bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical efficacy analysis of preoperative neoadjuvant chemotherapy in patients with pulmonary adenocarcinoma during stage IIIA.
Authors: Zhang Ting ting , Cheng Ying
Published: October 2019

128

Background: The purpose of this study is to compare the effectiveness and safety of neoadjuvant chemotherapy with targeted therapy. In order to explore the best treatment mode of lung cancer in local progression period. Methods: 42 patients with stage IIIA lung adenocarcinoma who were admitted to the Cancer Hospital of Jilin Province from 2015 to 2017 were retrospectively analyzed. They received at least 2 cycles of neoadjuvant chemotherapy or at least 6 weeks of new adjuvant targeted therapy before surgery. Results: 42 patients who met the criteria were included in this study, all of them were stage IIIA lung adenocarcinoma. Of the total number of cases, a total of 13 patients received preoperative assisted single drug EGFR-TKI treatment (including Eluotini) and 27 patients received preoperative assisted chemotherapy. Two patients received neoadjuvant chemotherapy before receiving new adjuvant targeted therapy. In patients with EGFR sensitive mutations in stage IIIA, the objective remission rate of newly assisted TKI therapy was 63.2 %, while neoadjuvant chemotherapy was 36.8 % (P = 0.021). Of the 13 patients who received new assisted targeted treatment before surgery, 11 patients continued to receive targeted treatment after the first efficacy evaluation (3 weeks): After the first efficacy evaluation PR case continued to be treated with TKI The tumor can continue to shrink until 3 months, However, there was no significant change in tumor size after the first evaluation of SD continued with TKI treatment. There was no difference between the two groups in postoperative complications, postoperative pleural drainage and postoperative hospitalization time. Conclusions: Compared with preoperative neoadjuvant chemotherapy, neoadjuvant targeted therapy has a good effect in patients with pulmonary adenocarcinoma with EGFR mutation in stage IIIA. Patients with partial remission for the first treatment evaluation can try to continue TKI treatment for 1 month after surgical resection.
Prognostic value of tumor parameters measured by MRI in cervical cancer patients receiving CCRT.
Authors: Sun Chang , Zhang Hanyi , Lang Jinyi , Lu Shun
Published: October 2019

129

Background: This study aimed to evaluate the response of solid tumors after the completion of external beam radiotherapy (EBRT) and investigate the prognostic value of tumor parameters such as tumor volume and size (TV & TS) and tumor volume reduction rate (TVRR) early during the treatment in local advanced cervical cancer patients. Methods: We retrospectively reviewed 310 Chinese patients with locally advanced cervical cancer. They were all received concurrent chemoradiotherapy (CCRT) during the treatment based on intensity modulated radiotherapy (IMRT). Clinical data at the time of diagnosis, including FIGO stage, TV and TS were measured by pelvic magnetic resonance imaging (MRI) before and after EBRT were available. Information about distant metastasis, relapse and date of death was also collected, with a follow-up until Aug 2018. Youden index was used to identify the optimal cut-off point of continuous tumor parameters and divide patients into subgroups. Prognostic factors (age, FIGO stage, RT dose, pre-RT TS and TV, mid-RT TS and TV, TVRR) were using the log-rank test and Cox regression models to analyze the association between predictors and time-to-event outcomes. Results: The median follow-up time was 50 months. In univariate analysis, the FIGO stage, TVRR, TV and TS were associated with overall survival rate. Interestingly, the group of higher TVRR showed a better OS, PFS and LRFS than the group of lower TVRR ( P <0.05). Moreover, the groups of lower TV and TS showed better OS, PFS and LRFS than the higher groups, respectively. In the OS-related multivariate analysis, the mid-RT TV remained statistically significant after adjustment for age and FIGO stage ( P < 0.05). In the PFS-related multivariate analysis, the tumor volume reduction rate (TVRR) remained statistically significant after adjustment for age, FIGO stage, TS, and TV ( P <0.05). In addition, in the LRFS-related multivariate analysis, TVRR also remained statistically significant after adjustment for age, FIGO stage, TS, and TV ( P<0.05). Conclusions: Our results confirmed that tumor parameters including TS, TV and TVRR, measured before the completion of CCRT, are valuable prognostic factors in patients with locally advanced cervical cancer.
Genomic analysis reveals somatic mutations of ATM gene in DNA repair confer exceptional target lesion response to radiation therapy.
Authors: Lee Jason Joon Bock , Yang Andrew Jihoon , Chang Jee Suk , Kim Han Sang , Yoon Hong In , Shin Sang Joon , Kim Yong Bae , Koom Woong Sub , Ahn Joong Bae
Published: October 2019

130

Background: Somatic mutations of genes involved in DNA repair (e.g. ATM and BRCA1/2) may result in chemotherapy resistance and poor prognosis, but may confer sensitivity to radiation therapy. In this study, we aimed to the hypothesis that patients with such mutations may be more susceptible to radiotherapy. Methods: Using prospectively collected RT registry, we identified patients who underwent both RT to gross disease and NGS panel screening between 2013 and 2019 (N = 27,664). From a cohort of 134 patients, 33 patients with somatic mutation in ATM or BRCA 1/2 were identified and closely matched with 33 patients without mutation using propensity score based on radiation dose and histology. Results: Infield response rate was evaluated in 66 patients with 90 gross lesions (ATM mutation, 11 patients and BRCA 1/2 mutation, 22 patients). The median tumor size and RT dose was 24 mm (3-140) and 40 Gy (12-66), respectively. Stark differences were seen in infield complete response rate, overall response rate, and local control rate at target lesions by ATM mutation (mutation vs. no mutation; 50% vs. 8%, 61% vs. 24%, and 94% vs. 58%, P < .05). Response duration was also longer ATM mutation (median 11 vs. 3 months, P = .001). However, RT-related toxicities were not different (17% vs. 11%, P = .515) and no severe toxicity occurred. Conclusions: ATM mutations confer exceptional responses to radiation therapy, even with palliative dose, which has potential therapeutic implications.
Cost effectiveness of treatment-free remission in chronic myeloid leukemia patients: A report from a developing country.
Authors: Sattar Wasim
Published: October 2019

131

Background: Current recommendations for first line therapy in chronic phase chronic myeloid leukemia (CP-CML) is life-time use of tyrosine kinase inhibitors (TKI's). Unfortunately, the financial burden of continuous TKI therapy is unsustainable especially in developing countries. In Pakistan, an access-program for Imatinib (IM) and Nilotinib is available; the cost of therapy is subsidized with the Government paying for 3 months and Novartis for 9 months. Updated results from several trials support continued long term durability of treatment free remission (TFR). We attempted TFR in our patients in an attempt to reduce financial burden and improve quality of life for the patients. We aimed to evaluate the economic impact of discontinuing imatinib versus continuous use of imatinib in patients taking IM 400mg. Methods: 57 patients of CP-CML taking Imatinib 400 mg for the last 10 years who were negative by FISH for at least 3 years or in MR 4.5 at least once in 12 months were evaluated. Of these 30 were screening failures, 4 patients refused consent prior to screening and 25 were eligible for the trial. Two consecutive RQ-PCR were performed 3 months apart prior to enrollment. Patients were eligible if they achieved MR 4.5 for at least 3 months prior to entering the study. Molecular response was assessed by Quantitative BCR-ABL RQ-PCR every 4 weeks after discontinuation for year 1 and 8 weeks at year 2. Cost of Imatinib 400 mg per month was calculated as well as the cost of BCR-ABL RQ-PCR by gene expert for the trial. Results: Of the enrolled 25 patients, 10 lost their deep molecular response and were restarted on therapy, 5 withdrew consent after screening.10 patients are currently on trial at varying time intervals (10-14 months) of cessation of imatinib. The cost of one month of imatinib is US $ 800 and the cost of RT PCR is $ 67. TFR translated into approximately US 1.2 million saved. Conclusions: The discontinuation of TKI in this small subset of patients has resulted in remarkably large savings with significant impact on the meager health budget in our resource limited setting.
Impact of adjuvant chemotherapy using gemcitabine plus S-1 after surgical resection for advanced biliary cancer.
Authors: Fukushima Kentaro , Motoyama Hiroaki , Shimizu Akira , Notake Tsuyoshi , Ikehara Tomohiko , Hayashi Hikaru , Yasukawa Koya , Kobayashi Akira , Soejima Yuji
Published: October 2019

132

Background: The impact of adjuvant chemotherapy for advanced biliary cancer remains controversial. We previously failed to show survival benefit of adjuvant gemcitabine chemotherapy (UMIN000014018). The aim of this study was to evaluate the safety and efficacy of adjuvant gemcitabine plus S-1 chemotherapy after surgical resection for advanced biliary cancer. Methods: Between January 2006 and May 2019, a total of 110 patients who underwent surgical resection for biliary cancer (UICC Stage II or more) were enrolled in this study. Of these, 33 patients subsequently received 12 cycles of adjuvant chemotherapy (GS group), and 77 patients underwent surgery alone (S group). A cycle of chemotherapy consisted of oral S-1 70mg/m2 for 7 consecutive days and intravenous gemcitabine 1000mg/m2 on day 7, followed by a 1-week break from chemotherapy. Clinicopathological factors and patient survival were compared between the two groups. Results: GS group had significantly younger patients ( P = 0.036) and higher UICC T factor ( P = 0.001). Surgical procedure was significantly different in the two groups (P = 0.010). Other patient demographics and tumor characteristics were similar between the two groups. The completion rate of adjuvant chemotherapy was 57.6%, and there was no treatment-related deaths. All grades and grade 3/4 adverse event were seen in 60.6% and 33.3%, respectively. Three-year recurrence-free and overall survival rates were significantly higher in GS group than S group (61.9% vs. 34.4%, P = 0.016; 77.6% vs. 39.7%, P < 0.001, respectively). Conclusions: Adjuvant chemotherapy using gemcitabine plus S-1 was well tolerated and it would be an effective treatment strategy for the patients with resected advanced biliary cancer. Based on these results, randomized controlled study should be warranted.
Comprehensive analysis of maintenance therapy after first-line treatment with pemetrexed and platinum-containing double drug regimen combined by bevacizumab in EGFR wild type advanced non-squamous NSCLC.
Authors: Zhang XiangHua , Ma LiXia , Cheng Ying , Cui HongXia
Published: October 2019

133

Background: Pemetrexed combined with platinum was the standard treatment for first-line EGFR wild type non-squamous NSCLC , but further research is needed to confirm the safety of pemetrexed and bevacizumab treatment in maintenance therapy after first-line treatment in advenced non-squamous NSCLC. Methods: Total 60 patients with newly diagnosed advanced non-squamous NSCLC admitted to the hospital from June 2015 to June 2017, which were ARMS confirmed the EGFR wild type. In the observation group, bevacizumab +pemetrexed+ platinum was maintained with bevacizumab (BAP-B group). Control group: bevacizumab + pemetrexed + platinum was maintained with pemetrexed (BAP-A group). 60 patients completed 4- 6 cycles of chemotherapy and maintenance therapy for more than 4 cycles. The curative effect was evaluated According to Recis 1.1.The toxic reaction was evaluated WHO chemotherapeutic drug toxicity. The quality of life of patients were evaluated by EORTC QLQ-LC43. All the data were processed by SPSS19.0. P < 0.05 was statistically significant. Results: 33 cases in BAP-B and 27 cases in BAP-A . In this study, BAP-B & BAP-A : ORR 61.0% & 50.0% (P > 0.05);DCR 73.5 & 64.8 % ( P>0.05), median PFS 9.6 m & 7.2 m (P < 0.05), OS:18.2 m & 12.6 m (P < 0.05). Adverse incidence: BAP-B & BAP-A: leukopenia rate 43.0% & 41.2% hemoglobin reduction 40.0% & 38.5%; The reaction rate of digestive tract was 35.3% & 34.5%. There was no significant difference between the two groups. The incidence of hypertension in BAP-B (18.8%) was higher than that in BAP-A (0%) (P < 0.05). The incidence of proteuria in BAP-B (8.8%) was higher than that in BAP-A (2.0%) (P < 0.05), BAP-A and BAP-B (P < 0.05). The quality of life score of EORTC QLQ-C43 was (73.17 ±2.75) & (59.68 ±2.52), which was higher than that before treatment (52.75 ±2.02) & (53.01 ±1.98), and the score of BAP-A was higher than that of BAP-B(P < 0.05). Conclusions: The first line treatment of advanced EGFR wild type non-squamous NSCLC needs comprehensive consideration of curative effect, survival time, safety, quality of life and economic problems in order to choose the most suitable treatment.
The landscape of treatment and overall survival analysis of elderly patients with advanced breast cancer in China National Cancer Center.
Authors: Guan Xiuwen , Ma Fei , Xu Binghe
Published: October 2019

137

Background: As elderly patients usually suffer from medical complications of cardiovascular diseases, respiratory diseases, diabetes, etc, they lack of tolerance to surgery, anesthesia and chemotherapy. Therefore, the choice of treatment in elderly advanced breast cancer (ABC) patients may be different from the young. Methods: We summarized the clinicopathological characteristics and therapeutic regimens of 2063 females with ABC hospitalized between January 2003 and December 2018 from Database in China National Cancer Center. Contemporary comparison was performed between 221 elderly patients (≥60) and 1204 young patients (<60). Besides, survival data was compared with 21185 ABC in SEER database. Results: The median overall survival (OS) of elderly patients in China National Cancer Center was 35.5 months (95% CI 28.1 to 43.0), significantly longer than that in SEER database (20.0 months, P< 0.001). The median OS of elderly patients was significantly shorter than that of the young (35.5 vs 43.9 months, P= 0.007), which is similar to the survival feature in SEER database (34.0 vs 20.0 months, P< 0.001). Compared with the young, significantly more elderly patients suffered from the medical complications of hypertension (30.3% vs 9.5%, χ2= 73.194, P< 0.001), diabetes (14.5% vs 4.7%, χ2= 30.302, P< 0.001) and heart disease (6.3% vs 1.7%, χ2= 18.141, P< 0.001). In Luminal-like patients, the percentage of receiving first-line endocrine therapy in elderly patients was significantly larger than that of the young(26.9% vs 9.5%, χ2= 37.599, P< 0.001). Moreover, in Luminal-like population, the elderly patients underwent first-line endocrine therapy resulted in better OS than those underwent first-line chemotherapy (49.9 vs 32.6 months, P= 0.029), while no significant difference was observed between these two therapeutic mode in the young( 56.9 vs 48.8 months, P= 0.294). Conclusions:The proportion of elderly ABC patients with medical complications is significantly larger than that of the young, which may lead to the difference in treatment decision making. In Luminal-like elderly patients, receiving first-line endocrine therapy may result in better survival than chemotherapy.
Cancer care through the fire and flames: Three-year experience in utilizing of oncologic electronic consultation and referral system in the red zone of Thailand.
Authors: Rattanakhot Nanthiya , Dechaphunkul Arunee , Sunpaweravong Patrapim , Sathitruangsak Chirawadee , Songserm Maliwan , Jiratrachu Rungarun , Sangthawan Duangjai , Peerawong Thanarpan , Rordlamool Paytai , Phungrassami Temsak , Sakdejayont Siwat
Published: October 2019

14

Background: “The South Thailand Insurgency” is burning violence in the deep south of Thailand. The insurgency which has been ongoing since 2004 has played out in the three southernmost districts of the country Pattani, Yala and Narathiwat and some area of Songkhla, so-called the “Red Zone”. The chronic terrorism had major affected on cancer service. Many cancer patients gave up on their lives due to struggle with the disease itself, financial constraints due to longstanding economic downturn and security concerns during travelling led to high loss to follow-up rate and treatment delay. We, an oncology service team working at Songklanagarind hospital, the only one cancer center served this area together with primary doctors and nurses in the Red Zone created a network and utilized an oncology-specific electronic consultation and referral system to make more efficient care. We reported its performance in 3 years period. Methods: Electronic consultation system (E-consult) was a web-based program developed to provide advice and facilitate the referral process in cancer care. Since October 2015, we prospectively surveyed the impact of this pilot project on the quality of service by counting waiting time, number of center visit until treatment, unnecessary referral avoidance, patient and potential cost saving compared to normal referral system. Results: E-consult reached out to 7 hospitals and 589 cancer patients successfully referred through E-consult. Among patients from the Red Zone, without E-consult, their average waiting time was 56.4 days, number of visit was 6.5 visits. The estimated financial burden was $758.8 per patient. After implementation of E-consult in 259 patients, average time to treatment was 41.5 days (p = 0.006) and a number of the counter visit was 2.3 visits (p < 0.001). Estimated financial burden could be reduced to $358.7(p < 0.001). Ultimately, we prevented 28 patients from unnecessary referral. Conclusions: In this special context the electronic referral system was helpful to improve medical access, timeliness to specialist care, saving the patients’ family time and resources. This model is widely applicable to oncology referral chain.
Oncotarget (ONCOALVO): A custom NGS panel for therapeutic decision in solid tumors refractory to conventional therapy.
Authors: Murad Andre Marcio
Published: October 2019

140

Background: Next-generation sequencing (NGS) of tumor biopsies of solid tumors using commercially available platforms has broadly entered routine clinical practice to test for predictive biomarkers for patients with no available further standard therapies, as diagnostics rely on genomic testing of molecular alterations to enable effective cancer treatment. However, the high cost of large multigenic panels and especially the sequencing of the entire tumor exome is a concern, especially in a developing country such as Brazil. Methods: We report the clinical application of a panel of 57 genes that we call ONCOTARGET (ONCOALVO) which is based on the Thermo Fisher Oncomine Focus Assay, for the rapid and simultaneous detection of single nucleotide variants, short insertions and deletions, copy number variations, and gene rearrangements in 52 cancer genes with therapeutic relevance, but with the addition of 5 additional genes: the homologous recombination repair (HRR) genes BCRA1, BRCA2, ATM and CHEK2 that determine tumor sensitivity to inhibitors of the PARP enzyme and also KDR. 60 diagnostic samples of formalin-fixed, paraffin-embedded material submitted for molecular testing over a 2 year time period were analyzed so far. All patients had advanced solid tumors already refractory to conventional systemic therapy. Libraries were prepared from isolated nucleic acids and sequenced on the Ion Torrent S5 sequencer. Results: We found 40 potential therapy target pathogenic gene aberrations in 30 (50%) patients: KRAS - 10 (25%), BRCA1 - 8(20%), BRCA2 - 8(20%), PIK3CA - 4 (10%) mutations; and also 2 of each: ERBB2 (5%), BRAF-V600E (5%), KIT (5%), ALK (5%) mutations and one (2.5%) CCND1 amplification and one (2.5%) CDK4 mutacion. In 3 (7.5%) patients there were double mutations: BRCA1 and BRCA2 in 2 cases and BRCA2 and KRAS and one case. The Oncotarget workflow enabled a turnaround of 18½ days. Conclusions: ONCOTARGET was found to be a convenient tool for fast, reliable, broadly applicable and cost-effective targeted NGS of tumor samples in routine diagnostics and therapeutic decisions with a potential to become an important asset for precision oncology in Brazil.
Associations between the use of Twitter as a technology platform in oncology and the scientific impact of its users.
Authors: Cheung Winson Y. , Lim Elisa , Kong Shiying
Published: October 2019

16

Background: Social media channels, such as Twitter, represent relatively new technology platforms for scientific users to disseminate research findings and communicate their views and interpretations to colleagues and followers. To date, the associations between the use of Twitter and the scientific impact of its users are unclear. Methods: All Canadian oncologists who are full members of the American Society of Clinical Oncology were identified from the online membership directory. Users of Twitter were defined as those with an active Twitter account, as of June 2019, and posted at least one tweet within the past year. Data regarding the number of tweets, likes, and followers were collected by an online search of Twitter. Scientific impact of each individual was assessed based on a user’s h-index and number of citations from Google Scholar as well as score from Research Gate. Associations were examined with summary statistics and correlation coefficients. Results: We identified 676 eligible oncologists of whom 80 (12%) and 596 (88%) currently use and do not use Twitter. Among the users, the median number (IQR) of tweets, likes, and followers were 196 (45-865), 325 (86-1,246), and 198 (89-449), respectively. The scientific impact of Twitter users versus non-users was statistically similar (see Table). Likewise, within the group of users, there was no correlation between the number of tweets, likes, and followers and the scientific impact of individuals (correlation coefficients 0.38, 0.34, and 0.41, respectively, all p > 0.05). Conclusions: Only 1 in 10 oncologists use Twitter, but those who use Twitter leveraged this technology platform frequently. There was no association between the use of Twitter and the scientific impact of its users. Views from a minority of oncologists are represented on Twitter. Such bias underscores the need to exercise caution when using social media for scientific knowledge exchange. Regular evaluations of new technologies are warranted to ensure the quality and rigor of their scientific content. [Table: see text]
SYNERGY-AI: Artificial intelligence-based precision oncology clinical trial matching and registry.
Authors: Kurnaz Selin , Loaiza-Bonilla Arturo
Published: October 2019

22

Background: Precision oncology encompasses the implementation of high level of evidence disease-specific and biomarker-driven diagnostic and treatment recommendations for optimized cancer care. Artificial Intelligence (AI), telemedicine and value-based care may optimize clinical trial enrollment (CTE) and overall cost-benefit. This ongoing, international registry for cancer pts evaluates the feasibility and clinical utility of an AI-based precision oncology clinical trial matching tool, powered by a virtual tumor boards (VTB) program, and its clinical impact on pts with advanced cancer to facilitate CTE, as well as the financial impact, and potential outcomes of the intervention. Methods: The SYNERGY-AI Registry is an international prospective, observational cohort study of eligible adult and pediatric pts with advanced solid and hematological malignancies, for whom the decision to consider CTE has already been made by their primary providers (PP). Using a proprietary application programming interface (API) linked to existing electronic health records (EHR) platforms, individual clinical data is extracted, analyzed and matched to a parametric database of existing institutional and non-institutional CTs. Machine learning algorithms allow for dynamic matching based on CT allocation and availability for optimized matching. Patients voluntarily enroll into registry, which is non-interventional with no protocol-mandated tests/procedures—all treatment decisions are made at the discretion of PP in consultation with their pts, based on the AI CT matching report, and VTB support. CTE will be assessed on variables including biomarkers, barriers to enrollment. Study duration anticipated as ~36 mo. The impact time to initiation of CTE on PFS and OS will be estimated by Kaplan-Meier and Cox multivariable survival analysis. Enrollment is ongoing, with a target of ≥ 1500 patients. Key inclusion criteria: Pts with solid and hematological malignancies; Pts cancer-related biomarkers. Key exclusion: ECOG PS > 2; abnormal organ function; hospice. Results: To be presented. Conclusions: AI-based, patient-driven CTE is feasible, highly effective and paradigm-changing. Clinical trial information: NCT03452774.
A pilot course of intensive training in radiation biology and physics for oncologists in sub-Saharan Africa.
Authors: Taniguchi Cullen M. , Jhingran Anuja , Stecklein Shane Richard , Melancon Adam , Court Laurence , Ohrt Jared , Kupferman Michael Elliot , Msadabwe Susan Citonje
Published: October 2019

24

Background: Radiation therapy is an essential component of cancer care used for palliative and curative treatments access a wide spectrum of disease, but many low- and middle-income countries do not have equitable access to this technology or training in the radiation sciences. Towards this end, we launched a pilot program to teach the principles of radiation biology and radiation physics that are a basic component of training and credentialing of radiation oncologists in the United States. Methods: We designed a 5 days curriculum for radiation biology and radiation physics that were similar in depth and scope to the courses taught to residents at MD Anderson. Medical oncologists, medical students and radiation therapists from Zambia, Tanzania, Lesotho, as well as Papua New Guinea attended the course. All have experience with direct patient care in oncology, but no formal training in radiation biology or physics. A pre-test of 50 multiple choice questions for radiation biology and 40 multiple choice questions for radiation physics was administered to all students prior any instruction on the first day of the course, and the same test was given on the last day. Each question stem had 4 possible choices. Instructions consisted of lectures and problems sets with an emphasis on practical applications of radiation biology and physics. Results: The students (N = 22) scored a mean of 30.6±13.5% correct on the radiation biology pre-test and this improved to a mean of 57.7±13.1% after 5 days of instruction (P < 0.0001). Similarly, the students who took the medical physics exam (N = 22) had a mean 33.0±8.8% correct at baseline, which improved to 61.7±18.1% on the post-test (P < 0.0001). Conclusions: Despite almost no prior exposure to these complicated concepts, students exhibited nearly a two-fold increase in scores on a standardized test of radiation biology and medical physics. This pilot study demonstrates a proof-of-concept that this material can be taught effectively in a short time frame. Further refinement of this material may allow similar in-person intensive courses, teleconferencing, or archived videos to improve the education of radiation therapists in low- and middle-income countries.
Tumor-associated myeloid-derived suppressor cells as a potential biomarker for prognostication of response in treatment of diffuse large cell lymphoma.
Authors: Mukherjee Kalyan KUSUM , Dhar Sukanya , Bhattacharjee Rajib , Das Subhadip , Chakraborty Mohona , Bhanja Shayani , Ghosh Sarbari , Sarkar Madhurima , Dasgupta Shayani , Ghosh Diptendu , Bose Anamika , Baral Rathindranath
Published: October 2019

30

Background: NHL is a type of lymphoma either B or T cell origin. However, 85% is of B cell type, especially diffuse large B cell lymphoma (DLBCL) with CD20+ in nature. Standard of care of CD20+DLBCL is R-CHOP 6 to 8 cycles and 66% patients generally respond to this treatment. Remaining 34% is still unresponsive to R-CHOP. Thus, establishment of a biomarker is required to intensify the treatment.Out of different scope of biomarker development, alterations in immune cellular components within tumor microenvironment may be tried as a potential biomarker to assess the possibility of occurrence of residual disease and relapse within 2 years for the DLBCL patients with 6-8 cycles of R-CHOP. Methods: : Selected CD20+ DLBCL patients (n=51) were treated with 6-8 cycles of R-CHOP and included in the present study with their informed consent. A panel of immune cells, like, T (CD4+, CD8+)-cells, regulatory T (CD4+CD25+FoxP3)-cells, MDSCs (CD33+CD11b+CD14-/+), memory T (CD8+CD45RO+)-cells and multidrug resistance (MDR) phenotypes (P-gp, MRP1), were studied by flow-cytometry and RT-PCR at different phases of treatment. Results: Within 51 selected patients, 9 were disease free and 11 patients exhibited stable disease for 2 years following the completion of treatment. Rest of the patients (n=31) showed relapse in different time periods. Among several immune cells studied, CD33+CD11b+MDSCs were remarkably elevated in high-grade residual-and-relapsed DLBCL patients compared to non-relapsed patients and normal healthy individuals. CD33+CD14+ monocytic, but not CD33+CD14-granulocytic MDSCs were mostly increased in relapsed patients than control. Moreover, expression of MDR phenotypic markers was found to be elevated in these relapsed patients. Among relapsed patients CD8+CD45RO+ memory T cells were increased, however, these cells are mostly corrupted in nature. Conclusions: Observed correlation between increased monocytic MDSCs with the occurrence of residual disease and/or relapse suggests monocytic MDSCs might be a potential biomarker for prediction of residual-and-relapsed DLBCL patients.
CENP-U function on TNBC.
Authors: Zhang Jin
Published: October 2019

31

Background: Centromere protein (CENP-U) gene, as an important constitutive kinetochorecomponent, plays significant roles in cell caryomitosis. Our previous research found that about 25% of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression. Furthermore, the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue.Here we aimed to investigate the biological functions and potential molecular mechanism of CENP-U in breast cancer tumorigenesis. Methods: Gene knockdown was accomplished by transient transfection. In addition, cell proliferation was analyzed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay while cell apoptosis was measured by flow cytometry using an annexin V-FITC apoptosis detection kit. Then, VEGF secretion in the supernatant was detected with an enzyme-linked immunosorbent assay (ELISA). Furthermore,Vascular endothelial markers of nude mouse were discovered by immunohistochemistry. And the signaling activation in the breast cancer cells was accessed by western blot using specific antibodies. Results: We observed higher CENP-U expression in breast cancer compared to adjacent normal breast tissue, especially in TNBC.The MTT and EdU assay showed that CENP-U promoted the proliferation of the triple negative breast cancer (TNBC) cells while CENP-U downregulated promoted cell apoptosis. Furthermore, the ELISA results revealed that CENP-U significantly promoted the production and secretion of VEGF in TNBC cells. In addition, CENP-U downregulated inhibits tumor growth and angiogenesis in vivo. Importantly, CENP-U targeted HIF-1α,VEGFA and COX-2, which were shown by the specific antibodies in the western blot. Conclusions: The results showed that CENP-U influence the proliferation, apoptosis and angiogenesis especially of TNBC cells. But the affected signaling pathways require further study.
XenoSarc: A comprehensive platform of patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) for early drug testing.
Authors: Schoffski Patrick , Van Renterghem Britt , Cornillie Jasmien , Wang Yannick , Gebreyohannes Yemarshet Kelemework , Lee Che-Jui , Wellens Jasmien , Vanleeuw Ulla , Nysen Madita , Hompes Daphne , Stas Marguerite , Sinnaeve Friedl , Wafa Hazem , Topal Baki , Verbelen Tom , Debiec-Rychter Maria , Sciot Raf , Wozniak Agnieszka
Published: October 2019

37

Background: STS is a family of rare, heterogeneous tumors with > 70 subtypes. There is an urgent need for reliable preclinical models, especially for orphan subtypes of STS, given the limited treatment options. Methods: A panel of PDX models was established by s.c. implantation of fresh tumor specimens in athymic NMRI mice. Growing pieces of tumor were re-transplanted to next generations of mice. At each passage fragments were collected for histological/molecular characterization. A model was considered “established” after observing stable features for at least 2 passages. Ex-mouse tissue samples were stored, characterized by immunohistochemistry/flow cytometry and used for in vitro drug testing. Results: Between 2011-2019, 329 samples from 301 consenting patients were transplanted; 56 models are established, 16 additional models are in early passaging. Clinical information about donor and tumor (including sensitivity to standard and experimental agents) is available. The platform includes models of dedifferentiated lipo- (10 models), myxofibro- (8), leiomyo- (7), synovial (2), intimal (2), CIC-positive round cell (1), mesenchymal chondro- (1), extraskeletal osteo- (1), myxoid lipo- (1), myxoinflammatory fibroblastic (1), rhabdomyo- (2) and high-grade undifferentiated pleomorphic sarcoma (7), as well as GIST (8), MPNST (4) and epithelioid hemangioendothelioma (1). Models are well-characterized, with molecular information on copy number changes (low-coverage whole genome sequencing) and gene expression profile (RNA-Seq) available. We also constructed tissue microarrays from the xenografts which are used for target identification and model selection for preclinical studies. Xenografts are available for in vivo testing of novel agents, and results already served as a rationale for a number of prospective clinical trials. Conclusions: XenoSarc offers opportunities for studying the biology of a variety of sarcoma subtypes including ultra-rare entities and is a valuable tool for early drug screening in preparation of clinical STS trials. The platform is well maintained and continuously expanded, and available to collaborators from academia and industry.
Establishment of a tissue microarray (TMA) platform as an efficient tool for soft tissue sarcoma (STS) research available for collaboration.
Authors: Schoffski Patrick , Lee Che-Jui , Van Cann Tom , Wellens Jasmien , Zlobec Inti , Bovée Judith V.M.G. , Britschgi Christian , Sciot Raf , Wozniak Agnieszka
Published: October 2019

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Background: STS is a very heterogeneous family of orphan malignancies, characterized by morphological and genetic diversity. Tissue samples from individual STS patients are commonly used for routine diagnostic and research purposes. TMAs from multiple sarcoma tissue blocks have potential advantages over conventional tissue analysis in terms of efficiency and cost-effectiveness. We have established a comprehensive sarcoma TMA research platform. Methods: TMAs were constructed using left-over tissue from STS patients diagnosed at University Hospitals Leuven (B), Leiden University Medical Center (NL) and University Hospital Zürich (CH), and from patients with orphan sarcomas enrolled in EORTC trial 90101 “CREATE”. The clinical cases are well annotated in terms of diagnosis, treatment and follow-up. Each TMA block contains duplicate/triplicate 1.0-1.5 mm tissue cores from representative areas selected by sarcoma pathologists. The construction of TMAs was performed using TMA Grand Master (3DHistech) at University of Bern (CH) and in Leiden (NL). Results: The following subtype-specific TMAs have been created: clear cell sarcoma (CCSA, 54 cases), alveolar soft part sarcoma (ASPS, 59), inflammatory myofibroblastic tumor (IMFT, 33), alveolar rhabdomyo- (24) and leiomyosarcoma (55). For CCSA, ASPS and IMFT we have matching TMAs from clinical routine and patients entered in EORTC 90101. As a tool for broader drug- and target-screening purposes in STS we also produced a multi-sarcoma TMA combining multiple, more common subtypes on one block: angio-, dedifferentiated, pleomorphic and myxoid lipo-, leiomyo-, myxofibro-, rhabdomyo-, synovial and undifferentiated pleomorphic sarcoma, and MPNST, with 7-11 individual cases per tumor type. TMA construction is ongoing in other relevant sarcoma subtypes. Conclusions: We are currently expanding a very useful TMA platform representing the broad heterogeneity of STS, from more common to ultra-rare variants. TMAs are available for rapid, cost-effective morphological, histochemical and molecular characterization and identification of novel drug targets in collaboration with academic and commercial partners.
Image-guided vacuum-assisted biopsy to assess pathologic complete response in breast cancer patients with exceptional response to neoadjuvant chemotherapy.
Authors: Teoh Victoria , MacNeill Fiona , Roche Nicola , Gui Gerald , Pope Romney , Downey Kate , Bishop Briony , Nerurkar Ashutosh , Tasoulis Marios Konstantinos
Published: October 2019

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Background: Image-guided vacuum-assisted biopsy (VAB) is increasingly used after completion of neoadjuvant chemotherapy (NAC) to assess residual disease in the breast, facilitate risk-adaptive surgery and potentially identify exceptional responders who may not require surgical intervention. The aim of this analysis was to investigate the diagnostic performance of a standardized post-NAC VAB protocol, developed following retrospective analysis of institutional data (1). Methods: Prospective cohort study of patients with HER2 positive and triple negative (TN) invasive ductal carcinoma, treated with NAC, who had partial/complete imaging response and underwent post-NAC VAB to aid surgical planning between 02/2018 and 06/2019. The aim of VAB was to sample the site of residual imaging abnormality (breast residuum <2cm) previously marked by clip insertion. Pathologic complete response (pCR) was defined as no residual disease in the breast (ypT0). Diagnostic accuracy of VAB was calculated using final surgical pathology as the reference standard. Simple descriptive statistics were performed. Results: 26 eligible patients underwent post-NAC VAB. This was representative in 23 cases. The overall pCR rate was 46.2% (42.1% for HER2 positive, 57.1% for TN phenotypes). The post-NAC VAB false negative rate (FNR) was 9.1% (95% CI: 0-26.1) and the negative predictive value (NPV) was 90.91% (95% CI: 60.27-98.51) with an overall accuracy of 86.96% (95% CI: 66.41-97.22). Conclusions: This data suggests that post-NAC VAB may reliably predict pCR in patients with HER2 positive and TN invasive ductal carcinoma with good response to NAC. Further technical refinements in VAB technique, standardization in patient selection and prospective trials are warranted to further explore the role of post-NAC VAB in supporting minimal or no surgery trials. References 1. Tasoulis MK, Roche N, Rusby JE, Pope R, Allen S, Downey K, Nerurkar A, Osin P, Wilson R, MacNeill F. Post neoadjuvant chemotherapy vacuum assisted biopsy in breast cancer: Can it determine pathologic complete response before surgery? J Clin Oncol 2018;36 (Supplement): abstr 567.
Clinical validation of GAGE family protein as a biomarker for radiotherapy resistance in cervical cancer.
Authors: Wujanto Caryn , Nin Dawn Sijin , Leong Yiat Horng , Tan David Shao Peng , Low Jeffrey Jen Hui , Ng Joseph Soon Yau , Arunachalam Ilancheran , Lim Diana , Choo Bok Ai , Deng Lih Wen
Published: October 2019

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Background: Cervical cancer is the 4th most common cancer in females. Treatment recommendation for locally advanced cervical cancer includes concurrent chemo-radiotherapy (RT) followed by brachytherapy. However, primary treatment failure is not uncommon and is attributed to RT resistance. In view of RT-associated complications, identification of RT-resistant groups at diagnosis will help to minimize exposure to unnecessary toxicities. Methods: Our initial studies analyzing the genetic profile of RT-sensitive and RT-resistant tumours from xenograft models have identified the GAGE-family protein as a genetic marker that is selectively upregulated in RT-resistant xenograft tumours in vitro & in animal studies and is associated with more aggressive phenotypes of these tumors. To clinically validate these findings, we carried out a pilot study on 8 patients and also analyzed GAGE-family protein levels in retrospective study samples obtained from initial biopsy samples from from patients who have completed chemoRT and brachytherapy for cervical cancer to correlate their initial GAGE-family protein levels with treatment response. Results: Immuno-histological staining of pathology samples from 8 patients in our pilot study have shown that those with a higher expression of GAGE-family protein at mRNA and protein levels are more resistant to standard RT. Our retrospective analysis of 43 cervical cancer biopsy samples showed significantly elevated levels of GAGE-family protein mRNA ( P= 0.0028) and GAGE-family protein intensity score ( P= 0.026) in the 20 patients who were found to be resistant to standard definitive RT on subsequent follow-up compared to 23 patients who responded well. Median follow-up was 42 months. Conclusions: GAGE-family protein mRNA and protein expressions are elevated in patients resistant to standard definitive RT. We aim to develop a classification system to stratify patients into responders versus poor responders based on their GAGE-family protein levels at initial diagnosis in order to personalize treatment regimen whereby good responders can be treated with reduced RT dose and poor responders can receive escalated RT dose and further therapies in order to improve outcome.
A novel computational OMICS and non-OMICS approach for identifying true pathogenic risk variants for Asian prostate cancer.
Authors: Chimmiri Anusha , Wang Hai-Tao , Yeo Eugenia Li Ling , Low Kar Perng , Tan Agnes Chong Yin , Woo Wai Yee , Ong Enya Hui Wen , Tan Terence Wee Kiat , Looi Wen Shen , Nei Wen Long , Tuan Jeffrey , Wang Michael Lian Chek , Tan Janice Ser Huey , Lee Lui Shiong , Tay Kae-Jack , Kanesvaran Ravindran , Khor Li Yan , Yeong Joe Poh Sheng , Tan Chien sheng , Chua Melvin Lee Kiang
Published: October 2019

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Background: Large-scale genome-wide association studies have established germline polygenic risk loci that underpin the susceptibility to prostate cancer (PCa). However, most trials conducted are in men of European ancestry with data missing for Asian male PCa. Here, we report on an in-house multidimensional bioinformatics pipeline that integrates OMICS and non-OMICS approaches in identifying true germline risk-variants for PCa in Asian men. Methods: We utilized a prospective cohort study of Asian men who were newly diagnosed with PCa. Whole exome sequencing (Illumina Hiseq, CA) of blood (100X) was performed. The OMICS-based approach entailed a stepwise screen for hallmarks of cancer-specific pathways. A genome-proteome network was then developed to filter for known pathogenic variants; this was followed by comparison against a large artificial database of aggregated germline variants (N = 95,000) with reported linkage to PCa susceptibility. Finally, mutations were filtered through a non-OMICS pipeline that entailed data synchronization with population-level statistics and clinical outcomes (recurrence and survival). Results: Preliminary analyses were based on 277 PCa cases; of which 50 were M1 cases. Screening using a non-combined unbiased approach yielded 36,157 germline variants. This contrast against our OMICS-based approach, which reduced the variant calls to 6,144 significantly associated mutations. Next, by focusing on pathway-specific genes related to hormonal regulation and known cancer hotspot mutations, we could further tighten our variant calls to 3,562 hormone-related variants (rs9269958 on HLA-DRB1) and 2,125 variants in known cancer genes, notably (rs8176320 on BRCA1/2, rs2555691 on LILRA2, rs8036934 on TP53BP1). Conclusions: Here, we show that application of an OMICS approach that combines pathway-driven analyses and an artificial dataset, along with population-level statistics and clinical relevance resulted in more robust annotation of germline variants that were associated with PCa.
An optimized ultra-deep massively parallel sequencing with unique molecular identifier tagging for detection and quantification of circulating tumor DNA from lung cancer patients.
Authors: Pham Hong-Anh Thi , Tran Le Son , Tran Uyen Vu , Tran Thanh-Truong , Nguyen Hoai-Nghia , Giang Hoa , Dang Anh-Thu Huynh , Le Dinh-Thong Vu , Nguyen Son-Lam Vu , Nguyen Ngoc-Vu Vu , Nguyen Vu Trieu , Vo Binh Thanh , Nguyen Nguyen Huu , Nguyen Chu Van , Pham Cam Phuong , Dang-Mai Anh Tuan , Dinh-Nguyen Thien Kim , Phan Van Hieu , Do Thuy Thanh , Dinh Kiet Truong
Published: October 2019

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Background: The identification and quantification of actionable mutations are of critical importance for effective genotype-directed therapies, prognosis and drug response monitoring in patients with non-small-cell lung cancer (NSCLC). Although tumor tissue biopsy remains the gold standard for diagnosis of NSCLC, the analysis of plasma circulating tumor DNA (ctDNA), known as liquid biopsy, has recently emerged as an alternative and noninvasive approach for exploring tumor genetic constitution. In this study, we developed a mutation detection approach for liquid biopsy using ultra-deep massively parallel sequencing (MPS) with unique molecular identifier (UID) tagging and evaluated its performance for the identification and quantification of tumor-derived mutations from plasma of patients with advanced NSCLC. Methods: Tissue biopsy and plasma samples were collected from a total of 58 patients diagnosed with NSCLC in Vietnam. Genetic alterations in four driver genes including EGFR, KRAS, NRAS and BRAF were identified by using ultra-deep MPS combined with UID tagging. Subsequently, the concordance rate of mutation testing between matched plasma and tissue samples was assessed. Additionally, a commercially available ddPCR (Bio-rad) assay was used to conduct a cross-platform comparison with ultra-deep MPS for the detection and quantification of the three most common actionable EGFR mutations (del19, L858R and T790M). Results: Compared to the mutations detected in paired tissue samples, the plasma based ultra-deep MPS achieved high concordance rate of 87.5%. Cross-platform comparison with droplet digital PCR demonstrated comparable detection performance (91.4% concordance, Cohen's kappa coefficient of 0.85 with 95% CI = 0.72 – 0.97) and great reliability in quantification of mutation allele frequency (Intraclass correlation coefficient of 0.96 with 95% CI = 0.90 – 0.98). Conclusions: Our results highlight the potential application of liquid biopsy using ultra-deep MPS as a routine assay in clinical practice for both detection and quantification of actionable mutation landscape in NSCLC patients.