Breast Lymphoma Research Articles

Primary breast lymphoma of childhood: a case report and review of literature

BackgroundPrimary breast lymphoma (PBL) is an extremely rare neoplasm in children; by definition, it manifests in the breast without evidence of lymphoma elsewhere, except ipsilateral axillary nodes.Case presentationWe report a case of a 15-year-old girl diagnosed with diffuse large B-cell lymphoma (DLBCL) of the right breast: the patient received chemotherapy and rituximab, achieving complete remission. A literature review revealed other 11 cases of pediatric PBL; it mainly affects female adolescents and can involve right and left breast equally. Different histologic subtypes have been described, arising from both B-cell and T-cell. Therapeutic approaches were very different, from chemotherapy to local treatment with surgery and/or radiotherapy.ConclusionsOur case is the first in which rituximab was administered, suggesting to be a promising therapy in B-cell PBL, as already demonstrated in pediatric B-cell lymphoma from other sites. Further investigations are needed to identify prognostic factors and establish the most effective treatment.

Warburg Effect and Cancer Survival

Warburg effect is a major metabolic shift of glycolysis in cancer cells towards anaerobic fermentation. Key reaction here overproduces lactate from pyruvate catalyzed by lactate dehydrogenase-A (LDHA). Augmented Warburg effect and oncometabolism may contribute to cancer progression worsening patients’ survival. Expressions of various key enzymes were used as surrogates to validate the clinical influence of metabolic alterations in cancers. Expression and Kaplan-Meier survival data were extracted from the R2 Genomics Analysis and Visualization Platform (R2) and Human Protein Atlas (HPA). Expression of LDHA gene was 2-4 times higher than normal tissues in certain cancers including breast, colon, genitourinary and B-cell lymphomas. No cancer specificity or strong associations were observed between RNA and protein expressions of LDHA. However, higher LDHA gene expression correlated with poorer survival in renal, liver, lung, pancreatic, cervical and breast cancers. These cancers moderately or strongly stained for LDHA protein. Per HPA, gliomas had low LDHA without survival correlation. Nevertheless, this correlation was observed in the largest glioblastoma database (R2). Furthermore, 3 of 4 medulloblastoma subtypes showed poor survival with higher LDHA. Contrarily, in B-cell lymphomas and colon cancer high LDHA was a favorable prognostic marker. Poor survival correlated with high expression of other enzymes for glycolysis and amino acid metabolism (PFK-isoenzymes, GFPT2 and BCAT1). Warburg effect may not be universally dominant for all cancers, but most cancers have high LDHA and/or associated poor survival, confirming importance of this metabolic derangement in cancers. Heterogeneity of metabolic alterations can serve to diversify anti-metabolic strategies for targeted anti-cancer therapies.

Computational Optics for Point-of-Care Breast Cancer Profiling.

With the global burden of cancer on the rise, it is critical to developing new modalities that could detect cancer and guide targeted treatments in fast and inexpensive ways. The need for such technologies is vital, especially in underserved regions where severe diagnostic bottlenecks exist. Recently, we developed a low-cost digital diagnostic system for breast cancer using fine-needle aspirates (FNAs). Named, AIDA (artificial intelligence diffraction analysis), the system combines lens-free digital diffraction imaging with deep-learning algorithms to achieve automated, rapid, and high-throughput cellular analyses for breast cancer diagnosis of FNA and subtype classification for better-guided treatments (Min et al. ACS Nano 12:9081-9090, 2018). Although primarily validated for breast cancer and lymphoma (Min et al. ACS Nano 12:9081-9090, 2018; Im et al. Nat Biomed Eng 2:666-674, 2018), the system could be easily adapted to diagnosing other prevalent cancers and thus find widespread use for global health.

Using Patient-Generated Health Data From Twitter to Identify, Engage, and Recruit Cancer Survivors in Clinical Trials in Los Angeles County: Evaluation of a Feasibility Study.

BackgroundFailure to find and attract clinical trial participants remains a persistent barrier to clinical research. Researchers increasingly complement recruitment methods with social media–based methods. We hypothesized that user-generated data from cancer survivors and their family members and friends on the social network Twitter could be used to identify, engage, and recruit cancer survivors for cancer trials.ObjectiveThis pilot study aims to examine the feasibility of using user-reported health data from cancer survivors and family members and friends on Twitter in Los Angeles (LA) County to enhance clinical trial recruitment. We focus on 6 cancer conditions (breast cancer, colon cancer, kidney cancer, lymphoma, lung cancer, and prostate cancer).MethodsThe social media intervention involved monitoring cancer-specific posts about the 6 cancer conditions by Twitter users in LA County to identify cancer survivors and their family members and friends and contacting eligible Twitter users with information about open cancer trials at the University of Southern California (USC) Norris Comprehensive Cancer Center. We reviewed both retrospective and prospective data published by Twitter users in LA County between July 28, 2017, and November 29, 2018. The study enrolled 124 open clinical trials at USC Norris. We used descriptive statistics to report the proportion of Twitter users who were identified, engaged, and enrolled.ResultsWe analyzed 107,424 Twitter posts in English by 25,032 unique Twitter users in LA County for the 6 cancer conditions. We identified and contacted 1.73% (434/25,032) of eligible Twitter users (127/434, 29.3% cancer survivors; 305/434, 70.3% family members and friends; and 2/434, 0.5% Twitter users were excluded). Of them, 51.4% (223/434) were female and approximately one-third were male. About one-fifth were people of color, whereas most of them were White. Approximately one-fifth (85/434, 19.6%) engaged with the outreach messages (cancer survivors: 33/85, 38% and family members and friends: 52/85, 61%). Of those who engaged with the messages, one-fourth were male, the majority were female, and approximately one-fifth were people of color, whereas the majority were White. Approximately 12% (10/85) of the contacted users requested more information and 40% (4/10) set up a prescreening. Two eligible candidates were transferred to USC Norris for further screening, but neither was enrolled.ConclusionsOur findings demonstrate the potential of identifying and engaging cancer survivors and their family members and friends on Twitter. Optimization of downstream recruitment efforts such as screening for digital populations on social media may be required. Future research could test the feasibility of the approach for other diseases, locations, languages, social media platforms, and types of research involvement (eg, survey research). Computer science methods could help to scale up the analysis of larger data sets to support more rigorous testing of the intervention.Trial RegistrationClinicalTrials.gov NCT03408561; https://clinicaltrials.gov/ct2/show/NCT03408561

Application of iPDMS protein microarray in screening of tumor-associated antigen autoantibodies

The rapid screening of tumor markers is a challenging task for early diagnosis of cancer. This study aims to use highly sensitive chemiluminescent protein microarray technology to efficiently screen a variety of low abundance tumor related markers. A new material, termed integrated polydimethylsiloxane modified silica gel (iPDMS), was obtained by adding a surface polymerization initiator with olefin end to the conventional polydimethylsiloxane, and fixing into the three-dimensional structure of polydimethylsiloxane by thermal crosslinking through silicon hydrogen bonding. In order to make the iPDMS material resistant to non-specific protein adsorption, a poly(OEGMA) polymer brush was synthesized by surface-initiated atom transfer radical polymerization at the active initiation site. Finally, 20 tumor-related antigens were printed into the specific areas of the microarray by high-throughput spray printing technology, and assembled into 48-well detection microtiterplates of the iPDMS microarray. It was found the VEGFR and VEGF121 autoantibodies that obtained from 8 common tumors (breast cancer, lung cancer, colon cancer, gastric cancer, liver cancer, leukemia, lymphoma and ovarian cancer) can be used as potential tumor markers. The chemiluminescence labeled iPDMS protein microarray can be used for the screening of tumor autoantibodies at early stage.

Extranodal natural killer/T-cell lymphoma of the breast: a retrospective clinicopathological analysis of a consecutive 11-year case series

BackgroundExtranodal NK/T-cell lymphoma of the breast (ENKTL-Breast) is rarely detected in clinical practice, and its clinicopathological features remain unclear.ResultsA consecutive 11-year (2010–2020) ENKTL-Breast case series was retrospectively analyzed. Eight cases of ENKTL-Breast were selected, with three primary and five secondary lesions, accounting for 3.5% (8/228) of all breast lymphomas. All patients were female with a median age of 46 years. Lesions presented as solid breast masses (8/8, 100%) and were usually located in the upper outer quadrant of the breast (7/8, 87.5%). B-symptoms were observed in seven (7/8, 87.5%) cases. Two primary ENKTL-Breast cases showed concomitant diseases (IgA nephropathy and chronic active hepatitis B). Histological and immunohistochemical features of ENKTL-Breast were similar to those of ENKTL at other sites. T-cell receptor rearrangement revealed clonality in all examined primary cases (2/2, 100%), but only in one secondary case (1/5, 20%). The disease progressed rapidly in two primary cases and both patients died within 3 and 9 months. For secondary cases, the disease manifested as a disseminated disease, with a median survival time of 6 months.ConclusionsOur data suggested that ENKTL-Breast clinically mimics breast cancer to some extent, though B-symptoms might serve as a distinguishing factor. ENKTL-Breast is highly aggressive and patients with this disease exhibit a short survival time. Primary ENKTL-Breast tends to originate from activated cytotoxic T-cells, and immune-related diseases may be involved in its pathogenesis and development.

Optimizing Cancer Associated Thrombosis (CAT) Risk Assessment Model at a Safety-Net Healthcare System

Introduction: Cancer associated thrombosis is a preventable complication that impacts the quality of life of patients with cancer. The Khorana score (KS) is the most widely used risk assessment model (RAM) to predict venous thromboembolism (VTE) in ambulatory patients undergoing chemotherapy. Potential limitations of the score include modest discrimination and small proportion of patients in the highest risk subgroup. We aimed to examine if a clinical informatics approach incorporating race/ethnicity, cancer staging, type of systemic therapy, and other known VTE risk factors from the electronic health record (EHR) can improve the RAM.Methods: We performed a retrospective cohort study at Harris Health System (HHS), a safety-net healthcare system that provides care for underserved minorities and uninsured patients in Houston. We created an integrated database that linked consecutive patients with newly diagnosed invasive cancer in the cancer registry with structured data from EPIC Caboodle database 2011-2020. Inclusion/exclusion criteria are shown in Figure 1. We followed patients from time of initial systemic therapy to time of first VTE, death, or loss of follow-up. VTE was defined as radiologically confirmed pulmonary embolism (PE), proximal or distal lower extremity deep vein thrombosis (LE-DVT), catheter-related DVT (CR-DVT), or splanchnic vein thrombosis (SVT) in inpatient or outpatient setting. We used acute, chronic or historical VTE ICD9/ICD10 facility billing codes to assess for potential events and confirmed incident and recurrent events through medical record review. We used multivariable Cox regression to assess potential risk predictors. The model was built iteratively to expand upon the KS. Kaplan Meier failures curves were used to estimate the VTE incidence. C statistic was assessed with binary outcomes at 3- and 6-month.Results: A total of 4,546 patients with newly diagnosed cancer receiving 1 st line systemic therapy met the inclusion/exclusion criteria. Relevant demographics showed a median age of 54 (IQR 46-61), 57% female, 50% Hispanic, 27% Black, and 75% uninsured. Most common cancer types included breast (17%), colorectal (13%), lung (10%), and non-Hodgkin lymphoma (8%); 32% of patients had metastatic disease. First-line systemic therapy included 89% cytotoxic chemotherapy, 9% small molecule targeted +/- endocrine therapy, and 2% PD-1/PD-L1 immunotherapy. Only 1% had remote VTE history after excluding 317 patients already on therapeutic anticoagulation.Incident VTE occurred in 477 patients during a median follow-up of 11.3 months. There were 229 PE +/- other, 140 LE-DVT, 94 CR-DVT, and 14 SVT. In addition to the KS covariates (Table 1), recent cancer diagnosis (≤ 1 month) (HR 1.43, 1.16-1.76), metastatic disease (HR 1.46, 1.20-1.76), recent hospitalization (≤ 3 month) (HR 1.54, 1.24-1.90) were also associated with higher risk of VTE, whereas Hispanic ethnicity (HR 0.65, 0.51-0.84) and Asian race (HR 0.30, 0.16-0.54) were associated with a lower risk. Other appreciable predictors included targeted vs. chemotherapy (HR 0.75, 0.51-1.10) and history of PE/LE-DVT (HR 1.74, 0.93-3.27). Immunotherapy (vs. chemotherapy) and black (vs. white) were not associated with VTE.Figure 2 shows the comparison of VTE incidence using the 2 RAMs. Original KS RAM had c statistic of 0.66 and 0.62 at 3- and 6-month, respectively (Table 2). The highest risk group (3+) included 16% of patients (n=723) and 23% of all VTE (n=108). The modified RAM had better discrimination with c statistic of 0.71 and 0.67 at 3- and 6-month, respectively. The highest risk group (3+) included 33% of patients (n=1509) and 51% of all VTE (n=244).Conclusions: The KS performed reasonably well in a large safety-net healthcare system with predominantly uninsured patients with advanced cancer initiating systemic therapy. Nonetheless, simple structured data elements from the EHR such as race/ethnicity, staging, therapy type, and recent hospitalization improved the performance of the KS-based RAM and doubled the number of patients in the high-risk stratum and the number of preventable VTE. An integrated clinical informatics approach adapted to the local population can improve outcomes by identifying patients most appropriate for ambulatory thromboprophylaxis. [Display omitted] DisclosuresCarrier: Sanofi: Honoraria; Leo Pharma: Honoraria, Research Funding; Servier: Honoraria; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; BMS: Honoraria, Research Funding.

Evolution in the Presence and Evidence Category of Radiation Therapy Treatment Recommendations in National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology

Some perceptions exist regarding potential decline in the utilization of radiation therapy (RT) with expanding systemic therapy options. We sought to understand the recommended utilization of RT across a broad range of solid tumors by examining National Comprehensive Cancer Network (NCCN) Guidelines. We conducted a comprehensive review and categorization of RT recommendations, with their subsequent supporting evidence categories, in NCCN Guidelines from 2000 through 2019.The 2000, 2009, and 2019 versions of NCCN Guidelines were individually examined for RT-specific recommendations among the 10 most common solid tumors. The presence of RT as a recommended modality was recorded for each tumor type, along with the branch of management. Recommendation categories including Category 1, 2A, 2B and 3 were tallied and compared descriptively to examine totals and percentage distributions.3858 recommendations were individually reviewed. The presence of a recommendation inclusive of RT increased by 129% from 2000 to 2009 and by 111% from 2009 to 2019. From 2000 to 2019, RT recommendations overall increased by 206%. In 2019 NCCN Guidelines, the most Category 1 RT recommendations were found within small cell lung (13%), non-small cell lung (5%), breast (5%), bladder (2%), rectal (2%) and non-Hodgkin lymphoma (1%). Pancreatic, uterine, prostate, melanoma, kidney, and colon cancer guidelines had no Category 1 RT recommendations. Of note, rectal cancer had 31 (27%) preferred recommendations. The majority (89%) of 2019 RT recommendations were for initial therapy, while 9% were specific to salvage therapy. Tumor sites with the highest proportion of RT Category 1 evidence were small cell lung (29%), non-small cell lung (24%), and breast cancer (24%).The frequency of RT recommendations in NCCN Guidelines has increased over the past 20 years among the 10 most common solid tumors. A majority of recommendations remain Category 2A, and this proportional percentage of 2A recommendations is increasing. Consideration of evidence categories by solid tumor type is highly relevant to identify areas in need of expanded prospective, randomized, evidence regarding the use of RT.

Eight-Year Experience of the Certificate of Competence and Advanced Studies Program Organized by the European School of Oncology.

The Certificate of Competence and Advanced Studies Program is an academically recognized postgraduate program that is organized by the European School of Oncology in collaboration with the University of Ulm and the University of Zurich. It is a part-time educational activity that aims to provide physicians and scientists with advanced knowledge in the management of patients with breast cancer, lymphoma, and lung cancer. The program encloses three attendance seminars and four to five e-learning modules that extend over 12 to 14 months. To be certified, participants have to pass an online test after each module followed by a final certification exam at the end of the program. This article reports on the 8-year experience of the 166 graduated fellows who have attended the program.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13187-021-02105-z.

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives.

In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

Prevalence and predictors of right ventricular dysfunction in cancer patients treated with cardiotoxic chemotherapy – a prospective cardiovascular magnetic resonance study

Abstract Background Right ventricular (RV) function has an established incremental prognostic value in cardiomyopathy. Studies on cancer therapeutics-related cardiac dysfunction (CTRCD) primarily focused on the left ventricle (LV), with conflicting results from small studies dedicated to RV dysfunction. Purpose We sought to investigate the influence of chemotherapy on RV function relative to LV function using serial cardiac magnetic resonance (CMR). Methods Patients were enrolled as part of Cardiotoxicity Prevention Research Initiative (CAPRI) Registry aimed at evaluating CMR-based markers for surveillance of CTRCD. Patients underwent non-contrast CMR imaging prior to initiation of anthracyclines and/or trastuzumab and serially every 3 months during the first year, then annually thereafter. We included patients who had a baseline and ≥1 follow-up scan and excluded those with baseline LV ejection fraction (EF)<50%, providing 320 patients completing 1,453 CMR studies. Cine images were analysed to calculate chamber volumes indexed to body surface area and EF. We defined LV CTRCD using CMR modality specific criteria of a drop in LV EF ≥5% from baseline to <57%; RV CTRCD as a drop ≥5% to <49% in females and <47% in males. We used linear mixed models to study the changes in ventricular volumes and EF with time. Results The majority of patients were females (80%), had breast cancer (68%) or lymphoma (32%), with a mean age of 52.7±13 years. Figure 1 shows temporal changes in mean ventricular volumes and function over the first year. Mean changes in RV function followed those of the LV, with the nadir of EF and maximum of volumes occurring at 6 months. Respective values for mean decrease in LV and RV EF at this time point versus baseline were 4.1 and 2.9% (p<0.001). Concomitant mean increase in indexed RV end-diastolic (ED) and end-systolic (ES) volumes were 1.6 and 2.7 ml/m2 (p=0.2 and <0.001). There was significant interaction of chemotherapy regimen with time for RV volumes (p=0.001 and 0.003), but not RV EF (p=0.7), with worst changes occurring with combined anthracyclines and trastuzumab. In all, 70 (22%) and 28 (9%) patients met criteria for LV and RV CTRCD, respectively. Among those who developed RV CTRCD, 10 had persistently normal LV function. Figure 2 shows the results of logistic regression to predict RV CTRCD. Significant univariable predictors included combined chemotherapy regimen and baseline LV and RV volumes and LV EF. Adjusting for age, sex, and chemotherapy regimen, baseline RV ED volume remained associated with RV CTRCD (odds ratio 1.6; p=0.005). Conclusion In this large study, RV volumes and function were similarly influenced by chemotherapy versus comparable LV-based measures. Using similar threshold criteria, the incidence of RV CTRCD was lower than for LV CTRCD; however, one third of those who develop RV CTRCD showed normal LV function. Future studies are warranted to study the prognostic influence of RV injury in cancer patients. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Alberta InnovatesGenome Alberta Figure 1. Temporal changes in LV & RV functionFigure 2. Predictors of RV CTRCD

Cat Scratch Disease as a Mimicker of Malignancy.

Cat scratch disease (CSD) infrequently mimics malignancy. We reviewed 11 such cases at MD Anderson Cancer Center and an additional 36 reported from the literature. Breast cancer, sarcoma, and lymphoma were the most commonly suspected malignancies. Most patients were young, female, had prior cat exposure, and had no systemic symptoms. Regional lymphadenopathy was the most common finding.

Improving referrals to survivorship: A patient-driven initiative.

44 Background: Patients often feel lost in the transition from cancer patient to survivor. As cancer treatment improves, the number of survivors in the US is expected to approach 22 million by the year 2029. Smaller increases in the MD workforce coupled with long-term effects of new treatments necessitate the creation survivorship clinics led by advanced practice providers (APP) who are disease-specialized and specifically trained to manage unique survivor needs. Although the institutions Survivorship program was established more than a decade ago, the average referral rate to the program is only 30%. Given the high levels of patient satisfaction with the program, we sought to understand and address clinician awareness and referral obstacles. Methods: Based on patient input, members of our Patient & Family Advisory Council for Quality (PFACQ) put forth a proposal aimed at increasing referrals to the Survivorship program. A multidisciplinary working group comprising patients, clinicians, administrators and process engineers was assembled. Process Improvement training was conducted, and a primary goal was developed: increase Survivorship referrals by 25%. Central to the approach was engagement with referring physicians and APPs on a service-by-service basis. A four-question survey was developed to address timing of initial discussion, challenges to referring, knowledge of visit elements, and materials needed to support referrals. A customized ‘roadshow’ presentation was created and delivered by a PFACQ member at a faculty meeting. Highlights included: the importance of Survivorship care to patients and details of the visit, survey responses, and additional faculty discussion and input. Results: Four roadshows were completed from August 2020-June 2021: Gynecologic Surgery, Endocrine, Breast Medicine and Lymphoma. Based on survey responses and dialogue with providers, new material to support patient discussions and education have been developed: a patient-facing brochure, clinician- & patient-facing video, and clinician talking points. Methods to facilitate identifying eligible patients were also discussed, as well as automatic referrals to Survivorship for selected services. Data reveal a significant increase in referral rates from GYN and Endocrine services (follow up > 6 months) of 63% and 228%, respectively. (Breast Medicine and Lymphoma with shorter follow up will be reported.) Engagement with other services is underway. Conclusions: Results have exceeded the goal of increasing referral rates to the program. This process suggests that ongoing engagement with referring clinicians is essential to achieving and maintaining higher referral rates. The patient voice throughout this process has been a powerful tool in raising clinician awareness of their experiences and expectations for comprehensive follow up care, which can be delivered on a greater scale by survivorship providers.

Evaluation of Biochemical and Hematological Profile Changes in Cancer Patients Pre- and Postchemotherapy Treatment

Background: Cancer is the world's most hazardous and severe disease in the 21st century, and it is the world's second-largest cause of death. A patient's cancer therapy is decided by the stage of cancer at diagnosis, the type and location of cancer, and the patient's country's normal medical procedures and treatment recommendations. Surgery, chemotherapy, and radiation therapy are just a few of the cancer treatment options accessible. However, these treatments are rarely curative and might cause a variety of negative effects in individuals. Materials and Methods: This retrospective observational study was carried out in Veer Surendra Sai Institute of Medical Sciences and Research, Burla, Odisha. Prechemotherapy hematological profiles: laboratory results of hematological profiles at the time of cancer diagnosis. Postchemotherapy hematological profiles: laboratory results of hematological profiles following the completion of Phase 4 chemotherapy treatments. Results: There were 97 males (41.27%) and 138 females (58.72%) in the group. Breast cancer, lymphoma, and sarcoma were the most common kinds of cancer in this study, accounting for 37.44%, 25.1%, and 11.06%, respectively. Stage II was found in 8.93% of the study participants, 62.12% in stage III, and 28.93% in stage IV, but no stage I was found. Conclusion: Postchemotherapy hematological profiles, with the exception of lymphocytes, were found to be considerably lower than prechemotherapy. Biochemical profiles such as urea and creatinine reduced insignificantly, but aspartate aminotransferase and alanine aminotransferase levels increased nonsignificantly after treatment compared to before.

Epigenetic Alterations and Mechanisms That Drive Resistance to Targeted Cancer Therapies.

Cancer is a complex disease and cancer cells typically harbor multiple genetic and epigenetic alterations. Large-scale sequencing of patient-derived cancer samples has identified several druggable driver oncogenes. Many of these oncogenes can be pharmacologically targeted to provide effective therapies for breast cancer, leukemia, lung cancer, melanoma, lymphoma, and other cancer types. Initial responses to these agents can be robust in many cancer types and some patients with cancer experience sustained tumor inhibition. However, resistance to these targeted therapeutics frequently emerges, either from intrinsic or acquired mechanisms, posing a major clinical hurdle for effective treatment. Several resistance mechanisms, both cell autonomous and cell nonautonomous, have been identified in different cancer types. Here we describe how alterations of the transcriptome, transcription factors, DNA, and chromatin regulatory proteins confer resistance to targeted therapeutic agents. We also elaborate on how these studies have identified underlying epigenetic factors that drive drug resistance and oncogenic pathways, with direct implications for the prevention and treatment of drug-resistant cancer.

Design and application of hybrid cyclic-linear peptide-doxorubicin conjugates as a strategy to overcome doxorubicin resistance and toxicity

Doxorubicin (Dox) is used for breast cancer, leukemia, and lymphoma treatment as an effective chemotherapeutic agent. However, Dox use is restricted due to inherent and acquired resistance and an 8-fold increase in the risk of potentially fatal cardiotoxicity. Hybrid cyclic-linear peptide [R5K]W7A and linear peptide R5KW7A were conjugated with Dox through a glutarate linker to afford [R5K]W7A-Dox and R5KW7A-Dox conjugates to generate Dox derivatives. Alternatively, [R5K]W7C was conjugated with Dox via a disulfide linker to generate [R5K]W7C–S–S-Dox conjugate, where S–S is a disulfide bond. Comparative antiproliferative assays between conjugates [R5K]W7A-Dox, [R5K]W7C–S–S-Dox, linear R5KW7A-Dox, the corresponding physical mixtures of the peptides, and Dox were performed in normal and cancer cells. [R5K]W7A-Dox conjugate was 2-fold more efficient than R5KW7A-Dox, and [R5K]W7C–S–S-Dox conjugates in inhibiting the cell proliferation of human leukemia cells (CCRF-CEM). Therefore, hybrid cyclic-linear [R5K]W7A-Dox conjugate was selected for further studies and inhibited the cell viability of CCRF-CEM (84%), ovarian adenocarcinoma (SK-OV-3, 39%), and gastric carcinoma (AGS, 73%) at a concentration of 5 μM after 72 h of incubation, which was comparable to Dox (5 μM) efficacy (CCRF-CEM (85%), SK-OV-3 (33%), and AGS (87%)). While [R5K]W7A-Dox had a significant effect on the viability of cancer cells, it exhibited minimal cytotoxicity to normal kidney (LLC-PK1, 5–7%) and heart cells (H9C2, <9%) at concentrations of 5–10 μM (compared to free Dox at 5 μM that reduced the viability of kidney and heart cells by 85% and 44%, respectively). The fluorescence microscopy images were consistent with the cytotoxicity studies, indicating minimal uptake of the cyclic-linear [R5K]W7A-Dox (5 μM) in H9C2 cells. In comparison, Dox (5 μM) showed significant uptake, reduced cell viability, and changed the morphology of the cells after 24 h. [R5K]W7A-Dox showed 16-fold and 9.5-fold higher activity against Dox-resistant cells MDA231R and MES-SA/MX2 (lethal dose for 50% cell death or LC50 of 2.3 and 4.3 μM, respectively) compared to free Dox (LC50 of 36–41 μM, respectively). These data, along with the results obtained from the cell viability tests, indicate comparable efficiency of [R5K]W7A-Dox to free Dox in leukemia, ovarian, and gastric cancer cells, significantly reduced toxicity in normal kidney LLC-PK1 and heart H9C2 cells, and significantly higher efficiency in Dox-resistant cells. A number of endocytosis inhibitors did not affect the cellular uptake of [R5K]W7A-Dox.

Deep Learning for Detection of Pulmonary Metastasis on Chest Radiographs.

Background A computer-aided detection (CAD) system may help surveillance for pulmonary metastasis at chest radiography in situations where there is limited access to CT. Purpose To evaluate whether a deep learning (DL)-based CAD system can improve diagnostic yield for newly visible lung metastasis on chest radiographs in patients with cancer. Materials and Methods A regulatory-approved CAD system for lung nodules was implemented to interpret chest radiographs from patients referred by the medical oncology department in clinical practice. In this retrospective diagnostic cohort study, chest radiographs interpreted with assistance from a CAD system after the implementation (January to April 2019, CAD-assisted interpretation group) and those interpreted before the implementation (September to December 2018, conventional interpretation group) of the CAD system were consecutively included. The diagnostic yield (frequency of true-positive detections) and false-referral rate (frequency of false-positive detections) of formal reports of chest radiographs for newly visible lung metastasis were compared between the two groups using generalized estimating equations. Propensity score matching was performed between the two groups for age, sex, and primary cancer. Results A total of 2916 chest radiographs from 1521 patients (1546 men, 1370 women; mean age, 62 years) and 5681 chest radiographs from 3456 patients (2941 men, 2740 women; mean age, 62 years) were analyzed in the CAD-assisted interpretation and conventional interpretation groups, respectively. The diagnostic yield for newly visible metastasis was higher in the CAD-assisted interpretation group (0.86%, 25 of 2916 [95% CI: 0.58, 1.3] vs 0.32%, 18 of 568 [95% CI: 0.20, 0.50%]; P = .004). The false-referral rate in the CAD-assisted interpretation group (0.34%, 10 of 2916 [95% CI: 0.19, 0.64]) was not inferior to that in the conventional interpretation group (0.25%, 14 of 5681 [95% CI: 0.15, 0.42]) at the noninferiority margin of 0.5% (95% CI of difference: -0.15, 0.35). Conclusion A deep learning-based computer-aided detection system improved the diagnostic yield for newly visible metastasis on chest radiographs in patients with cancer with a similar false-referral rate. © RSNA, 2021 Online supplemental material is available for this article.

CLL-140: Chronic Lymphocytic Leukemia Presenting as a Solitary Breast Mass

An 80-year-old woman with a past medical history of hypertension and no prior history of malignancy underwent a screening mammogram followed by a breast ultrasound that showed a right breast mass. She remained asymptomatic. The physical exam did not reveal any palpable lymphadenopathy nor hepatosplenomegaly. Peripheral blood smear showed absolute lymphocytosis of 69% with a normal total white blood cell count of 8.1 without dysplastic cells, blasts, anemia, or thrombocytopenia. Breast ultrasound showed an irregular hypoechoic mass measuring 0.7 x 0.5 x 0.5 cm. Subsequent US-guided core biopsy showed non-Hodgkin B-cell lymphoma positive for cluster designation (CD)20 and CD5. Bone marrow aspirate and core biopsy revealed clusters of small-to-medium atypical lymphocytes positive for CD20, CD79a (weak), with a co-expression of CD5 (strong) and CD23CD138, findings that are compatible with Small Lymphocytic Lymphoma (SLL)/Chronic Lymphocytic Leukemia (CLL). Positron Emission Tomography scan showed an uptake within the right breast only. She is being managed with observation and close follow-up. Breast lymphoma (BL) represents around 0.5% of malignant breast neoplasms. Diffuse Large B-Cell Lymphoma (DLBCL) and follicular lymphoma are the predominant subtypes. SLL and CLL are subtypes of non-Hodgkin lymphoma originating from a B-cell lineage. While there have been reported cases of CLL and SLL manifesting as BL, the incidence still is very low and limited to case reports. Moreover, they have been reported to be found concomitantly with breast carcinoma. Most BL are asymptomatic when found incidentally on screening imaging, as in our patient. A hypoechoic round mass is the most common reported appearance. There are no current established guidelines for the treatment of BL. In our patient, we followed the recommendations for managing CLL. Not all breast masses are adenocarcinoma. It is critical to keep in mind the differential diagnosis lymphoproliferative disorders, melanoma, lung cancer, and gynecological malignancies.

Acute and Delayed Doxorubicin-Induced Myocardiotoxicity Associated with Elevation of Cardiac Biomarkers, Depletion of Cellular Antioxidant Enzymes, and Several Histopathological and Ultrastructural Changes.

Doxorubicin (DOX; Adricin) is an anthracycline antibiotic, which is an efficient anticancer chemotherapeutic agent that targets many types of adult and pediatric tumors, such as breast cancer, leukemia, and lymphomas. However, use of DOX is limited due to its cardiotoxic effects. This study sequentially investigated the mechanistic pathways of the cardiotoxic process of DOX in rats at different post-treatment periods using cumulative dose, which is used in therapeutic regimes. In this regard, 56 male albino rats were used for the experiment. The experimental animals were divided into seven groups (n = 8/group) based on dose and sacrifice schedule as follows: G1 (2 mg/kg body weight [BW] and sacrificed at day 4), G2 (4 mg/kg BW and sacrificed at day 8), G3 (6 mg/kg BW and sacrificed at day 15), G4 (8 mg/kg BW and sacrificed at day 30), G5 (10 mg/kg BW and sacrificed at day 60), G6 (10 mg/kg BW and sacrificed at day 90), and G7 (10 mg/kg BW and sacrificed at day 120). As expected, G1, G2, and G3-treated groups revealed features of acute toxic myocarditis associated with degenerative and necrotic changes in myocytes, mitochondrial damage, elevation of cardiac biomarkers, and depletion of cellular antioxidant enzymes. However, these changes increased in severity with subsequent treatment with the same dose until reaching a cumulative dose of 10 mg/kg BW for 30 d. Furthermore, after a cumulative dose of 10 mg/kg BW with a withdrawal period of 2–3 months, various predominant changes in chronicity were reported, such as disorganization and atrophy of myocytes, condensation and atrophy of mitochondria, degranulation of mast cells, and fibrosis with occasional focal necrosis, indicating incomplete elimination of DOX and/or its metabolites. Altogether, these data provide interesting observations associated with the cardiotoxic process of DOX in rats that would help understand the accompanying changes underlying the major toxic effects of the drug. Future research is suggested to explore more about the dose-dependent mechanisms of such induced toxicity of DOX that would help determine the proper doses and understand the resulting cardiomyopathy.

Contribution of nuclear BCL10 expression to tumor progression and poor prognosis of advanced and/or metastatic pancreatic ductal adenocarcinoma by activating NF-\u03baB-related signaling

BackgroundWe previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC).Method and materialsWe analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining.ResultsWe revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p < 0.001), and patients with nuclear BCL10 expression had the worse median overall survival than those without nuclear BCL10 expression (6.90 months versus 9.53 months, p = 0.019).ConclusionNuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.