A MXene-Based Bionic Cascaded-Enzyme Nanoreactor for Tumor Phototherapy/Enzyme Dynamic Therapy and Hypoxia-Activated Chemotherapy

The enzyme-mediated elevation of reactive oxygen species (ROS) at the tumor sites has become an emerging strategy for regulating intracellular redox status for anticancer treatment. Herein, we proposed a camouflaged bionic cascaded-enzyme nanoreactor based on Ti3C2 nanosheets for combined tumor enzyme dynamic therapy (EDT), phototherapy and deoxygenation-activated chemotherapy. Briefly, glucose oxidase (GOX) and chloroperoxidase (CPO) were chemically conjugated onto Ti3C2 nanosheets, where the deoxygenation-activated drug tirapazamine (TPZ) was also loaded, and the Ti3C2-GOX-CPO/TPZ (TGCT) was embedded into nanosized cancer cell-derived membrane vesicles with high-expressed CD47 (meTGCT). Due to biomimetic membrane camouflage and CD47 overexpression, meTGCT exhibited superior immune escape and homologous targeting capacities, which could effectively enhance the tumor preferential targeting and internalization. Once internalized into tumor cells, the cascade reaction of GOX and CPO could generate HClO for efficient EDT. Simultaneously, additional laser irradiation could accelerate the enzymic-catalytic reaction rate and increase the generation of singlet oxygen (1O2). Furthermore, local hypoxia environment with the oxygen depletion by EDT would activate deoxygenation-sensitive prodrug for additional chemotherapy. Consequently, meTGCT exhibits amplified synergistic therapeutic effects of tumor phototherapy, EDT and chemotherapy for efficient tumor inhibition. This intelligent cascaded-enzyme nanoreactor provides a promising approach to achieve concurrent and significant antitumor therapy.

Survival impact of additional chemotherapy after adjuvant concurrent chemoradiation in patients with early cervical cancer who underwent radical hysterectomy

Background To determine whether additional chemotherapy after concurrent chemoradiation (CCRT) improves survival outcomes in patients with early cervical cancer who undergo radical hysterectomy (RH). Methods We included high- or intermediate-risk patients from two institutions, with 2009 FIGO stage IB–IIA, who underwent primary RH and pelvic lymphadenectomy between January 2007 and June 2020, and had completed adjuvant CCRT. Survival outcomes were compared between patients who received additional chemotherapy (study group) and those who did not (control group). Results A total of 198 patients were included in this analysis. The study (n = 61) and control groups (n = 137) had similar patient age, histologic cancer type, 2009 FIGO stage, and tumor size. However, minimally invasive surgery was performed less frequently in the study group than in the control group (19.7% vs. 46.0%, P < 0.001). The presence of pathologic risk factors was similar, except for lymph node metastasis, which was more frequent in the study group (72.1% vs. 46.0%; P = 0.001). In survival analyses, no differences in the disease-free survival (DFS; P = 0.539) and overall survival (OS; P = 0.121) were observed between the groups. Multivariate analyses adjusting for surgical approach and other factors revealed that additional chemotherapy was not associated with DFS (adjusted HR, 1.149; 95% CI, 0.552–2.391; P = 0.710) and OS (adjusted HR, 1.877; 95% CI, 0.621–5.673; P = 0.264). The recurrence patterns did not differ with additional chemotherapy. Consistent results were observed in a subset of high-risk patients (n = 139). Conclusions Additional chemotherapy after CCRT might not improve survival outcomes in patients with early cervical cancer who undergo RH.

Trial-in-Progress: Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma (NCT#03269669): SWOG S1608

While the majority of follicular lymphoma (FL) patients have an overall survival of nearly 2 decades, a subset of patients has a markedly inferior survival. Across randomized studies, 20% of patients will respond poorly to first-line chemoimmunotherapy and account largely for the early deaths in the larger FL population. This group represents the largest unmet need in FL, for which a precision approach to therapy must be developed. With the development of newer monoclonal antibodies, immunomodulatory agents, therapies targeting molecules downstream of the B-cell receptor and novel cellular strategies, non-cytotoxic treatment has the potential to improve outcomes for patients with early progressing FL. There are several validated clinical factors known to correlate with disease outcome in newly diagnosed FL including age, lactate dehydrogenase, β2-microglobulin and disease extent that have been incorporated in prognostic systems such as FLIPI and FLIPI2. More recently, genetic biomarkers have been identified, including MLL2, EZH2, IRF4, CREPPB, and EPHA7 which reflect the disease biology as well as the impact of the lymphoma microenvironment. The addition of these molecular aberrations to clinical factors has led to the development of the M7-FLIPI as well as a 23-gene score, improving risk prognostication for newly diagnosed FL patients. However, such systems have shown a limited ability to predict progression or relapse within 2 years of chemotherapy. As such, identification of these patients at diagnosis or prior to therapy is currently not possible. S1608 was developed to 1) enable identification of high-risk patients using clinical and molecular markers by validating the m7-FLIPI prognostic system and to 2) identify the novel therapeutic approaches most active in this population. This study is enrolling high-risk patients, refractory to chemoimmunotherapy, and in randomized fashion, comparing novel regimens against additional chemotherapy to identify the most active non-chemotherapeutic strategies for this population. Eligible patients must be 18 years or older with grade 1, 2 or 3a FL and have relapsed or progressed with 2 years of finishing their first course of chemoimmunotherapy. Previous chemotherapy must have been CHOP or bendamustine based. Patients are eligible regardless of anti-CD20 therapy used, whether radiation therapy had been administered and whether or not maintenance therapy was utilized. Note that patients are required to have evidence of progressive disease within 2 years but do not have to be registered within 2 years. These high-risk patients are randomized to 12 months of lenalidomide, umbralisib or additional chemotherapy (for 6 months), all combined with 12 months of obinutuzumab. The primary clinical endpoint is CR rate after 6 cycles, allowing responding patient to proceed with consolidative cellular therapies if desired by the treating physician. Biopsies from diagnosis and at the time of relapse as well as circulating tumor DNA are being collected to prospectively evaluate the m7-FLIPI and to identify additional predictive markers. S1608 is a collaborative effort amongst the SWOG, Alliance and ECOG-ACRIN cooperative groups. The study represents one of the only prospective efforts to characterize early progressing FL and the only randomized trial comparing treatment strategies for this group of follicular lymphoma patients most in need of alternative therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, U10CA180821; and TG Therapeutics, Inc. Figure 1 Figure 1. Disclosures Barr: Genentech: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Beigene: Consultancy; Abbvie/Pharmacyclics: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Gilead: Consultancy. Link: Novartis, Jannsen: Research Funding; MEI: Consultancy; Genentech/Roche: Consultancy, Research Funding. Flowers: Cellectis: Research Funding; Nektar: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; BeiGene: Consultancy; 4D: Research Funding; Karyopharm: Consultancy; Morphosys: Research Funding; Guardant: Research Funding; Bayer: Consultancy, Research Funding; Genmab: Consultancy; Eastern Cooperative Oncology Group: Research Funding; SeaGen: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Adaptimmune: Research Funding; Janssen: Research Funding; Iovance: Research Funding; Acerta: Research Funding; Kite: Research Funding; Allogene: Research Funding; EMD: Research Funding; Amgen: Research Funding; Celgene: Consultancy, Research Funding; Ziopharm: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; National Cancer Institute: Research Funding; Xencor: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Biopharma: Consultancy; Denovo: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Weigert: Janssen: Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Herrera: ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Kite, a Gilead Company: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Weinstock: SecuraBio: Consultancy; ASELL: Consultancy; Bantam: Consultancy; Abcuro: Research Funding; Verastem: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Consultancy; Travera: Other: Founder/Equity; Ajax: Other: Founder/Equity. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Kahl: Abbvie, BeiGene, AstraZeneca, Acerta: Research Funding; Research to Practice: Speakers Bureau; Abbvie, ADCT, AstraZeneca, Beigene, Celgene, Teva, Janssen, MTEM, Bayer, InCyte, Adaptive, Genentech, Roche, MEI, KITE, TG Therapeutics, Epizyme, Takeda: Consultancy. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC .

Financial Implications of Early Hospital Discharge After AML-Like Induction Chemotherapy: A 4-Year Retrospective Analysis

Background: Early hospital discharge (EHD) after intensive acute myeloid leukemia (AML) induction chemotherapy has become routine at the University of Washington/Seattle Cancer Care Alliance over the past several years. We assessed the financial implications of EHD over the first 4 years after its broad adoption for patients with AML and other high-grade myeloid neoplasms undergoing AML-like induction chemotherapy. Patients and Methods: We retrospectively compared charges between 189 patients with EHD who received all postinduction inpatient/outpatient care within our care system between August 2014 and July 2018 and 139 medically matched control patients who remained hospitalized for logistical reasons. Charges from the day of initial discharge (patients with EHD) or end of chemotherapy (control patients) until blood count recovery, additional chemotherapy or care transition, hospital discharge (for control patients only), an elapse of 42 days, or death were extracted from financial databases and separated into categories: facility/provider, emergency department, transfusions, laboratory, imaging, pharmacy, and miscellaneous. Results: Combined charges averaged $4,157/day (range, $905–$13,119/day) for patients with EHD versus $9,248/day (range, $4,363–$48,522/day) for control patients (P<.001). The EHD cohort had lower mean facility/provider, transfusion, laboratory, and pharmacy charges but not imaging or miscellaneous charges. During readmissions, there was no statistically significant difference in daily inpatient charges between the EHD and control cohorts. After multivariable adjustment, average charges were $3,837/day lower for patients with EHD (P<.001). Conclusions: Together with previous data from our center showing that EHD is safe and associated with reduced healthcare resource utilization, this study further supports this care approach for AML and other high-grade myeloid neoplasms if infrastructure is available to enable close outpatient follow-up.

Development and Validation of a Prognostic Model for Predicting Overall Survival in Patients With Bladder Cancer: A SEER-Based Study

ObjectiveTo establish a prognostic model for Bladder cancer (BLCA) based on demographic information, the American Joint Commission on Cancer (AJCC) 7th staging system, and additional treatment using the surveillance, epidemiology, and end results (SEER) database.MethodsCases with BLCA diagnosed from 2010–2015 were collected from the SEER database, while patient records with incomplete information on pre-specified variables were excluded. All eligible cases were included in the full analysis set, which was then split into training set and test set with a 1:1 ratio. Univariate and multivariate Cox regression analyses were conducted to identify prognostic factors for overall survival (OS) in BLCA patients. With selected independent prognosticators, a nomogram was mapped to predict OS for BLCA. The nomogram was evaluated using receiver operating characteristic (ROC) analysis and calibration plot in both the training and test sets. The area under curve [AUC] of the nomogram was calculated and compared with clinicopathological indicators using the full analysis set. Statistical analyses were conducted using the R software, where P-value &lt;0.05 was considered significant.ResultsThe results indicated that age, race, sex, marital status, histology, tumor-node-metastasis (TNM) stages based on the AJCC 7th edition, and additional chemotherapy were independent prognostic factors for OS in patients with BLCA. Patients receiving chemotherapy tend to have better survival outcomes than those without. The proposed nomogram showed decent classification (AUCs &gt;0.8) and prediction accuracy in both the training and test sets. Additionally, the AUC of the nomogram was observed to be better than that of conventional clinical indicators.ConclusionsThe proposed nomogram incorporated independent prognostic factors including age, race, sex, marital status, histology, tumor-node-metastasis (TNM) stages, and additional chemotherapy. Patients with BLCA benefit from chemotherapy on overall survival. The nomogram-based prognostic model could predict overall survival for patients with BLCA with accurate stratification, which is superior to clinicopathological factors.

An interdisciplinary integrative approach to pregnancy management in benign and borderline ovarian tumors: a case report and а literature review

The management and treatment of patients with various malignancies during pregnancy appears to be a pressing issue to date. Ovarian tumors take the 4th place among all neoplasms diagnosed during pregnancy. The study aimed to investigate an interdisciplinary integrative approach to pregnancy management in case of benign and borderline ovarian tumors.The article presents the analysis of the pregnancy course in women with borderline and malignant ovarian tumors. When detecting a tumor during pregnancy, obstetric and surgical tactics is determined in a multidisciplinary team together with an oncologist.It is possible not only to prolong pregnancy without additional chemotherapy but also to preserve fertility in the future in patients with borderline tumors and stage I malignant tumors.

Role of palliative radiotherapy in bleeding control in patients with unresectable advanced gastric cancer

Background This study analyzed the clinical results of palliative radiotherapy for bleeding control in patients with unresectable advanced gastric cancer. Methods We retrospectively reviewed the medical records of patients who met the following inclusion criteria between January 2002 and June 2018: histologically proven gastric cancer, gastric tumor bleeding confirmed by upper gastrointestinal endoscopy, and palliative radiotherapy performed for hemostasis. The median radiotherapy dose was 30 Gy, with a daily dose ranging from 1.8 to 3 Gy. Results Sixty-one patients were included in this analysis. The study population was predominantly male (72.1%), with a median age of 62 years (range: 32–92). The median baseline hemoglobin level was 7.1 g/dL, and the most common presenting symptom of gastric tumor bleeding was melena (85.2%). Bleeding control was achieved in 54 (88.5%) patients. The median levels of hemoglobin at 1, 2, and 3 months after completion of radiotherapy were 10.1 g/dL, 10.2 g/dL, and 10.4 g/dL, respectively; these values were significantly different from that before radiotherapy (7.1 g/dL; p < 0.001). The median overall survival was 4.8 months. Among the 54 patients who achieved bleeding control after radiotherapy, 19 (35.2%) experienced re-bleeding during the follow-up period. The median time to re-bleeding was 6.0 months. Multivariate analysis demonstrated that a higher radiation dose (p = 0.007) and additional chemotherapy after radiotherapy (p = 0.004) were significant factors for prolonging the time to re-bleeding. Conclusions Tumor bleeding was adequately controlled by radiotherapy in patients with unresectable advanced gastric cancer.

The Ideal Approach for Treatment of cT1N+ and cT2Nany Esophageal Cancer.: A NCDB Analysis

Background Neoadjuvant therapy followed by surgery is recommended for locally advanced esophageal cancer. With the inaccuracies of clinical staging particularly for cT1N+ and cT2Nany tumors, some have proposed consideration of surgery followed by adjuvant treatment. Our objective is to evaluate the efficacy of neoadjuvant therapy vs surgery followed by adjuvant therapy, and to identify the ideal sequence of treatment in patients with cT1N+ and cT2Nany tumors.Methods We performed an analysis utilizing the National Cancer Database (2006-2015) identifying all patients with cT1N+ and cT2Nany esophageal cancer undergoing esophagectomy and additional chemotherapy or radiotherapy. The treatment was stratified as: neoadjuvant therapy (NT), adjuvant therapy (AT) and combination therapy of neoadjuvant and adjuvant (CT) groups and outcomes were analyzed.Results We identified 2795 patients with 81.9% (n=2289) receiving NT, 10.2% (n=285) AT, and 7.9% (n=221) CT. There were no significant differences noted in survival among AT, NT, and CT group in cT1N+(P=0.376), cT2N-(P=0.436), cT2N+(P=0.261) esophageal cancer by multivariate analysis using Cox regression model. This relationship held true in both squamous cell carcinoma and adenocarcinoma. Conclusion In clinical T1N+, T2Nany patients, there was no evident superiority of NT over AT. Surgery followed by adjuvant therapy can be considered to be an alternative option in these patients. Further prospective studies are needed to validate these findings.