in patients with stage 1 cutaneous melanoma. However, the impact of surgical timing on survival in stage 3 cutaneous melanoma remains unknown, especially in the era of immunotherapy. We sought to evaluate to the effect of time to definitive surgical intervention on OS in stage 3 cutaneous melanoma at Commission on Cancer accredited institutions. Methods: The National Cancer Database (2012-2016) was used to identify patients who underwent biopsy and definitive surgical intervention of cutaneous melanoma. Time to intervention (TTI) was analyzed from the time of initial biopsy to definitive surgical resection and classified into quartiles, (Q1≤22 days; Q2 = 23-33 days; Q3 = 34-49 days; Q4≥50 days) using χ2 and multivariable logistic regression. Survival was analyzed using Kaplan-Meier and Cox proportional hazard models. Results: We analyzed 4560 patients with a median age of 61 years (18-90) and most patients being non-Hispanic white and male (91.6% and 63%, respectively). Median Breslow thickness was 2.8 mm (0-9.8 mm). Median TTI was 33 days (0-352 days) with a mean OS of 52, 49.8, 48.4, 48.3 months for Q1 to Q4 respectively (p = 0.008). Age ≤50 years, treatment at a comprehensive community cancer center and only 1 positive lymph node (LN) were all associated with Q1 TTI (p = 0.002, p < 0.001 and p < 0.001, respectively). Black race, treatment at an academic facility, > 4 LN positive, > 4 mm thickness, and no administration of immunotherapy were all associated with Q4 TTI (p = 0.002, p < 0.0001, p < 0.0001, p < 0.0001 and p < 0.0001 respectively) on univariate analysis. Patients in Q4 TTI were more likely to be older (OR 1.01, 95% CI 1.00-1.02, p = 0.01), have T2-T4 tumors (OR 1.6, 95% CI 1.2-2.2, p < 0.001), and be treated at an academic facility (OR 2.4, 95% CI 1.8-3.5, p < 0.001) on multivariable analysis. In the survival analysis, multiple positive LNs (2, 3-4, > 4 LNs; HR 1.4, 1.6 and 2.9, p < 0.001), lymphovascular invasion (HR 1.4, p < 0.001), Breslow thickness > 4 mm (HR 1.7, p < 0.001), Charlson-Deyo score ≥2 (HR 1.5, p < 0.001), increasing age (HR 1.03, p < 0.001), and longer TTI (Q3-Q4) (HR 1.2, p = 0.001) were all associated with worse OS. There was no difference in survival based on TTI in patients who had received adjuvant immunotherapy in Q1-Q2 vs Q3-Q4 (p = 0.3). Conclusions: In stage 3 cutaneous melanoma, longer TTI ( > 33 days) was associated with worse OS but may be due to older age, higher T stage, and barriers to access. However, adjuvant immunotherapy may offer protection from delays in definitive surgery.
Improved risk stratification in an adjuvant radiation therapy (ART) eligible cutaneous squamous cell carcinoma (cSCC) patient population by integration of the 40-gene expression profile prognostic test (40-GEP).
Authors: Koyfman Shlomo A. , Wysong Ashley , Arron Sarah , Somani Ally-Khan B. , Siegel Jennifer , Fitzgerald Alison , Kurley Sarah J. , Goldberg Matthew S. , Schmults Chrysalyne , Newman Jason
Published: June 2021

e21589

Background: Although cure rates are high for cSCC, an estimated 2-6% of cSCC patients will develop regional/distant metastasis and due to high incidence, mortality levels are similar to melanoma. ART is used for high-risk cSCC (HRcSCC) patients to reduce the risk of recurrence and/or metastasis, but guidelines are confounding and lack clarity regarding which patients may benefit from ART. The 40-GEP test has been validated to predict a patient’s risk for regional/distant metastasis: Class 1-low; Class 2A-moderate; and Class 2B-high risk for metastasis. We hypothesize that a 40-GEP Class result could help further stratify patient risk within an ART-eligible population. Methods: Using criteria within NCCN guidelines and other high-risk features to determine ART-eligibility, 86 cases of the 420 HRcSCC patients having known outcomes from the 40-GEP multicenter validation cohort were identified. Criteria included patients presenting with two or more risk factors: tumor diameter ≥2 cm, poor differentiation, perineural invasion ≥0.1 mm, invasion beyond subcutaneous fat, and immunosuppression. Kaplan-Meier survival analysis and log rank test were used to assess metastasis free survival (MFS). Univariate Cox regression compared metastasis rates between 40-GEP Class results. Results: The 3-year MFS rate for the overall ART-eligible cohort was 65% (n = 86, 32 events, 95% CI: 56 – 76%). The 40-GEP demonstrated statistically significant stratification of risk with MFS rates of 79%, 63% and 33% for Class 1, Class 2A and Class 2B, respectively (p = 0.005). Cox regression was significant between Class 1 and Class 2B 40-GEP results (p = 0.002), with Class 2B having a 4.59-fold increase in metastases. 40% (34/86) of the cohort received a Class 1 result, highlighting HRcSCC patients who may be considered for reduction or avoidance of ART. In 14% (12/86) of cases with a Class 2B result, 2 of 3 patients went on to have metastasis and thus may be appropriate for more aggressive intervention in the setting of a clinical trial. Those cases meeting eligibility for 40-GEP testing but not ART-criteria (n = 334) and with a Class 2B result (n = 11) had a 64% MFS rate, similar to the ART-eligible population. Conclusions: The 40-GEP test stratifies a patient’s risk of regional and/or distant metastasis in patients for whom ART is typically considered. Incorporation of 40-GEP testing may help guide patient management decisions in HRcSCC by potentially decreasing over-treatment of patients with HRcSCC and identifying patients with otherwise lower risk disease who may benefit from ART and/or other adjunctive therapies.
Extremity bone sarcoma: Evolution from primary amputation to limb salvage surgery (LSS).
Authors: Rao Bhaskar N. , Neel Michael D. , Abdel-Hafeez Hafeez , Murphy Sandra
Published: June 2021

e22012

Background: Primary Extremity Bone Sarcomas (PEBS) were historically managed by upfront amputation. Early success rates utilizing neoadjuvant chemotherapy followed by LSS showed promise in halting disease progression and achieving local control. This prompted surgical oncologists to consider LSS in more patients. In anatomic locations for which no functional reconstruction exists, amputation is still considered the best option. Oncologic control, patient satisfaction and improved function are the primary goals of LSS. Three Dimensional CT and MRI have made for more accurate surgical planning, ensuring adequate margins and improved local control. Methods: Between January 1983 and December 2019 the senior author (BNR) has performed, or mentored over 590 LSS worldwide.Improvement in imaging modalities has been the most important advancement contributing to decreasing tumor margins. Initially bone scans determined the margins at 7cm. In the 1970s CT became the modality used to determine local tumor extent. The resection margins were reduced to 5 cm. The early 90’s saw MRI as the main imaging modality. Margins are now set at 1-2cm.LSS was initiated in the mid 80’s using the strict criteria of age > 13, no metastasis, intramedullary extension less than 50%, and small extraosseus extent. Results: Of the 134 cases enrolled through 1990, the local control rate was 90%. Between July 1991 through December 2019, 388 patients enrolled in bone sarcoma protocols, 354 patients underwent LSS ( > 95%). The primary site was the femur (171 cases, 43%) Histological Diagnosis was OS in 93%. Ages ranged from 3-25 years (median 10.8 years) The average length of tumor resection was 7cms(range 1-38cms). 5 patients presented with pathological fracture. All successfully underwent LSS without an increase in local recurrence. Intraoperative complications included, excessive hemorrhage defined as > 10%of blood volume in 88 patients, 25%, Vascular injuries requiring repair in 9 patients, post operative neuropraxia in 28 patients. Mid and late term complications included, Superficial wound infection in 45 patients (19 requiring some surgical intervention), Deep wound problems were identified in 11 patients ( 3 required subsequent amputation), 9 patients had their prosthesis revised due to refractory infection, Local relapse in 5 patients , < 1%. Long term implant related complications, loosening of the prosthesis in 16 , Stem fracture in 13, nonunion of the allograft in 3 patients. Conclusions: Disadvantages are the need for repeat surgeries consequent to either growth discrepancy, loosening, or implant fracture.LSS is feasible in over 95% of patients, complications are generally manageable. Successful oncologic results, satisfaction and function are readily obtained. Early rehabilitation is key to functional success.
Evaluation of age, gender, prenatal characteristics, and treatment results of 380 babies with infantile hemangioma.
Authors: Suzen Orhan Eda , Unal Emel Cabi , Tacyildiz Nurdan , Dincaslan Handan
Published: June 2021

e22018

Background: Infantile hemangiomas' incidence is 5% & are locally proliferated vascular structures. Methods: Fourhundred cases were analyzed,380 are presented. Results: Majority pts dx between 0-3 mos(88.8%), females (64.5 %), 26.6% had preterm birth,21.8% lbw 2500g. Maternal characteristics 17.1% were > age35, 8.5% multipar, 61.5% multiple gestation. Placental anomaly in 5.5%, preeclampsia in 10.3%, gestational diabetes in 7%, intervention in pregnancy 4.9%, smoking 7.6%, hyperemesis 29.9%. Treatment modality was topical timolol drops in 41.9%, oral propranolol solution in 37.6%, wait&see group 13.5%,surgical excision in 5.6%. Conclusions: Hemangioma, a multifactorial disease, lbw is an important risk factor.Oral propranolol solution for the babies <1yr of age avoided the use of intralesional steroids. It is essential to treat the babies especially who have the risk of developing amblyopia or other functional/cosmetic sequelae.
Pediatric cancer registry in Turkey 2009-2020 (TPOG & TPHD).
Authors: Kutluk M. Tezer , Yeşilipek Akif
Published: June 2021

e22519

Background: Global actions on pediatric cancer control is targeting to improve the survival rates in low and middle income countries which already exceeded 80% in high income countries. Almost 300.000 pediatric cancer cases annually are expected in children and adolescents aged 0-14 globally. Pediatric cancer registry must be a priority within the pediatric cancer control programs. Here, we present the most updated results of the pediatric cancer registry in Turkey. Methods: Pediatric cancer registry has been established by the Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association in 2002. The childhood cancer cases registered between 2009-2020 was included in this analysis. International Childhood Cancer Classification System was used for the classification. Essential demographic findings, ICD-O-3 morphology and topography codes were recorded for each case. Results: During the 12 years from 2009 to 2020, 21792 cases were registered. For all cases, median age was 6.7 year (0-19; M/F 12198/9584, 4 hermaphrodite, 6 unknown). Age distribution was 0-4 yrs, 40.9%; 5-9 yrs, 23.7%; 10-14 yrs, 23.4%; 15-19 yrs, 12.0%) The distribution of the tumor types were [number of cases, percentage of total, median age yrs, M/F]: Leukemia (5208, 23.9%, 5.5, 3004/2204); Lymphoma & other RES tumors (4103, 18.8%, 9.8, 2733/1367, 1 hermaphrodite & 2 unknown); CNS [brain & spinal] (3269, 15.0%, 6.8, 1794/1474, 1 unkown); Symphatetic system (1794, 8.2%, 2.4, 933/861); Retinoblastoma (610, 2.8%, 1.4, 339/271); Renal (1079, 5.0%, 3.1, 524/553, 1 hermaphrodite & 1 unknown); Liver (376, 1.7%, 2.2, 216/160); Malignant bone (1448, 6.6%, 12.5, 787/661); Soft tissue sarcomas (1554, 7.1%, 7.6, 888/666); Germ cell (1461, 6.7%, 9.3, 547/910, 2 hermaphrodite, 2 unknown); Carcinoma & other malignant epithelial (745, 3.4%, 13.5, 362/383); Other/non-specific malignant (145, 0.7%, 7.9, 71/74). Five year survival rate was found as 72%. Conclusions: This registry shows the imrovement of survival rates to 72% in Turkey which is comparable with middle income countries. The pediatric cancer control community is investing on the control of childhood cancer for further improvement and this registry became a valuable source for pediatric oncology community at national and international level.
The impact of an expert exchange-based educational initiative on urologist confidence and knowledge in implementing immunotherapy for bladder cancer.
Authors: Gitzinger Susan H. , Taylor Bryan Carson , Fowler Joan B. , Carranza Vanessa , Weaver Rebecca
Published: June 2021

e23001

Background: The rapid and robust emergence of the immunotherapy era in bladder cancer has prompted a paradigmatic shift in both early and late-stage bladder cancer management. Given this change, it is imperative that members of the bladder cancer care team, most notably urologists, medical oncologists, and urologic oncologists, be well-equipped to safely and effectively integrate immune checkpoint inhibitors into the treatment armamentarium. Methods: CEC Oncology delivered education at select meetings throughout 2019-2021 including ASCO GU, AUA, and SUO Annual Meetings; in addition to live presentations, the content was streamed live and on-demand on www.ceconceptslive.com and endured on myCME.com. Learning and knowledge was objectively assessed by analyzing pre- and post-test results before and after the educational activities. To determine retention of knowledge over time, follow-up assessments were sent to participants after each live activity. Assessment questions in the form of case studies were utilized to gauge whether participants translated knowledge into practice at follow-up. Statistical testing between pre- and post-tests and from pre-test to follow-up were conducted via chi square analysis with a priori significance set at 0.05. Results: Executed five live educational activities and a spin-off enduring component hosted on myCME.com. 765 total clinicians educated across the live elements of the curriculum. Across the curriculum, over 70% of attendees indicated at post-activity assessment that they would use systemic immunotherapy either primarily or exclusively in their practice compared to just 25% at pre-activity. Among urologists practicing at academic medical centers, confidence in appropriate implementation of immunotherapy increased for all participants, and more specifically, for clinicians practicing at academic medical centers (on a 4-point scale, All Participants demonstrated a confidence increase from 2.70 to 2.91; Academic Medical Center clinicians demonstrated an increase of 2.75 to 3.00); 97% said that the initiative increased their knowledge of ongoing ICI clinical trials in bladder cancer; Attendee ability to appropriately manage an irAE increased substantially from pre-test to post-test assessment (37% vs. 63%; P=.057). Clinicians practicing in community settings are the only attendees who did not exhibit an increase in mean confidence in appropriately implementing immunotherapy at post-activity assessment. Conclusions: Our Expert Exchange Bladder Cancer Curriculum precipitated substantive practice advances related to appropriate implementation of ICI therapy. Many of these advances, however, were specific to academic urologists and urologic oncologists; outcomes analyses have revealed tangible educational gaps among community-based urologists.
Collaborating with low- and middle-income countries: Experience from two of the United Kingdom’s comprehensive cancer centers.
Authors: Foreman Emma , Leslie Isla , Lyons Hannah , Piddock Katherine , Sadanandam Anguraj , Sanneh Alison , Stanway Susannah Jane , Webb Julie , Cowan Richard
Published: June 2021

e23014

Background: The number of annual global cancer deaths is rising and the majority of this burden, for a multitude of reasons, falls in low- and middle- income countries (LMICs). With the United Nations’ 3rd and 17th Sustainable Development Goals in mind (which include by 2030 “reduce by one third premature mortality from non-communicable diseases” and “partnership for the goals”) a survey was undertaken at the UK’s two largest comprehensive cancer centres to scope individual and team endeavours to work with colleagues in less well-resourced countries. Methods: Employees at the Royal Marsden Foundation Trust (RM) and Institute of Cancer Research (ICR) in London and Surrey, UK and The Christie NHS Foundation Trust (Christie), Manchester were invited to complete a survey to capture collaborative clinical care, research, education and training. Results: Responses were received from 520 multidisciplinary individuals across the 2 centres to two similar questionnaires. A large number had experience of working in some capacity in, or in collaboration with an LMIC. At the RM 14.62% of respondees were currently working with colleagues in LMICs. At The Christie 13.22% of staff had experience of working in LMICs in a supportive capacity. Those currently collaborating with colleagues in LMICs were working in a wide range of countries across Asia, Africa and South America in a range of initiatives spanning clinical care, research, education and training. Of those who answered the survey 64% at The Christie said they’d like to hear more about opportunities to be involved in supporting global health care, and 89% at RM/ICR said they’d be interested in joining a collaborative group working on global oncology initiatives at the institutions. Conclusions: This survey highlights the body of willing, interested individuals keen to work with colleagues in LMICs to improve cancer outcomes. The launch of the UK Global Cancer Network in 2020 will build upon these two surveys with a planned national survey of global health and cancer work undertaken by individuals in 2021.
Efficacy and safety of anlotinib hydrochloride in the treatment of advanced bone and soft tissue sarcoma after failure of first-line chemotherapy.
Authors: Yao Weitao , Wang Jiaqiang , Zhang Peng , Wang Xin , Yan Qiang , Du Xinhui , Tian Zhichao , Niu Xiaoying
Published: June 2021

e23504

Background: There were limit treatments for bone and soft tissue sarcomas that have failed chemotherapy. Anlotinib hydrochloride is a multi-targeted receptor of tyrosine kinase inhibitors (TKI), which has shown therapeutic effects on soft tissue sarcoma. Methods: This is a single-arm, prospective, single-center clinical study. The included criteria were patients with pathological diagnose of bone and soft tissue sarcoma, at least one measurable lesion (criteria of RECIST 1.1), failed of more than one line therapy (except for sarcoma subtypes insensitive to chemotherapy), with the normal function of main organs. All patients received 12mg of anlotinib once daily, 2 weeks on and 1 week off until progression or unacceptable toxicity. The primary endpoint was ORR. We also observed PFS, OS, DCR and AEs. Results: From October 2018to October 2020, a total of 40 patients were enrolled. 25 were men and the median age of the patients was 43.28 (8-79) years. The tumor was located on the trunk in 14 cases, on the limbs in 24 cases and on the abdominal wall in 2 cases. 77.5%, 10%, 7.5% and 5% of patients have lung metastases, bone metastasis, liver metastasis and lymph node metastasis, respectively. The main subtypes included synovial sarcoma (20%), alveolar soft tissue sarcoma (15%), osteosarcoma (12.5%), fibrosarcoma (10%), undifferentiated pleomorphic sarcoma (7.5%). 32.5% of patients had received for at least second-line prior therapy and 25% of patients had received apatinib as a previous treatment. The ORR was 15% and the DCR was 77.5%. Patients who had received apatinib had an ORR of 10% and a DCR of 80% in this group. mPFS were 7.0 months (95%CI = 5.07-8.93) and 7.13 months (95%CI = 5.28-8.98) in overall patients and patients who had received apatinib respectively. The mPFS of ASPS, synovial sarcoma, fibrosarcoma, and osteosarcoma were 17.0 months, 8.2 months, 7.1 months, 2.9 months (p = 0.017). The mOS has not been reached. Adverse events were mainly in grades I and II, The ≥3 AEs were hypertension (2.5%), proteinuria (2.5%), leukopenia (2.5%), thrombocytopenia (2.5%), anorexia (2.5%) and elevated transaminase (5.0%). Conclusions: Anlotinib is effective and safe in the treatment of bone and soft tissue sarcoma, and its efficacy is positively correlated with special types (such as ASPS, synovial sarcoma), effectiveness can also be observed in patients who have failed in other targeted therapy. Clinical trial information: NCT04223583.
Metastatic osteosarcoma at diagnosis: Analysis of 92 cases from a single institution.
Authors: Longhi Alessandra , Broll Valquiria , Righi Alberto , Carella Antonio , Pierini Michela , Ferrari Cristina , Cesari Marilena , Hakim Rossella , Paioli Anna , Palmerini Emanuela
Published: June 2021

e23506

Background: Metastatic osteosarcoma (MOS) with synchronous metastases accounts for 20-25% of all new cases of osteosarcoma. Lungs are the most common site of metastases at presentation (80%) followed by Bone (10%). 5- years Overall Survival (OS) of MOS ranges from 11 to 40%. In a previous study from our institution (Bacci G 2006) on 57 pts < 40 years old (1995-2000) the 2- and 5-year OS were 55% and 18%. Methods: Data of patients with pathologic and radiologic confirmed MOS with adequate follow up were reviewed (EC Approval N 916/2020/Oss/IOR). Time-to-event outcomes were estimate with Kaplan-Meier method and compared between groups with log-rank test and Cox model. Results: From August 2000 to October 2018, 92 patients had a diagnosis of MOS: median age 16.5 yrs (6-73, twelve pts > 40 ), gender rate was M 51/F 41, axial primary tumor in 15 cases, extremity in 77. Lung only metastases were described in 66 (71.7%). In 75/90 cases primary tumor was surgically removed, 43 (46%) cases had at least one surgical metastasectomy. All patients received chemotherapy: preoperative only in 6 cases, postoperative in 6, and pre and postoperative in 66 patients. The 1st line chemotherapy was a combination of drugs: Adriamycin in 91/92 pts, Cisplatin in 89/92, Ifosfamide in 88/92, Methotrexate in 83/92; 59 patients received a 2nd line chemotherapy, 34 pts received a 3rd line; most employed regimen were Gemcitabine-Docetaxel, Ifosfamide 15 gr/m2, Cyclophosphamyde-Etoposide, TKI (Pazopanib, Sorafenib), and a few received experimental drugs. Complete remission (CR) was obtained in 26/92 (28%), in 19 cases after surgical metastasectomy.In 30 pts the information of PGP (P- glycoprotein) was available; patients with positive PGP (19/30) had a worst overall survival as compared to those PGP negative (P = 0.038). Of those in Complete Remission 14/26 relapsed. At December 2020 with a median follow-up of 95 ms (IQR 34-159): 65/92 (70%) died , 12 are alive and free from disease , 6 are alive with disease, 9 were lost . The 2-yrs OS for all 92 pts from diagnosis was 66% (95%CI 55-75) and 5-yrs OS was 26% (95% CI 16-37). From the end of treatment, for those who reached a CR the 5-year OS was 57% vs 9% for those who did not (P < 0.001). At univariate analysis, primary tumor site (2-y OS 48% axial vs 72% extremity, P < 0.001), site of metastases (2-y OS 74% only lung vs 48% other, P = 0.004) and number of lung nodules (P = 0.007), were significantly associated to OS. At multivariate analysis, only site of metastases (other vs. only lung HR = 2.26, 95%CI: 1.21-4.22) and number of lung nodules (≥10 nodules vs ≤3 HR = 2.44, 95%CI: 1.24-4.81) were confirmed as significant for OS. Conclusions: Compared to our previous report from 20 yrs ago, 2-years and 5 yrs OS of MOS has improved but it remain unsatisfactory (66% vs 55% and 26% vs 18%).
Clinicopathological features and treatment of perivascular epithelioid cell tumor.
Authors: Lin Ying , Liu Xin , Zhang Xiaowei , Chen Yong , Wang Chunmeng , Wang Shengping , WANG Jian , Luo Zhiguo
Published: June 2021

e23538

Background: Perivascular epithelioid cell tumor (PEComa) is a rare form of mesenchymal neoplasms. No clinical trial of large sample size regarding medical treatment of PEComa has been reported so far. Previous retrospective studies with small sample size have showed efficacy of mTOR inhibitors as treatment of PEComa. This study aimed to analyze the clinicopathological features of PEComa, and the efficacy of mTOR inhibitor in advanced PEComa. Methods: Medical information of patients diagnosed with PEComa and treated in Fudan University Shanghai Cancer Center were collected. Survival analysis was performed by Kaplan-Meier method. Radiological response was assessed according to RECIST version1.1. Results: A total of 17 patients were treated in our center during June 2007 to June 2020. PEComa mostly occurs in middle-aged women. The most common primary sites are pelvis, lung and abdomen. Relapse usually occurs within 2 years after radical surgery. Radical surgery is the main treatment for PEComa of limited stage, and remains the main option for those with limited recurrent lesions. Of the 13 patients with advanced malignant PEComa in our cohorts, the objective response rate of mTOR inhibitors in advanced malignant PEComa was 45.5%, and median progression-free survival was 27.7 months (95% CI 4.7-50.5 months). 2 patients discontinued mTOR inhibitor treatment due to pneumonitis combined with dyspnea and fever respectively. Conclusions: For advanced malignant PEComa, mTOR inhibitors are effective. Lung toxicity of mTOR inhibitor should be monitored.
Loss of 5'ALK leads to better response to crizotinib in sarcomas with ALK rearrangement.
Authors: Li Bin , Hu Yongbin , He Qiongzhi , Lu Jingchen , Huang Gengwen , Xiao Sheng
Published: June 2021

e23554

Background: Crizotinib targets abnormal ALK activation, however, the clinical responses vary among patients with ALK rearrangement. A recent study showed that the NSCLC patients with 5'ALK loss have a favorable response to Crizotinib with doubled progression-free survival (PFS). We asked whether sarcoma patients with ALK rearrangement have a similar correlation between 5'ALK loss and clinical response to Crizotinib. Methods: The histopathologic diagnosis was made on H&E staining and IHC, including anti-ALK(D5F3). DNA isolated from FFPE materials was subjected to an NGS assay targeting 295 genes including ALK rearrangement. Results: 4 cases were detailed in Table. Case#1 is an inflammatory myofibroblastic tumor with a PLEKHH2-ALK rearrangement, which was previously reported in an NSCLC but not in sarcomas. Case #2 is an undifferentiated sarcoma with 2 ALK fusions, RANBP2-ALK and TMEM217-ALK, both in-frame fusions containing intact tyrosine kinase domains. The TMEM217-ALK is a novel fusion. Case#3 is a leiomyosarcoma with MYH9-ALK fusion, which was often seen in ALK-positive large B-cell lymphoma but not in sarcoma. Case #4 is an undifferentiated sarcoma with EML4-ALK fusion. All 4 cases had positive ALK IHC, consistent with the expression of ALK fusion proteins. Case#1 and #2 had a loss of 5' ALK, while case #3 and #4 retained the 5' ALK. All cases received and responded to Crizotinib therapy, with the Karnofsky Performance Status (KPS) improved from 30-60 score pre-therapy to 90-100 score after 3 months of Crizotinib. While Case#3 and #4, both retained the 5' ALK, relapsed at 9.4 m and 6.1 m, case#1 and #2, both lost 5' ALK, remain progression-free at 15m and 27m, respectively. The side effect was manageable with a grade II hepatic toxicity in only one patient. Conclusions: We report here 4 sarcomas with ALK rearrangement, including a novel fusion TMEM217-ALK. Two of these cases had a 5' ALK loss in addition to the 3' ALK rearrangement, and both had much longer PFS on Crizotinib therapy. The underlying mechanism deserved further investigation. Four fibrosarcomas with ALK rearrangements and their response to Crizotinib therapy.[Table: see text]
Feasibility of a telemedicine lifestyle-based rehabilitation program (HEAL) for gynecologic cancer patients.
Authors: McKenzie Nathalie Dauphin , Gwacham Nnamdi Ifekandu , Pepe Julie W. , Ahmad Sarfraz , Kendrick James Erasmus , Holloway Robert W.
Published: June 2021

e24033

Background: General health related factors such as obesity, unhealthy diets disproportionate with sugary and highly processed foods, inactivity, and smoking have repeatedly been shown to negatively impact survival and quality of life outcomes in cancer survivors. The Healthy Eating Active Lifestyle (HEAL) – GYN “rehabilitation” cancer program was developed to provide intensive group lifestyle training on exercise, nutrition, sleep, social integration, and stress management via a telemedicine platform. The aim of this study was to determine the feasibility of such an intervention and its tolerability, in addition to its impact on short-term quality of life for gynecologic cancer patients. Methods: HEAL – GYN consists of 8 weekly group sessions offering experiential instruction and personalized goal setting for patients with diagnosis of gynecologic cancer. Components are drawn from the tenets of lifestyle medicine. An oncologist certified in lifestyle medicine along with a multidisciplinary rehabilitation team addressed diet, physical activity, strategies for sleep and stress management, smoking cessation, and alcohol intake. The intervention included training to address unmet psychologic, emotional, physical, sexual, social, and spiritual needs common to cancer survivors. American College of Lifestyle Medicine questionnaires were administered, utilizing Likert scales (1-5) in a pre- and post- fashion to assess improvements in physical activity levels, dietary habits, sleep hygiene, and quality of life. Medical records were reviewed including anthropometric data. Results: 26 patients have enrolled thus far, and we report outcomes on the first 20 participants. The mean age was 58.8 years; 22 were Caucasian, and 7 were on maintenance therapies for gynecologic cancers. Average total severity of reported symptoms (scale = 100 points) on a general medical symptom questionnaire (MSQ) decreased by 22% (61 vs 48). Eight patients reported increased perceived levels of health and 6 had stable perception of health. There were also notable improvements from baseline in item assessments of eating behavior (34%), perceived stress (20%), and resilience (21%). Patients also reported a notable trend towards improvement in anxiety (35%) and depression (34%), as well as social integration and connectedness (30%). 100% of participants would “highly recommend the program” and none complained of stress or altered mood associated with online instruction. Conclusions: The telemedicine HEAL – GYN peri-habilitation program is feasible and well tolerated. In addition, the program may improve quality of life and may prevent further decline for those on treatment or maintenance therapy. These preliminary findings support continued investigation of a telemedicine healthy lifestyle peri-habilitative program.
Predictors of venous thromboembolism in cancer patients using machine learning.
Authors: Cali Daylan Ayse Ece , Khemasuwan Danai , Kim Hyun S. , Geetha Parvathy , Alarcon Velasco Sylvia Vania , Lathan Christopher S.
Published: June 2021

e24042

Background: The increased risk of venous thromboembolism (VTE) in cancer patients is clearly documented. However, given the heterogeneity and increased risk of bleeding in cancer population, patient selection for thromboprophylaxis is still challenging. Methods: In order to predict risk factors of VTE in cancer patients, we performed a retrospective study of 706 patients who were diagnosed with either solid or hematological malignancies between 2015 and 2019. Demographics, body mass index, complete blood count with differential, kidney function tests, electrolytes, liver function tests, lipid profile and cancer staging were recorded. Random forest analysis with bagging was used to rank these variables and the Kaplan-Meier survival analysis was implemented to stratify cancer subtypes based on the risk of VTE occurrence. Results: The mean follow-up time was 19 months. 8.2% of the patients developed VTE. Based on the random forest analysis, the most important five factors in prediction of VTE in cancer patients were determined as cancer subtype, white blood cell count, platelets, neutrophil and hemoglobin. At one-year mark, the risk of VTE in lung cancer and hematological malignancies was found to be significantly higher than breast, colorectal and endometrial cancer (p<0.05). Conclusions: Machine learning approach is infrequently used in risk factor prediction of VTE in cancer patients. The risk factors identified by the machine learning algorithm in our study are consistent with prior studies and show a clear difference in risk of VTE in various cancer subtypes. Moreover, hematological malignancies and lung cancer patients may develop VTE earlier than other cancer subtypes based on the Kaplan-Meier analysis. Further prospective studies with longer follow up are needed to better risk-stratify cancer patients and explore the temporal associations of VTE risk factors. [Table: see text]
Association of OPRM1, MIR23B, and MIR107 genetic variability with acute and chronic pain after postoperative tramadol treatment in breast cancer.
Authors: Besic Nikola , Goricar Katja , Vidic Zala , Strazisar Branka , Dolzan Vita
Published: June 2021

e24052

Background: Tramadol is an opioid analgesic often used for pain management after axillary lymph node dissection in breast cancer. It exerts its analgesic activity through activation of the G protein-coupled µ-opioid receptor, encoded by the OPRM1 gene. Genetic factors that may modify activity or expression of OPRM1 could thus affect the efficacy of tramadol treatment. This study investigated the association of genetic variability of OPRM1 and genes coding for miRNAs regulating OPRM1 expression with pain management in breast cancer patients treated with tramadol after surgery. Methods: The study included 113 breast cancer patients treated with either 75 or 37.5 mg of tramadol for pain relief after breast cancer surgery within the randomized clinical trial KCT 04/2015-DORETAonko/si at Institute of Oncology Ljubljana. All patients were genotyped for OPRM1 rs1799971 and rs677830, MIR23B rs1011784 and MIR107 rs2296616 using competitive allele-specific PCR. The association of genetic factors with acute and chronic pain was evaluated using logistic regression, Fisher’s exact test and Mann-Whitney test. Results: The investigated OPRM1 related genetic factors were not associated with acute pain measured using VAS scale within four weeks after surgery, even after adjustment for tramadol dose (all P > 0.05). One year after surgery, 21 (21.1%) patients experienced chronic pain and 25 (25.3%) experienced neuropathic pain. In carriers of two polymorphic MIR107 rs2296616 alleles, chronic pain was significantly more common compared to carriers of two wild-type alleles (35.3% compared to 0% of patients, P = 0.004). Carriers of at least one polymorphic MIR23B rs1011784 allele experienced more neuropathic pain compared to carriers of two wild-type alleles after adjustment for tramadol dose (OR = 2.85, 95% CI = 1.07-7.59, P = 0.036). Conclusions: Genetic variability of miRNAs that could affect OPRM1 expression may be associated with chronic pain in breast cancer patients treated with postoperative tramadol.
Pre-anthracycline left ventricular ejection fraction (LVEF) assessment and long-term cardiovascular (CV) outcomes in adolescent and young adult (AYA) lymphoma survivors.
Authors: Farooque Alma , Carroll Cibele , Tevaarwerk Amye Juliet , Pophali Priyanka Avinash
Published: June 2021

e24060

Background: Anthracyclines are known to cause long-term cardiotoxicity. There are no specific guidelines for CV screening and follow-up of AYA patients treated with anthracyclines. Pediatric guidelines focus on long-term imaging surveillance, while for adults, LVEF assessment prior to anthracyclines is recommended. Multiple studies have demonstrated LVEF assessment rarely impacts treatment decisions, especially in the absence of CV symptoms/risk factors, adds to unnecessary costs and delays treatment initiation. Our study aimed to determine the pre-treatment LVEF assessment practices in AYA lymphoma patients treated with anthracyclines and its association with long-term cardiotoxicity. Methods: AYA survivors diagnosed with lymphoma > 5 years ago and treated with anthracyclines at age 15-39 years were identified in a retrospective single institution registry. To ensure adequate follow-up, at least 2 follow-up visits during 2015-19 were required. Data abstracted on eligible subjects included documentation of pre-treatment LVEF evaluation, clinical rationale and treatment regimen. CV risk factors and events were collected pre-treatment and during follow-up. Descriptive statistics were used to summarize data. Results: 64/115 (56%) of AYA lymphoma patients underwent pre-treatment LVEF assessment. Rationale for/against LVEF assessment was rarely documented: low CV risk was recorded as rationale for no LVEF assessment in 2 subjects. Among AYAs who underwent pre-treatment LVEF assessment, no significant abnormalities were detected and no changes in subsequent treatment plans were found. During median follow-up of 6.7 (inter-quartile range 5.4-9.5) years, 6/115 (5%) experienced CV events. Only 2 (1.7%) survivors experienced potential anthracycline-related CV events: 1 moderate cardiomyopathy at 9 years, 1 peri-partum cardiomyopathy and atrial fibrillation due to post-radiation SVC occlusion at 15 years post-treatment. Both these AYAs (aged 38 and 31 years at time of CV events) also had other CV risk factors- family history, smoking, obesity, and hyperlipidemia. Four (3.5%) survivors’ experienced CV events (1 sinus tachyarrhythmia, 1 junctional rhythm, 2 acute/asymptomatic drop in LVEF) unrelated to anthracyclines with clear alternative etiology e.g. sepsis/symptom burden. There was no correlation between having pre-treatment LVEF assessment and occurrence of CV events. 13/115 (11.3%) developed new CV risk factors: 4 hypertension, 6 hyperlipidemia, 3 diabetes. Conclusions: Pre-treatment LVEF assessment is done inconsistently in AYA lymphoma patients but does not impact initial treatment or predict late cardiotoxicity. CV events in long-term AYA lymphoma survivors are rare but evaluation of CV risk factors, early detection and management may be more important than focusing on LVEF assessment.