Candidates For Chemotherapy Research Articles

Breast Cancer: A Global Concern, Diagnostic and Therapeutic Perspectives, Mechanistic Targets in Drug Development.

Cancer is a complex multifactorial process, unchecked and abrupt division, and cell growth—conventional chemotherapy, along with radiotherapy, is used to treat breast cancer. Due to reduce efficacy and less survival rate, there is a particular need for the discovery of new active anticancer agents. Natural resources such as terrestrial/marine plants or organisms are a promising source for the generation of new therapeutics with improving efficacy. The screening of natural plant extracts and fractions, isolations of phytochemicals, and mechanistic study of those potential compounds play a remarkable role in the development of new therapeutic drugs with increased efficacy. Cancer is a multistage disease with complex signaling cascades. The initial study of screening whole extracts or fractions and later the isolation of secondary compounds and their mechanism of action study gives a clue of potential therapeutic agents for future drug development. The phytochemicals present in extracts/fractions produce remarkable effects due to synergistically targeting multiple signals. In this review, the molecular targets of extracts/ fractions and isolated compounds highlighted. The therapeutic agent's mechanistic targets in drug development focused involves; i) Induction of Apoptosis, ii) modulating cell cycle arrest, iii) Inhibition or suppression of invasion and metastasis and iv) various other pro-survival signaling pathways. The phytochemicals and their modified analogs identified as future potential candidates for anticancer chemotherapy.

Identifying optimal candidates for induction chemotherapy among stage II-IVa nasopharyngeal carcinoma based on pretreatment Epstein-Barr virus DNA and nodal maximal standard uptake values of [18 F]-fluorodeoxyglucose positron emission tomography.

ObjectiveThis study aimed to select optimal candidates benefiting from the addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in stage II–IVa nasopharyngeal carcinoma (NPC) based on Epstein–Barr virus (EBV) DNA and nodal maximal standardized uptake values (SUVmax‐N) of [18F]‐fluorodeoxyglucose positron emission tomography.Patients and materialsA total of 679 patients diagnosed with stage II–IVa (except N0) NPC were retrospectively included in this study. Overall survival was the primary endpoint. Survival differences between different groups were compared using the log‐rank test. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a multivariable Cox proportional hazards model.ResultsBoth high levels of EBV DNA (>1500 copies/mL) and SUVmax‐N (>12.3) indicated worse survival conditions. All patients were divided into low‐ and high‐risk groups based on these two biomarkers. The risk group was an independent prognostic factor in OS, progression‐free survival (PFS), and distant metastasis‐free survival (DMFS) (all p‐values<0.05). The addition of IC to CCRT was associated with survival improvement in OS, PFS, and DMFS in high‐risk patients, while no survival difference was found between CCRT and IC+CCRT in low‐risk patients.ConclusionsOur study can help clinicians select stage II–IVa NPC patients who benefit from IC, which is important in guiding individual treatment.

Prognostic Value of Serum Soluble Programmed Death-Ligand 1 and Dynamics During Chemotherapy in Advanced Gastric Cancer Patients.

PurposeThe soluble form programmed death-ligand 1 (sPDL1) has immunosuppressive properties and is being studied as a candidate biomarker for immuno-oncology drug development. We measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC).Materials and MethodsWe prospectively enrolled 68 GC patients who were candidates for palliative standard first-line chemotherapy, and serially collected blood at baseline and after one cycle of chemotherapy, at the best response and after disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progression-free survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off value of sPDL1 levels for survival analysis was found using C-statistics.ResultsThe median baseline sPDL1 was 0.8 ng/mL (range, 0.06 to 6.06 ng/mL). The median OS and PFS were 14.9 months and 8.0 months, respectively. sPDL1 and NLR showed a weak positive correlation (Spearman’s rho=0.301, p=0.013). Patients with low levels of sPDL1 at diagnosis (< 1.92 ng/mL) showed a better OS and PFS than patients with a high sPDL1. The baseline sPDL1 before treatment was higher in the progressive disease group than in the stable disease and partial response groups. Patients whose sPDL1 increased after the first cycle of chemotherapy showed worse PFS and OS. Following disease progression, sPDL1 increased compared with the baseline.ConclusionsPDL1 at prechemotherapy confers a prognostic value for PFS and OS in GC patients under palliative first-line chemotherapy. Dynamics of sPDL1 during chemotherapy correlates with disease progression.

Safe use of Peripherally Inserted Central Catheters for chemotherapy of solid malignancies in adult patients: A 1-year monocentric, prospectively-assessed, unselected cohort of 482 patients.

Aim of this study was to analyze the overall complication and failure rates of Peripherally Inserted Central Catheters (PICCs), in a 1-year consecutive unselected cohort of 482 adult patients, affected by non-hematological malignancies undergoing chemotherapy. Adult outpatients (aged 18-75 years), with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, bearing solid tumors and candidates for intravenous chemotherapy were eligible for the study. Exclusion criteria were active infections, coagulopathy (defined as platelet count <50,000/μL and/or prothrombin time more than 18 s), life expectancy <6 months, or inability to give written informed consent. Devices were all implanted in an outpatients' hospital facility, following predefined evidence-based institutional guidelines and protocols by a PICC-dedicated team at the European Institute of Oncology in Milan, Italy, during the 12-month period from January 1 to December 31, 2019. Five-hundred PICCs were implanted in a cohort of 482 patients during the time interval of this study. Thirty devices were overall removed (6.2%), 23 as a consequence of a complication occurred, and seven inadvertently. The inserted PICCs accounted for a total of 49,718 catheter days in situ, median duration was 85.5 days [interquartile range (IQR): 56-146]. Overall there were 42 (8.7%) complications, corresponding to 0.84 catheter-adverse events (CAE)/1000 PICC-days (95% CI: 0.61-1.14). There were N = 13 (2.7%) thromboses, N = 11 (2.3%) irreversible occlusions, N = 7 (1.5%) accidental removals, N = 5 (1.0%) infections [two Catheter Related Blood Stream Infection (CRBSI) and three exit site/local infection], N = 3 (0.6%) ruptures and N = 3 (0.6%) primary or secondary malpositions. This large prospective study supports the increasing use of PICCs in adult oncology outpatients treated in specialized centers with chemotherapy for non-hematological malignancies. In this clinical setting, PICC failure occurred in 6% only of the inserted devices.

S2347 The Case of the Missing Mass: Pancreatic Adenocarcinoma Presenting as Retroperitoneal Fibrosis

INTRODUCTION: Pancreatic adenocarcinoma is one of the most malignant and aggressive cancers, accounting for over 400,000 deaths annually. Classically, computed tomography (CT) is adequate in the diagnosis of pancreatic adenocarcinoma, with a reported sensitivity of up to 96%. This case describes an extremely unique presentation of pancreatic adenocarcinoma in a young female. CASE DESCRIPTION/METHODS: A 36-year-old female with history of iron deficiency anemia with several month history of abdominal pain and distention with associated non-bloody diarrhea. The patient also endorsed fifty pounds of unintentional weight loss. The patient had a hemoglobin of 8.8 mg/dL and a serum ferritin of 2 ng/mL. Her chemistries and liver function tests were within normal limits. A CT scan of the abdomen showed a large retroperitoneal mass encasing the celiac trunk and branchpoint of the superior mesenteric artery with associated retroperitoneal fibrosis. Additionally, there was chronic thrombosis of the splenoportal confluence and associated pelvic congestion syndrome and a moderate amount of abdominal ascites. MRI showed extrahepatic common bile duct stricture with proximal dilation and two cystic lesions in the neck of the pancreas with ductal dilatation. The patient subsequently underwent CT-guided retroperitoneal lymph node biopsy which only showed dense fibrous tissue consistent with retroperitoneal fibrosis. On EUS, an FNA of the pancreatic cyst was positive for pancreatic adenocarcinoma. Unfortunately, given the patient’s advanced disease, the patient was not a candidate for chemotherapy and was ultimately referred for palliative care. DISCUSSION: This case uniquely describes a case of pancreatic adenocarcinoma presenting as retroperitoneal fibrosis (RF). RF is most commonly idiopathic, accounting for up to 75% of cases. However, autoimmune processes such as immunoglobulin-G4 mediated disease have been implicated in its pathogenesis. Notably, there have been no significant associations between RF and pancreatic malignancies. This case highlights the importance of maintaining a high index of suspicion for malignancy in the differential for retroperitoneal fibrosis. Diagnosis in this patient was complicated by the proximity of the fibrotic tissue to the major branches of the aorta including the celiac trunk and superior mesenteric artery. However, definitive diagnostic modality such as EUS and FNA should not be delayed, especially in the presence of pancreatic masses.

S3057 Upper Gastrointestinal Bleeding Secondary to Gastric Metastasis of Pleomorphic Dermal Sarcoma

INTRODUCTION: Pleomorphic dermal sarcoma (PDS) is a rare cutaneous malignancy, seen primarily in sun exposed areas of elderly individuals. Along with atypical fibroxanthoma (AFX), it is believed to belong to a spectrum of malignant disorders arising from a similar fibrohistiocytic mesenchymal origin. Compared to AFX, PDS represents a more aggressive phenotype of disease with higher rates of recurrence and metastasis. CASE DESCRIPTION/METHODS: An 87-year-old male with a history PDS of the scalp with metastasis to the right humerus presented to the hospital with one week of melena. Pertinent past medical history included non-small cell lung cancer, chronic lymphocytic leukemia, melanoma, squamous and basal cell carcinoma of the skin. On presentation he was noted to be anemic with a hemoglobin of 6.8 g/dL and hematocrit of 22%. He was started on intravenous (IV) proton pump inhibitor (PPI) and underwent an esophagogastroduodenoscopy (EGD). Upon visualization of the stomach, four masses were identified along the greater curvature ranging between 1cm and 2.5cm in size, three of which were actively bleeding. Biopsies of these masses were obtained with cold biopsy forceps. No alternative source of bleeding was identified on exam. Following EGD, supportive measures were continued with IV PPI and packed RBC transfusions. Tissue histology of the gastric masses were consistent with a malignant spindle cell neoplasm, identical to that of the patient's known PDS. Additional imaging revealed new soft tissue lesions in the left hepatic lobe, right kidney, bladder and peritoneum. Given his diffusely metastatic disease, co-morbidities and frailty, therapeutic options were limited. He was deemed not an appropriate chemotherapy candidate and ultimately pursued hospice care. DISCUSSION: We present a case of upper gastrointestinal bleeding secondary to gastric metastasis of PDS. Metastasis occurs in approximately 10-20% of patients with PDS, most commonly involving the lungs and skin1. PDS had previously been classified as undifferentiated pleomorphic sarcoma or malignant fibrous histiocytoma. Under this nomenclature it has rarely been described to metastasize to the stomach and few cases have presented with gastrointestinal bleeding. This case contributes to the general understanding that the stomach can be a metastatic site for a wide variety of non-gastrointestinal cancers.Figure 1.: Proximal gastric body mass along the greater curvature.Figure 2.: Distal gastric body mass along the greater curvature.

THREE METACHRONOUS PRIMARY LUNG CANCERS IN A CHRONIC SMOKER: A CASE REPORT

SESSION TITLE: Fellows Lung Cancer Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Lung cancer is the worldwide leading cause of cancer-related deaths. Patients once treated curatively for lung cancer can develop subsequent primary lung cancer. Smoking is the major risk factor for the development of lung cancer and contributes to a higher risk of developing a second lung cancer in patients who continue to smoke after diagnosis and treatment of the initial cancer. The subsequent primary lung cancer can be treated successfully, however, both treatment regimen and prognosis depend on whether it is synchronous or metachronous. CASE PRESENTATION: A 60-year-old smoker with 55 pack-year history, presented with cough and hemoptysis. His physical exam was remarkable for clubbing. His pulmonary function testing revealed moderately severe chronic obstructive pulmonary disease (COPD). A Computerized Tomographic (CT) scan revealed a right upper lobe spiculated mass. Positron emission tomography (PET) scan showed standard uptake value (SUV) of 4.5 in the primary tumor and ipsilateral hilar and paratracheal nodes in metastatic range. Histopathologic examination of a transthoracic needle biopsy showed poorly differentiated adenocarcinoma (ADC) of the lung, stage IIIA. The patient was curatively treated with chemotherapy and radiation. After nine years he developed a new posterior left upper lobe spiculated nodule. PET/CT showed it to have an SUV of 4. The patient underwent apical wedge resection of the left upper lobe. Histopathological examination showed moderately differentiated keratinizing squamous cell carcinoma (SCC), stage IA1. He was given extensive counseling on smoking cessation, but he was still not able to quit. Six months later, CT of the chest showed increased soft tissue density and adenopathy of the right hilum with perilymphatic nodules in the right upper and lower lobes consistent with lymphangitic carcinomatosis. The patient underwent transbronchial biopsy reporting a small cell carcinoma (SCLC). Due to poor performance status, he was not a candidate for systemic chemotherapy, and he decided to go into hospice care. DISCUSSION: We reviewed the clinical and pathological features of synchronous and metachronous lung cancers in previously described patients. These patients were below the average age at which first lung cancer diagnosis is made in most patients, had long smoking histories, and histological type occurred in random order. The patients with metachronous cancers continued to smoke after the first or second cancer diagnosis which placed them at a higher risk for subsequent cancer(s). CONCLUSIONS: We recommend that patients with lung cancer diagnosis must quit smoking to reduce the risk of a second primary cancer, and those who do not quit should remain on long-term surveillance. Reference #1: de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res. 2018;7(3):220-233. Reference #2: Han SS, Rivera GA, Tammemagi MC, et al. Risk Stratification for Second Primary Lung Cancer. J Clin Oncol. 2017;35(25):2893-2899. Reference #3: Smith RA, Andrews KS, Brooks D, et al. Cancer screening in the United States, 2018: A review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2018;68(4):297-316 DISCLOSURES: No relevant relationships by Boris Betancourt, source=Web Response No relevant relationships by Lillian Chow, source=Web Response No relevant relationships by Dushyant Damania, source=Web Response No relevant relationships by Raavi Gupta, source=Web Response no disclosure on file for M Haseeb; no disclosure on file for Absia Jabbar; No relevant relationships by James Mahoney, source=Admin input No relevant relationships by gurinder sidhu, source=Web Response

Exopolysaccharides from Bacillus amyloliquefaciens DMBA-K4 ameliorate dextran sodium sulfate-induced colitis via gut microbiota modulation

Accumulating evidences have reported that polysaccharide could alleviate colitis through the maintenance of intestinal homeostasis. In this study, an exopolysaccharide (EPS-K4) from Bacillus amyloliquefaciens was obtained via anionic-exchange chromatography which was with an average molecular weight of 10,067 Da and consisted of mannose, rhamnose, glucuronic acid, and glucose with a molar ratio of 40.09:23.65:11.42:17.68. Furthermore, administration of EPS-K4 relieved symptoms in colitis mice via gut microbiota modulation. The levels of pathogenic bacteria, such as Enterococcus and Escherichia-Shigella, were significantly suppressed. In contrast, the levels of Lactobacillus and intestinal microbiota diversity were increased. EPS-K4 could stimulate mucin secretion to maintain the integrity of the gut barrier and decrease the levels of virulent substances (endotoxin, diamine oxidase, and D-lactic acid) in serum. The pro-inflammatory cytokines (TNF-α) in serum were reduced, conversely, anti-inflammatory cytokines (IL-10) were increased. These findings indicated the possibility of EPS-K4 as a chemotherapy candidate for the prevention of colitis.

The placement of multiple plastic stents still has important roles in candidates for chemotherapy for unresectable perihilar cholangiocarcinoma.

Placement of uncovered self-expandable metallic stents (U-SEMSs) of patients with unresectable perihilar cholangiocarcinoma (UPHC) is recommended as the treatment of first choice to address bile stasis. The aim of this study was to determine which of the following two endoscopic stents might be the stent of first choice for the treatment of biliary stasis in patients with UPHC: plastic stents (PSs) or U-SEMSs. U-SEMSs, deployed as a stent-in-stent, were selected as the stents of first choice from 2013 and 2014, while PSs began to be selected as the stents of first choice from 2015 onward. The median time to recurrent biliary obstruction were 66days in the PS group (N=38) and 105days in the U-SEMS group (N=37; P=.04). Emergency endoscopy was necessitated in 76.3% (29/38) of patients of the PS group and 54.1% (20/37) of patients of the U-SEMS group (P=.0434). The success rate of the first reintervention was 96.5% (27/29) in the PS group and 55% (11/20) in the U-SEMS group (P=.0002). Sustainable chemotherapy could be carried out in 55.2% of patients in the PS group and 32.4% of patients in the U-SEMS group (P=.0472). Multivariate analysis identified selection of U-SEMS as the stent of first choice as the only independent factor predictive of successful reintervention (P=.0016, odds ratio=0.058). However, the stent selection was not an independent factor for feasible chemotherapy. Plastic stent placement could enhance the success rate of reintervention in patients with UPHC and might be facilitated by sustainable chemotherapy. However, stent selection might not have an influence on the prognosis.

AML-190: Anti-TIM-3 Antibody MBG453 in Combination with Hypomethylating Agents (HMAs) in Patients with High-Risk Myelodysplastic Syndrome (HR-MDS) and Acute Myeloid Leukemia: A Phase 1 Study

Context MBG453 is an anti-TIM-3 antibody being developed for treatment of MDS and AML. TIM-3 is an immune checkpoint expressed on immune cells as well as leukemic stem cells and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS/AML. Objective To evaluate MBG453 plus decitabine (Dec) or azacitidine (Aza) in HR-MDS or AML ( NCT03066648 ). Design HMA-naive patients with high- or very high-risk MDS and newly diagnosed (ND) or relapsed/refractory (R/R; ≥1 prior therapy; MBG453+Dec arm only) AML were eligible if they were not candidates for intensive chemotherapy. Escalating doses of MBG453 were administered IV with Dec or Aza. Primary objectives were safety/tolerability. Results 69 patients with HR-MDS (n=19) or AML (n=50) received MBG453+Dec (cutoff 27Nov2019). 29 patients with HR-MDS (n=13) or AML (n=16) received MBG453+Aza (cutoff 14Jan2020). MTD was not reached for either combination. One DLT occurred with MBG453+Dec (at 240 mg Q2W): a corticosteroid-responsive grade 3 ALT elevation. No DLTs occurred with MBG453+Aza. Median exposure duration was 4.9 and 3.0 months for MBG453+Dec and MBG453+Aza. Both combinations were well tolerated. With MBG453+Dec and MBG453+Aza, respectively, most common grade 3/4 treatment-emergent (TE) AEs were thrombocytopenia (41%; 52%), febrile neutropenia (46%; 21%), neutropenia (42%; 38%), and anemia (25%; 28%). For MBG453+Dec, only 4 patients (6%; 3 AML, 1 MDS) experienced ≥1 potentially immune-related (IR) grade ≥3 AE reported as treatment-related (ALT increase, arthritis, hepatitis, hypothyroidism, rash). No treatment-related grade ≥3 potential IRAEs reported for MBG453+Aza. No treatment-related grade 4 IRAEs or deaths reported for either combination. For MBG453+Dec, ORR (evaluable patients) was 58% (11/19) for HR-MDS (5 CR, 4 mCR, 2 HI), 41% (7/17) for ND-AML (4 CR, 1 CRi, 2 PR), and 24% (6/25) for R/R-AML (6 CRi). Median exposure duration (responders): 8.6 months. For MBG453+Aza, ORR (evaluable patients) was 70% (7/10) for HR-MDS (6 mCR, 1 PR) and 27% (3/11) for ND-AML (1 CR, 2 PR) (median exposure duration, 3.0 months). Conclusions MBG453 plus Dec or Aza was safe and well tolerated in HR-MDS and AML, with TEAEs consistent with that for single-agent HMA. Both combinations showed encouraging response rates and emerging durability.

Synthesis, molecular modeling, TD‐DFT, antimicrobial, and in vitro therapeutic activity of new spherical nano‐sized sulfonamide imine ligands and their zinc (II) and copper (II) complexes

A series of nanometer‐sized spherical sulfonamide imine ligands HL1‐HL5 and their copper and zinc complexes were synthesized and fully characterized based on elemental analyses, spectroscopic (UV/vis, FT‐IR, NMR, EPR, SEM) studies, molar conductance and thermal analyses. Furthermore, computational studies of HL1‐HL5 were carried out by the DFT/B3LYP method. TD‐DFT, HOMO and LUMO energy values, chemical hardness, electronegativity, electrophilic index, softness, and other parameters were calculated. Screening against several pathogenic microorganisms indicated that HL1 exhibited high activity against the tested Gram‐negative bacteria relative to other analogues and the inhibition activity is greater than the standard Gentamicin. Analogously, HL2 exhibited high potent activity against the tested Gram‐positive bacteria. Copper complexes exhibited a higher potent activity than zinc analogues. Noteworthy, inhibition activity of [Cu (L3)(OAc)] complex is higher than that of the standard Ampicillin. [Cu (L2)(OAc)] complex displayed a similar activity of the standard bactericides and fungicides in use. The complexes showed appreciated values of MIC against bacterial strains: B. subtilis (MIC = 0.4 μg / mL), E. coli and S. pneumonia (MIC = 1.95 μg / mL) and P. aeruginosa (MIC = 7.81 μg / mL). in vitro cytotoxic activities study proved that [Cu (L3)(OAc)] complex exhibited appreciable activity versus (HEPG‐2); IC50 = 4.8 μg/ml, while [Cu(L2)(OAc)] complex showed a high activity against (MCF‐7); IC50 = 6.2 μg/ml. These results could be considered as new findings of promising antitumor candidates for experimental chemotherapy.

Abstract 3721: Relationship between insulin resistance and chemosensitivity of high grade bone sarcoma

Abstract Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Insulin-like Growth Factor (IGF) pathway was first linked with sarcoma biology approximately 30 years ago (El-Brady OM, 1990). Methods: We recruited 138 pts with newly diagnosed primary localized or metastatic BS. We measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance IR was calculated, and patients with HOMA-IR &amp;gt; 2.6 were considered as IR. We collected characteristics usually associated with insulin resistance: age, obesity, diabetes, dyslipidemia and hypertension. Results: Out of 138 pts, 50 (36%) were insulin resistant: HOMA-IR &amp;gt;2.6. Thirty-two IR patients (64%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI &amp;gt; 30 kg/m2)(22% vs 3%, p=0.0015), but not with age (median 36,8 vs 41 years, p=0.19). IR was more prevalent in Ewing sarcoma (14/29; 48%) and chondrosarcoma (7/16; 44%) followed by osteosarcoma (25/67; 37%) and other rare bone sarcomas (4/26; 15.3%), but not significantly (p=0.097). After neoadjuvant chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (88.9 vs 75%, p= 0.028). Conclusion: Our results suggest that metabolic profile may help to discriminate best candidates for neoadjuvant chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results. Citation Format: Pascaline Boudou-Rouquette, Ithar Gataa, Sixtine De Percin, Camille Tlemsani, David Biau, Valerie Dumaine, Virginie Audard, Frédérique Larousserie, Philippe Anract, Anne Jouinot, François Goldwasser. Relationship between insulin resistance and chemosensitivity of high grade bone sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3721.

Prognostic significance of p16 expression in high-grade prostate adenocarcinoma.

Management of advanced hormone-naïve prostate cancer (HNPC) is a critical public health issue. Useful prognostic markers are thus needed to select patients who will benefit from recently introduced upfront therapies. p16 expression is an adverse prognostic marker in prostate cancer. The present study aimed to determine whether p16 expression would serve as an adverse prognostic marker in advanced HNPC. A total of 79 patients diagnosed by needle biopsy with adenocarcinoma Gleason score ≥8 between 2010 and 2013 at Aichi Medical University were included in this study. The median patient age was 73 (range 52-87) years. The median follow-up was 62 months (range 2-98). Fourteen patients had p16-positive samples. Fifteen patients died from prostate cancer, 10 of whom were in the p16-positive group. p16 positivity was associated with clinical T stage (P < 0.001), presence of IDC-P (P < 0.001), distant metastasis (P < 0.001) and lymph node metastasis (P < 0.001). These results indicate that p16 expression is associated with adverse prognostic factor of prostate cancer and suggest that p16 expression may provide useful information for treatment planning and identifying suitable candidates for upfront chemotherapy or androgen receptor axis-targeted therapy.

Cardioncological Approach for Trastuzumab Therapy in Breast Cancer Patients With Cardiotoxicity: Impact on Adherence and Clinical Outcome.

BackgroundTreatment with Trastuzumab is associated with cardiotoxicity. If Trastuzumab could be administered in a safe manner to patients who develop a reduced left ventricular ejection fraction (EF) of < 50% remains poorly understood.ObjectiveTo evaluate the impact of a cardioncological approach in terms of adherence and continuation of oncological therapy with Trastuzumab.Methods and ResultsInternal databases of candidates for trastuzumab chemotherapy with evidence of cardiotoxicity according to echocardiographic criteria were retrospectively evaluated. Eighty-four female patients (age 51.7 years, 95% CI 49.5–53.8), were finally included. Patients were divided to receive a standard (n 27) or cardioncological (n 57) scheme. Baseline EF values were within normal limits (60.9, 95% CI 60 - 61.9%; p=0.5 between groups). The nadir of EF observed during trastuzumab therapy was more pronounced in the standard care group (40.6, 95% CI 37.3–43.9% vs. 46.3, 95% CI 44.3–48.3%; p=0.002). At re-challenge, after cardiotoxicity detection, all patients in the cardioncological arm resumed and completed trastuzumab therapy (p<0.0001). An overall reduction of EF was observed at the final evaluation (p <0.0001 vs. baseline). Cardioncological approach was the only independent determinant of ΔEF from baseline to final evaluation (R20.12; p=0.004). We observed a total of 13 (15%) HF events, seven (26%) in the standard, and six (10%) in the cardioncological approach group (p =0.1). Patients in the cardioncological approach arm had a better outcome (Log Rank Chi-squared 4.89; p=0.02).ConclusionsA targeted cardioncological approach, in patients with evidence of cardiotoxicity during HER-2 inhibitor therapy, could favorably influence the oncological management of breast cancer patients, reducing the adverse cardiovascular impact of chemotherapy.

Systemic Approach to Recurrent Primary CNS Lymphoma: Perspective on Current and Emerging Treatment Strategies.

There is no uniform standard of care for the treatment of refractory or recurrent primary central nervous lymphoma (r/r PCNSL). Many different systemic treatment regimens have been studied, but available data are based on small prospective or retrospective reports. There have been no randomized controlled trials in r/r PCNSL to date. Here, we provide an overview of published systemic regimens for the treatment of r/r PCNSL, as well as therapies that are under investigation. In addition, based on available data, we propose strategies of how to approach choice of therapy for different groups of patients in this disease setting. Patients can be mainly divided into three groups: 1) patients suitable for a re-challenge with high-dose methotrexate (HD-MTX)-based regimens and that may or may not be candidates for consolidation with high-dose chemotherapy with autologous stem cell transplant, 2) patients refractory to HD-MTX or that had early relapse, but suitable for an aggressive treatment strategy with re-induction with non-MTX-based therapy, possibly followed by high-dose chemotherapy with autologous transplant, and 3) patients not suitable for re-treatment with HD-MTX and that are not candidates for aggressive therapy. As PCNSL is a rare disease and as there is urgent need for better outcomes in r/r PCNSL, clinical trial participation is encouraged, especially in elderly or frail patients who are not candidates for high-dose chemotherapy and transplant.

Integration of geriatric assessment into routine oncologic care and advances in geriatric oncology: A young International Society of Geriatric Oncology Report of the 2020 American Society of Clinical Oncology (ASCO) annual meeting

Integration of geriatric assessment into routine oncologic care and advances in geriatric oncology: A young International Society of Geriatric Oncology Report of the 2020 American Society of Clinical Oncology (ASCO) annual meeting

A phase II study of pazopanib as front-line therapy in patients with non-resectable or metastatic soft-tissue sarcomas who are not candidates for chemotherapy

BackgroundCytotoxic chemotherapy remains the standard of care first-line treatment for advanced and metastatic soft-tissue sarcomas (STSs). Certain patients may not be chemotherapy candidates based upon age or co-morbidities, leaving limited treatment options. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA-approved for metastatic STS after the first line. We proposed a phase II study evaluating pazopanib as a first-line agent in patients with advanced disease who are deemed not to be candidates for chemotherapy. MethodsEligible patients were at least 18 years old, not candidates for chemotherapyand were treatment naive. Pazopanib was titrated from 200 mg twice daily to a goal of 800 mg daily. The primary end point was the clinical benefit rate (CBR) (CBR = completed response + partial response + stable disease per Response Evaluation Criteria in Solid Tumours [RECIST 1.1]) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesised CBR of ≥35% against an unfavourable CBR of ≤20%. If ≥ 17 patients achieved benefit, the null CBR of 20% would be rejected at a nominal 5% alpha level. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life and serum biomarkers. FindingsFifty-six patients were enrolled from May 2015 to February 2019 and are included in the intention-to-treat analysis. Median PFS was 3.67 (2.62–7.25) months. Median OS was 14.16 (95% confidence interval [CI]: 8.4-NR) months, CBR = 39.29% (22/56) (CI = 0.265–0.533, p = 0.0007). No new or unexpected adverse events were seen. The most common grade I–II events were diarrhoea, nausea and fatigue. The most common grade III–IV events were hypertension and liver function test abnormalities. InterpretationThese data suggest that there is a benefit to front-line pazopanib in patients with STS who are not candidates for cytotoxic chemotherapy.

A quality-adjusted survival time without symptoms or toxicities analysis of glasdegib plus low-dose cytarabine versus low-dose cytarabine as initial therapy for acute myeloid leukemia in patients who are not considered candidates for intensive chemotherapy.

BackgroundIn a randomized study, glasdegib (a hedgehog inhibitor) plus low‐dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality‐adjusted time without symptoms of disease progression or toxicity (Q‐TWiST) approach was used to evaluate comparative quality‐adjusted survival.MethodsOverall survival was partitioned into the following: time with any treatment‐emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q‐TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility‐adjusted time.ResultsAt 20 months of follow‐up, the survival probabilities for the glasdegib‐LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib‐LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8‐5.2 months) and TOX (+0.8 months; 95% CI, 0.1‐1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, −1.9 to 2.3 months). Q‐TWiST was 4.0 months (95% CI, 2.1‐5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality‐adjusted survival with respect to LDAC. Results were robust to the length of follow‐up (6‐24 months) and remained significant when all adverse events, regardless of grade, were included.ConclusionsThese results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively “good” health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option.

Myricetin induces apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling in human colon cancer cells

BackgroundThe compound 3,3′,4′,5,5′,7-hexahydroxyflavone (myricetin) is a natural flavonoid with antitumour activity. Most of the studies on myricetin have focused on the induction of tumour cell apoptosis, and little is known about the regulatory effects of myricetin on autophagy in colorectal cancer.MethodsHere, we studied the effects of myricetin on colon cancer cell proliferation, apoptosis and autophagy. We detected colon cancer cell apoptosis induced by myricetin via flow cytometry and Hoechst 33258 staining. Transmission electron microscopy was performed to observe the morphological changes associated with autophagy. The expression levels of apoptosis-, autophagy- and PI3K/Akt/mTOR signalling-related proteins were measured by Western blot analysis.ResultsThis study confirmed that myricetin inhibits the proliferation of 4 kinds of colon cancer cell lines. Myricetin induced cell apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling pathway. In addition, the inhibition of autophagy with 3-methyladenine (3-MA) promoted the apoptosis of myricetin-treated colon cancer cells.ConclusionsConsidering that myricetin induces apoptosis and autophagy in colon cancer cells, myricetin may become a viable candidate for chemotherapy; it could be used to exert tumour inhibitory effects alone or as adjuvant chemotherapy to inhibit autophagy. These studies may provide further evidence for the potential use of myricetin in the treatment of colon cancer.

Abstract B36: Antimalarial agent, atovaquone, inhibits cancer cell proliferation by targeting oxidative phosphorylation and is a candidate for chemoprevention and chemotherapy of ovarian cancer

Abstract Atovaquone is a FDA-approved antimalarial agent that has also shown potent anticancer properties. In the current study, we demonstrate that atovaquone is a prime candidate for treatment of high-grade serous ovarian cancer. We have tested atovaquone against a panel of ovarian cancer cells lines and shown that this drug inhibits proliferation and induces apoptosis at IC50 concentrations between 10-20 microM. Exposure to atovaquone results in increased apoptosis as indicated by an increase in cleaved caspase 3 and other relevant apoptotic markers. Additionally, our data also suggest that atovaquone is able to reactivate p53. Inhibition of p53 attenuates the cytotoxicity of atovaquone. However, the primary event that occurs in atovaquone-treated cells is the rapid surge in intracellular oxygen radicals. Imaging cytometry experiments conclusively demonstrate that the oxygen radical surge originates in the mitochondria. The oxidative stress caused by atovaquone is responsible for DNA damage and p53 activation. The atovaquone-induced oxygen radical surge also leads to damage to the Na+/K+-ATPase, perturbing the ability of the cancer cells to maintain an optimal membrane potential. This increase in oxygen radicals occurs because atovaquone targets the oxidative phosphorylation pathway in the mitochondria and blocks electron transport. Measurements conducted on the Seahorse analyzer show decreased consumption of oxygen and lower levels of ATP in the atovaquone-treated cells. In the malarial parasite, atovaquone targets mitochondrial complex III. In ovarian cancer cells, supplying succinate did not reverse atovaquone-induced inhibition of oxidative phosphorylation. On the other hand, when cells were supplemented with the substrate for complex IV, the oxygen consumption rate normalized in atovaquone-exposed cells. These experiments suggest that atovaquone is likely inhibiting complex I-III of mitochondria. Atovaquone is a naphthoquinone with significant structural similarity with the electron transporter ubiquinone. In silico modeling experiments indicate that atovaquone can bind to the ubiquinone binding pocket on complexes I-III. Based on these experiments, we propose that atovaquone is competing with ubiquinone to inhibit efficient electron transport and thereby increasing the intracellular oxygen radicals. Ovarian tumor-bearing mice tolerated prolonged treatment with Mepron®, the clinical formulation of atovaquone. Daily treatment of ID8 tumor-bearing C57BL/6 mice with atovaquone for 3-4 weeks resulted in a significant decrease in tumor growth. Additionally, we also show decreased proliferation of human ovarian tumors treated ex vivo with atovaquone. These experiments indicate that atovaquone can be used as a safe and effective drug for chemoprevention and chemotherapy of ovarian tumors. Citation Format: Arvinder Kapur, Mildred Felder, Yousef Alharbi, Allegra Cappuccini, Bikash Pattnaik, Lisa Barroilhet, Manish Patankar. Antimalarial agent, atovaquone, inhibits cancer cell proliferation by targeting oxidative phosphorylation and is a candidate for chemoprevention and chemotherapy of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B36.