Doxorubicin Therapy Research Articles

Neoadjuvant Chemotherapy Shifts Breast Tumor Microbiota Populations to Regulate Drug Responsiveness and the Development of Metastasis.

Breast tumors have their own specific microbiota, distinct from normal mammary gland tissue. Patients with breast cancer that present with locally advanced disease often undergo neoadjuvant chemotherapy to reduce tumor size prior to surgery to allow breast conservation or limit axillary lymph node dissection. The purpose of our study was to evaluate whether neoadjuvant chemotherapy modulates the tumor microbiome and the potential impact of microbes on breast cancer signaling. Using snap-frozen aseptically collected breast tumor tissue from women who underwent neoadjuvant chemotherapy (n = 15) or women with no prior therapy at time of surgery (n = 18), we performed 16S rRNA-sequencing to identify tumoral bacterial populations. We also stained breast tumor microarrays to confirm presence of identified microbiota. Using bacteria-conditioned media, we determined the effect of bacterial metabolites on breast cancer cell proliferation and doxorubicin therapy responsiveness. We show chemotherapy administration significantly increased breast tumor Pseudomonas spp. Primary breast tumors from patients who developed distant metastases displayed increased tumoral abundance of Brevundimonas and Staphylococcus. We confirmed presence of Pseudomonas in breast tumor tissue by IHC staining. Treatment of breast cancer cells with Pseudomonas aeruginosa conditioned media differentially effected proliferation in a dose-dependent manner and modulated doxorubicin-mediated cell death. Our results indicate chemotherapy shifts the breast tumor microbiome and specific microbes correlate with tumor recurrence. Further studies with a larger patient cohort may provide greater insights into the role of microbiota in therapeutic outcome and develop novel bacterial biomarkers that could predict distant metastases. IMPLICATIONS: Breast tumor microbiota are modified by therapy and affects molecular signaling.

Ultra-early changes in vascular parameters from dynamic contrast enhanced MRI of breast cancer xenografts following systemic therapy with doxorubicin and liver X receptor agonist

BackgroundDynamic contrast enhanced magnetic resonance imaging (DCE-MRI) may be used to depict tumour vascular structure and for therapy response assessment in various tumour sites. The purpose of the current work is to examine whether ultra-early changes in tumour physiology following cytotoxic treatment with doxorubicin and liver X receptor (LXR) agonist GW3965 are detectable by DCE-MRI.Methods36 female, athymic nude foxn1nu mice with bilaterally implanted breast cancer xenografts (17 with ER-positive HBCx34, 19 with triple-negative HBCx39) were randomised in the following treatment groups; control, GW3965 (40 mg/kg p.o.), doxorubicin (8 mg/kg i.v.) and a combination therapy of GW3965 and doxorubicin. DCE-MRI (3D FLASH on a 7 T preclinical scanner) was performed at baseline and one and six days after onset of treatment. Wash-in (30 s p.i.) and wash-out (300 s p.i.) enhancement were quantified from dynamic uptake curves, before voxel-by-voxel fitting to the pharmacokinetic Tofts model and generation of maps for the resulting parameters Ktrans, νe and νB. Treatment effect was evaluated by univariate repeated measures mixed-effects maximum likelihood regression models applied to median tumour data.ResultsWe found no effects of any treatment 24 h post treatment. After 6 days, doxorubicin given as both mono- and combination therapy gave significant increases of ~ 30% in wash-in enhancement (p < 0.011) and Ktrans (p < 0.017), and 40–50% in νB (p < 0.024) for HBCx34, but not for HBCx39. No effects of GW3965 were observed at any time (p > 0.1).ConclusionsTwenty-four h after onset of treatment was too early to evaluate treatment effects by DCE-MRI. Early enhancement and Ktrans were approximately equally sensitive metrics to capture treatment effects six days pt. Pharmacokinetic modelling however allowed us to attribute the observed effect to changes in tumour perfusion rather than increased retention.

Does Interim PET Scan After 2 Cycles of ABVD Predict Outcome in Hodgkin Lymphoma? Real-World Evidence.

PURPOSEEscalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) improves overall survival (OS) in patients with Hodgkin lymphoma (HL) relative to ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy. However, the associated higher cost and toxicity discourage clinicians from prescribing it. Identifying high-risk patients and administering escalated BEACOPP remains an effective strategy. We assessed the significance of interim positron emission tomography (iPET) scan after 2 cycles (iPET2) in identifying this high-risk subset.PATIENTS AND METHODSThis cohort study used secondary data from 12 tertiary care centers in South India gathered over 10 years (2008-2018). OS, event-free survival (EFS), determinants of EFS, and complete response (CR) in iPET2 were assessed.RESULTSThe study included 409 patients with HL (mean age, 34.5 years; male/female ratio, 1.4:1). The median duration of follow-up was 2.8 years. Of 409 patients, 63% underwent PET-based staging and 37% underwent computerized tomography (CT) staging. Stage IV (28.9%) and bone involvement (9.2%) were seen more often with PET than with CT staging (9.2% and 2%, respectively). Among 171 patients with iPET2 results, 24% did not achieve CR, and no factors were significantly associated. The 5-year EFS and OS rates of the entire cohort were 78% and 97%, respectively. The 5-year EFS and OS rates of patients with CR on iPET2 were 90% and 99%, respectively, whereas these were 65% and 100%, respectively, for patients not achieving CR. On univariable analysis, sex, stage, and iPET2 response significantly predicted inferior EFS. On multivariate analysis, only iPET2 response significantly predicted EFS (P < .000).CONCLUSIONOur study supports the use of PET for staging and iPET2 for response assessment. Nonachievement of CR on iPET2 indicates unfavorable outcome, and such patients may benefit from more intensive treatment.

Randomized, Double-Blind, Pharmacokinetic Equivalence Trial Comparing DRL-Rituximab With MabThera in Patients With Diffuse Large B-Cell Lymphoma

PURPOSEWe sought to compare the pharmacokinetics (PKs) of DRL-rituximab (DRL_RI; potential biosimilar) and innovator rituximab MabThera (Roche, Grenzach-Wyhlen, Germany; reference medicinal product [RMP]) in patients with diffuse large B-cell lymphoma (DLBCL). Efficacy, pharmacodynamics (PDs), safety, and immunogenicity were also compared.PATIENTS AND METHODSWe conducted a double-blind, parallel-group study in patients with untreated DLBCL who were eligible to receive cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Patients were randomly assigned at a one-to-one ratio to receive DRL_RI or RMP for six 21-day cycles of rituximab plus CHOP, with 18 months of follow-up after day 1, cycle 6 (C6). Primary end point was C1 PKs, measured as area under the plasma concentration–time curve from day 0 to 21 (AUC0-21 days) and maximum plasma concentration (Cmax). Equivalence was defined as 90% CIs for the DRL_RI/RMP geometric mean ratios (GMRs) within 80% and 125%. Secondary end points included efficacy noninferiority measured by objective response rate (ORR) at C6 and event-free survival and overall survival at 87 weeks, PK equivalence at C6 and PD equivalence (rate of B-cell depletion and repletion), safety, and immunogenicity. The trial was stopped after sufficient patients for primary end point evaluation were enrolled. Secondary end points are reported as observed.RESULTSA total of 151 patients were randomly assigned (DRL_RI, n = 76; RMP, n = 75). DRL_RI/RMP GMRs for AUC0-21 days and Cmax in C1 were 99.77 (90% CI, 87.60 to 113.63) and 96.19 (90% CI, 88.65 to 104.38), respectively. ORR at C6 for DRL_RI and RMP were 82.0% and 84.8%, respectively. Rates of B-cell depletion/repletion, immunogenicity, and adverse events were comparable in both groups.CONCLUSIONDRL_RI and RMP had equivalent PKs, with comparable efficacy, PDs, safety, and immunogenicity.

Synergistic effect of the combination therapy on ovarian cancer cells under microfluidic conditions

Ovarian cancer belongs to the group of gynecological cancers and indicates the high resistance to many drugs used in standard anticancer therapy. The treatment of ovarian cancer is a big challenge for the present medicine. In our report we tested the effectiveness of the combination anticancer therapy against ovarian cells: human ovarian carcinoma (A2780) and human ovarian fibroblasts (HOF). Two different types of drugs were used: doxorubicin (DOX) and a new-generation photosensitizer, nanoencapsulated meso-tetraphenylporphyrin (nano-TPP). The aim of the research was to compare the effect of the sequential combination therapy (chemotherapy with DOX and photodynamic therapy with nano-TPP) carried out in static and dynamic conditions. To achieve dynamic culture conditions, similar to in vivo environment, we designed a new microfluidic system in which the simultaneous, independent cultures of two cell lines (non-malignant and cancer cells) and their one-step analysis were possible. We observed that the sequential combination of photodynamic therapy (PDT) with chemotherapy allowed to obtain the synergistic effect of the treatment with using low doses of drugs. We also confirmed that the use of microfluidic conditions significantly increased the effectiveness of combination therapy and allowed for maintaining a high selectivity of the action of drugs on cancer cells. To the best of our knowledge, for the first time the microfluidic system was used to carry out sequential combination therapy against ovarian cancer.

Prognostic Significance of FOXO3 in Pediatric Acute Myeloid Leukemia (AML) Patients Treated with Bortezomib Addition to Standard Therapy: Results from a Children's Oncology Group Phase 3 Clinical Trial

The proteasome degrades unneeded and damaged proteins. Tumor cells highly depend on increased protein production and their degradation suggesting that malignant cells with a high proliferation index will be more sensitive to proteasome inhibition. The addition of the proteasome inhibitor Bortezomib (Velcade, 'BTZ') to standard pediatric AML chemotherapy (cytarabine, daunorubicin and etoposide, 'ADE') depleted leukemia-initiating cells in a phase 2 clinical trial in pediatric AML (pedi-AML) patients. A randomized phase 3 clinical trial was then conducted by the Children's Oncology Group (COG) comparing ADE and ADE+BTZ treatment regimes in pedi-AML (AAML1031). To determine if there were specific protein expression profiles that correlated with response to BTZ-containing chemotherapy, we analyzed key components of the proteome of pedi-AML that participated in the trial using reverse phase protein arrays (RPPA). RPPA-based expression of 293 validated antibodies was tested in 500 leukemia samples and compared to expression in CD34+ samples from healthy individuals (n=30). Among all proteins, FOXO3 expression was identified as the protein with the highest influence on outcome in the ADE group. The expression of FOXO3 was prognostic for event-free survival (EFS) in both univariate (HR = 0.56, 95% CI = 0.34-0.90, P = 0.017) and multivariate (HR = 0.55, 95% CI = 0.34-0.88, P = 0.013) analysis. All patients were divided into two clusters (low and high) based on their FOXO3 expression level using median FOXO3 expression in normal CD34+. Kaplan-Meier survival analysis showed poor OS (3 year OS 65.3% vs. 73.9%, P = 0.03) and EFS (3 year EFS, 42.8% vs. 55%, P = 0.01) in low FOXO3 expressors (n=119) compared to patients with high FOXO3 expression (n=291) (fig. 1A). Notably, the poor prognostic effect of low FOXO3 for OS was seen in ADE (3 year OS 60% vs. 72.3%, P = 0.03), but not in ADE-BTZ (3 year OS 70.3% vs. 75.3%, P = 0.23) (fig. 1B). This suggests that in particular patients with low FOXO3 may be eligible candidates for BTZ-addition. To validate our findings, we performed knockdown (KD) of FOXO3 using a short hairpin approach in OCI-AML3 (p53WT) and THP-1 (p53null) cell lines. KD FOXO3 in OCI-AML3 had a short-term growth advantage compared to controls (Day 4, P = 0.004), but not KD FOXO3 THP-1 cells suggesting a role for p53 in the FOXO3 functional pathway. KD FOXO3 cells were more resistant to doxorubicin and etoposide combination therapy than controls (P = 0.04), confirming our clinical observations. Since therapeutic regimes in AML are currently shifting towards Bcl-2 inhibition by Venetoclax (ABT-199, 'ABT'), we were eager to test whether BTZ and ABT could act in synergy, and if this is related to FOXO3 expression. Single low dose BTZ and ABT did not reduce cell numbers after 3 days, but were effective when used in combination (&lt;12% survival, P &lt; 0.001) in OCI-AML3 and THP-1. Although cell counts were lower regardless FOXO3 status in both cell lines, flow cytometry analysis using Annexin V staining revealed significant more apoptosis in KD FOXO3 THP-1 compared to controls. Using RPPA-based profiling, we identified a cluster of pedi-AMLs that benefitted from BTZ-addition to standard therapy. We hypothesize that AML patients with low FOXO3 levels have less activation of their apoptotic transcriptional programs and that this subgroup may benefit from proteasome blockage to prevent FOXO3 proteasomal degradation. The use of FOXO3 as potential biomarker may identify a prognostically adverse cluster in pedi-AML that could stratify patients for ADE+BTZ therapy. Patients with low FOXO3 expression may potentially benefit from ADE+BTZ in combination with ABT, a novel and promising combination approach in AML that warrants further investigation. Figure 1. A. Kaplan meier analysis comparing overall survival (OS) and event-free survival (EFS) between low (n=119, blue) and high (n=291, red) FOXO3 expression in pedi-AML patients. Children with low FOXO3 had significantly poorer OS (P = 0.033, Wilcoxon) and EFS (P = 0.011, Wilcoxon). B. Overall survival between ADE (solid) and ADE+BTZ (dashed) treated patients based on low (blue) or high (red) FOXO3 protein expression. The poor prognostic effect of FOXO3 is present in ADE, but not in ADE+BTZ treated patients (P = 0.028, Wilcoxon). Figure 1 Disclosures No relevant conflicts of interest to declare.

Improved pharmacokinetics and reduced side effects of doxorubicin therapy by liposomal co-encapsulation with curcumin

The goal of the current study was to investigate the pharmacokinetic profile, tissue distribution and adverse effects of long-circulating liposomes (LCL) with curcumin (CURC) and doxorubicin (DOX), in order to provide further evidence for previously demonstrated enhanced antitumor efficacy in colon cancer models. The pharmacokinetic studies were carried out in healthy rats, following the i.v. injection of a single dose of LCL-CURC-DOX (1 mg/kg DOX). For the tissue distribution study, DOX concentration in tumours, heart and liver were measured after the administration of two i.v. doses of LCL-CURC-DOX (2.5 mg/kg DOX and 5 mg/kg CURC) to Balb/c mice bearing C26 colon tumours. Markers of murine cardiac and hepatic oxidative status were determined to provide additional insights into the benefit of co-encapsulating CURC and DOX in LCL over DOX-induced adverse effects in these organs. The current study demonstrated that the liposomal association of CURC and DOX effectively improved the pharmacokinetics and biodistribution of DOX, limiting its side effects, via CURC-dependent antioxidant effects.

To study the usefulness and comparison of myocardial strain imaging by 2D and 3D echocardiography for early detection of cardiotoxicity in patients undergoing cardiotoxic chemotherapy

BackgroundChemotherapy-induced cardiotoxicity constitutes subclinical myocardial dysfunction, arrhythmias, pericarditis, coronary vasospasm, and significant symptomatic heart failure. Anthracyclines pose higher risk for long-term cardiac dysfunction, with increased incidences of morbidity and mortality. Hence, early detection of chemotherapy-induced cardiac dysfunction may prompt an earlier treatment modification. AimTo evaluate global, longitudinal, radial, and circumferential strain changes in adult patients undergoing anthracycline chemotherapy along with the usefulness of three-dimensional (3D) echocardiography as the new modality over two-dimensional (2D) echocardiography. MethodsThis was a single centre, prospective, observational study that included asymptomatic patients free from any cardiac signs and symptoms attributable to heart failure, who underwent potentially cardiotoxic chemotherapy for malignancy from December 2017 to November 2018 at a tertiary care centre in India. Baseline demographics were recorded, and 2D and 3D echocardiography was performed at baseline and after completion of four cycles of chemotherapy. ResultsAll the 55 patients received a cumulative dose of doxorubicin of less than 550 mg/m2. Follow-up period from the beginning of doxorubicin therapy was 108 ± 14 days. 9 patients were excluded from the study due to poor 3D images, so data analysis was done only for 46 patients. In 2D echocardiography, only global longitudinal strain (GLS) was observed to be significantly reduced (Δ18.33%; P < 0.001). 2D ejection fraction (EF) did not show significant change (Δ0.67%; P = 0.176), while by 3D echo, EF reduced significantly (Δ3.55%; P < 0.001). 3D global longitudinal (Δ29.19%; P < 0.001), circumferential (Δ30.65%; P < 0.001), area (Δ21.61%; P < 0.001), and radial (Δ29.66%; P < 0.001) strains were observed to be significantly reduced at follow-up. ConclusionMyocardial dysfunction induced by cardiotoxic chemotherapy can be detected earlier by using 2D GLS, 3D volumetric analysis, and 3D strain analysis by calculating global, longitudinal, radial, and circumferential strain changes. 3D echocardiographic assessment seems to be more accurate in picking out small changes in left ventricular functions, but at the cost of slightly poor image quality as compared to the 2D echocardiography. These newer techniques could potentially improve the ability for early detection of subclinical abnormalities of LV function in patients undergoing cardiotoxic chemotherapy and thus early initiation of treatment could be possible.

Major obstacles to doxorubicin therapy: Cardiotoxicity and drug resistance.

Doxorubicin is one of the most commonly prescribed and time-tested anticancer drugs. Although being considered as a first line drug in different types of cancers, the two main obstacles to doxorubicin therapy are drug-induced cardiotoxicity and drug resistance. The study utilizes systemic reviews on publications of previous studies obtained from scholarly journal databases including PubMed, Medline, Ebsco Host, Google Scholar, and Cochrane. The study utilizes secondary information obtained from health organizations using filters and keywords to sustain information relevancy. The study utilizes information retrieved from studies captured in the peer-reviewed journals on "doxorubicin-induced cardiotoxicity" and "doxorubicin resistance." The exact mechanisms of cardiotoxicity are not known; various hypotheses are studied. Doxorubicin can lead to free radical generation in various ways. The commonly proposed underlying mechanisms promoting doxorubicin resistance are the expression of multidrug resistance proteins as well as other causes. In this review, we have described the major obstacles to doxorubicin therapy, doxorubicin-induced cardiotoxicity as well as the mechanisms of cancer drug resistance and in following the treatment failures.

Recent Topics on Primary Bone and Soft Tissue Tumors and Metastatic Bone Tumors

Abstract Background: Recently, some drugs such as Pazopanib, Eribulin and Trabectedin can be used for advanced soft tissue sarcoma in Japan, but there are still few drugs useful for primary bone and soft tissue tumors. In metastatic bone tumors, bone modifying agents such as Zoledronic acid and Denosumab reduce skeletal related events (SREs) and are used clinically. Methods: I summarize and comment on recent findings from meetings and papers on primary bone and soft tissue tumors and metastatic bone tumors. Results and Conclusion: A phase III study was conducted using Olaratumab in addition to Doxorubicin as a primary treatment for advanced soft tissue tumors. Olaratumab plus Doxorubicin therapy did not show any advantage in the primary end point of survival in comparison with Doxorubicin alone. Infantile fibrosarcoma with the NTRK gene translocation and inflammatory myofibroblastic tumors with the ALK gene translocation are expected to obtain benefit from use of molecular target drugs. TRK inhibitors and ALK inhibitors have been used in clinical trials and some good results have been reported. Molecular targeting drugs have been used for advanced osteosarcoma as a second line treatment, and the median disease-free survival was relatively good at 4.0 months with Sorafenib, 16.4 weeks with Regorafenib, and 6.2 months with Cabozantinib. In metastatic bone tumors, an attempt has been made to extend the administration interval of Zoledronic acid, and the noninferiority of 12 weeks' administration has been reported as compared with 4 weeks' administration for the occurrence of SREs in breast cancer.

3142 Atypical Presentation of an Upper Gastrointestinal (GI) Bleed Manifesting as Extranodal Involvement of Diffuse Large B-Cell Lymphoma (DLBCL) Diagnosed in a Community Setting

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common type of Non-Hodgkin's Lymphoma (NHL), with 5.4 new cases diagnosed per 100,000 persons as of 2016. There is a male predominance, with an average age of 64.2. One extranodal site involves the GI tract, predominantly the stomach. Commonly seen are mucosa associated lymphoid tissue lymphomas and DLBCL. The majority of cases present at stage III/IV, with 40% presenting as local involvement. Here we present an unusual case of extranodal DLBCL in a patient presenting with dysphagia and an upper GI bleed. CASE DESCRIPTION/METHODS: An 85 year-old female presented for evaluation of dysphonia, ongoing for several months. The patient complained of bilateral submandibular adenopathy, dysphagia, trouble breathing, and a 15 pound weight loss over two weeks. Computed tomography of the neck revealed a nasopharyngeal mass in the left (L) nasopharynx extending into the nasal cavity, right (R) nasopharynx, and eroding into the skull. Additionally, bilateral necrotic cervical lymph nodes and L supraclavicular adenopathy were also seen. Histologic sample was consistent with DLBCL, non-germinal center type. Fluorescence in-situ hybridization was negative for MYC rearrangement, t(8:14), t(4:18), and Epstein Barr Virus, but indeterminate for BCL6 rearrangement. She was staged IIA and underwent radiation therapy without chemotherapy. During treatment, the patient was admitted for evaluation of an upper GI bleed associated with dysphagia, fatigue, and progressive weakness. She underwent an esophagogastroduodenoscopy with findings showing Los Angeles class A esophagitis, large, inflammatory nodular tissue within the lesser curvature of the stomach with associated linear ulcerations, multiple punctate ulcers throughout the gastric body and antrum, duodenitis, and a small, clean-based ulcer in the duodenal sweep. Histology of the gastric mass revealed an atypical clonal lymphoid infiltrate involving the gastric mucosa, suggestive of DLBCL, with clonal immunoglobulin heavy chain gene rearrangement. DISCUSSION: This case represents an atypical presentation of an upper GI bleed that is the result of extranodal involvement of DLBCL. An atypical presentation like this should have lymphoma in the differential for those with a history. Treatment is dependent upon the extent of disease, usually starting with the regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy. If left untreated, this disease can progress rapidly and prove fatal.

1410 A Rare Case of Extrahepatic Cholestasis Secondary to Acquired Immunodeficiency Syndrome (AIDS)—Related Kaposi Sarcoma

INTRODUCTION: Kaposi sarcoma is an aggressive cancer seen in immunocompromised patients caused by Human Herpesvirus-8 (HHV-8) infection. Cutaneous and pulmonary complications are the most frequent, biliary tract involvement is rarely reported, typically asymptomatic but may present as cholangitis or progress to liver failure. CASE DESCRIPTION/METHODS: 35-year-old male with HIV and CD4 count of 35 cells/uL, not on antiretroviral therapy for the past year, presented with fever, fatigue, diffuse lymphadenopathies, unintentional weight loss, generalized abdominal pain and scleral icterus for the last 2 weeks. Physical exam showed icterus, small hyperpigmented lesions throughout his trunk, a violaceous nodular enlargement of the hard palate, generalized lymphadenopathy, diffusely tender abdomen and hepatomegaly. Laboratory studies were significant for total bilirubin 23 mg/dL, direct bilirubin 16 mg/dL, ALP 288 U/L, GGT 193 U/L, AST 66 U/L, ALT 40 U/L, INR 1.3. CT of the abdomen showed hepatomegaly and an infiltrative process in the portal hepatis to the celiac area with obstruction of the biliary tract with intrahepatic biliary dilation. Endoscopic retrograde cholangiopancreatography demonstrated 3 cm stricture in the common hepatic duct, a biopsy was taken, and 2 stents were placed. Endoscopic ultrasound with biopsies taken from a stomach nodule and porta hepatis were performed as well. Pathology from porta hepatis mass showed blood clot however, HHV-8 stain from the common hepatic duct and stomach nodule biopsies was positive for Kaposi sarcoma. Doxorubicin and antiretroviral therapy were started, and patient was discharged in view of symptomatic improvement. Liver function tests normalized 8 weeks after presentation. DISCUSSION: Kaposi sarcoma involving the biliary tract has been associated with cholangitis and jaundice and may also be caused from extensive disease of the porta hepatis with compression of the extrahepatic biliary tree. Current first-line treatment for advanced Kaposi sarcoma is lipososomal anthracyclines (doxorubicin, daunorubicin). HHV-8 infection cannot be eradicated, but long-term remission is possible. Treatment is indicated in patients with progressive hepatic and biliary disease. Kaposi sarcoma has also been associated with AIDS (acquired immunodeficiency syndrome) cholangiopathy, a form of biliary tract inflammation with stricture formation in severely immunosuppressed HIV patients and management consists of endoscopic sphincterotomy for papillary stenosis and stenting.

Obstetric and maternal outcomes in patients diagnosed with Hodgkin lymphoma during pregnancy: a multicentre, retrospective, cohort study

Outcomes for mother and child following a diagnosis of Hodgkin lymphoma during pregnancy are underinvestigated, and antenatal management of the disease has not been reported on widely. The aim of this study was to assess obstetric outcomes, antenatal management, and maternal survival in patients with Hodgkin lymphoma diagnosed during pregnancy who were registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. We did a multicentre, retrospective cohort study including oncological and obstetric data from 134 pregnant patients diagnosed with Hodgkin lymphoma between Jan 1, 1969, and Aug 1, 2018. Data collected from the INCIP database were obtained from 17 academic centres in Belgium, Czech Republic, Denmark, Greece, Israel, Italy, Mexico, the Netherlands, Russia, the UK, and the USA. We analysed patients' management over three epochs (before 1995, 1995-2004, and 2005-18). Obstetric outcomes (birthweight, obstetric or neonatal complications, and admission to a neonatal intensive care unit [NICU]) of patients who received antenatal chemotherapy were compared to those of patients who did not receive antenatal treatment. Maternal progression-free and overall survival was assessed by disease stage at diagnosis in pregnant patients and compared with outcomes of non-pregnant patients with Hodgkin lymphoma selected from databases of three tertiary centres, matched for stage and prognostic score. All patients included in survival analyses received standard doxorubicin, bleomycin, vinblastine and dacarbazone (ABVD) therapy since Jan 1, 1997. Of the 134 pregnant patients diagnosed with Hodgkin lymphoma during pregnancy. 72 (54%) patients initiated antenatal chemotherapy, 56 (42%) did not receive treatment during pregnancy, and 6 (4%) received only radiotherapy. Over the years, chemotherapy was increasingly commenced during pregnancy. The incidence of neonates who were small for gestational age did not differ between chemotherapy-exposed neonates (15 [22%] of 69) and non-exposed neonates (six [16%] of 42; p=0·455). Admission to NICU also did not differ between groups (19 [29%] exposed to antenatal chemotherapy vs 12 [35%] unexposed to antenatal chemotherapy). Birthweight percentiles were lower in neonates prenatally exposed to chemotherapy compared with non-exposed neonates (p=0·035). Patients receiving antenatal therapy had more obstetric complications than those without antenatal therapy (p=0·005), the most common complications being preterm contractions (nine [12%] vs three [7%]) and preterm rupture of membranes (four [5%] vs 0). For the maternal survival analyses, we compared 77 pregnant patients and 211 non-pregnant, matched controls. 5-year progression-free survival for patients with early-stage Hodgkin lymphoma was 82·6% (95% CI 67·4-91·1) for 62 pregnant patients and 88·3% (81·6-92·7) for 142 controls (hazard ratio [HR] 1·80, 95% CI 0·84-3·87; p=0·130; 5-year overall survival was 97·3% (82·3-99·6) and 98·4% (93·6-99·6; HR 1·63, 0·35-7·65; p=0·534). In patients with advanced-stage disease (15 pregnant patients and 69 non-pregnant controls), 5-year progression-free survival was 90·9% (95% CI 50·8-98·7) versus 74·0% (60·9-83·3); HR 0·36, 95% CI 0·04-2·90; p=0·334. 5-year overall survival was 100% (no events occurred) and 96·2% (95% CI 85·5-99·1; HR cannot be estimated; p=0·146). Occurrence of preterm contractions or preterm rupture of membranes was higher in patients with Hodgkin lymphoma receiving antenatal treatment compared with those who did not initiate treatment during pregnancy. Maternal survival did not differ between pregnant and non-pregnant patients with Hodgkin lymphoma, suggesting that antenatal chemotherapy or deferral of treatment until postpartum in selected patients can be considered, with regular obstetric follow-up to safeguard foetal growth. European Research Council, Research foundation Flanders, and Charles University Ministry of Health of the Czech Republic.

Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium.

MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes. A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001). The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.

MiR-146a attenuates apoptosis and modulates autophagy by targeting TAF9b/P53 pathway in doxorubicin-induced cardiotoxicity

Clinical therapy of doxorubicin (DOX) is limited due to its cardiotoxicity. miR-146a was proved as a protective factor in many cardiovascular diseases, but its role in chronic DOX-induced cardiotoxicity is unclear. The objective of this study was to demonstrate the role of miR-146a in low-dose long-term DOX-induced cardiotoxicity. Experiments have shown that DOX intervention caused a dose-dependent and time-dependent cardiotoxicity involving the increased of apoptosis and dysregulation of autophagy. The cardiotoxicity was inhibited by overexpressed miR-146a and was more severe when miR-146a was downgraded. Further research proved that miR-146a targeted TATA-binding protein (TBP) associated factor 9b (TAF9b), a coactivator and stabilizer of P53, indirectly destroyed the stability of P53, thereby inhibiting apoptosis and improving autophagy in cardiomyocytes. Besides, miR-146a knockout mice were used for in vivo validation. In the DOX-induced model, miR-146a deficiency made it worse whether in cardiac function, cardiomyocyte apoptosis or basal level of autophagy, than wild-type. In conclusion, miR-146a partially reversed the DOX-induced cardiotoxicity by targeting TAF9b/P53 pathway to attenuate apoptosis and adjust autophagy levels.

Exercise stimulates beneficial adaptations to diminish doxorubicin-induced cellular toxicity.

Doxorubicin (DOX) is a highly effective antitumor agent used for the treatment of a wide range of cancers. Unfortunately, DOX treatment results in cytotoxic side effects due to its accumulation within off-target tissues. DOX-induced cellular toxicity occurs as a result of increased oxidative damage, resulting in apoptosis and cell death. While there is no standard-of-care practice to prevent DOX-induced toxicity to healthy organs, exercise has been shown to prevent cellular dysfunction when combined with DOX chemotherapy. Endurance exercise stimulates numerous biochemical adaptations that promote a healthy phenotype in several vulnerable tissues without affecting the antineoplastic properties of DOX. Therefore, for the development of an effective strategy to combat the pathological effects of DOX, it is important to determine the appropriate exercise regimen to prescribe to cancer patients receiving DOX therapy and to understand the mechanisms responsible for exercise-induced protection against DOX toxicity to noncancer cells. This review summarizes the cytotoxic effects of DOX on the heart, skeletal muscle, liver, and kidneys and discusses the current understanding of the clinical benefits of regular physical activity and the potential mechanisms mediating the positive effects of exercise on each organ system.

Age characteristics of risk cardiovascular complications in women with left breast cancer with preserved ejection fraction at the stage of chemotherapy and radiotherapy

A study of the risk factors for middle-aged and elderly women HER2neu with negative left breast cancer and a normal ejection fraction at the stage of chemoradiotherapy in everyday clinical practice. Matherial and methods. 61 women with left breast cancer without severe cardiovascular pathology were examined at the stage of doxorubicin therapy and 3D conformal radiation therapy. Group 1 comprised 32 patients of middle age (49.8 ± 4.5 years). Group 2 comprised 29 elderly patients (68.3 ± 3.6 years). In addition to Score risk assessment, additional factors, including psychosocial factors, were studied. All patients underwent ECG, echocardiography and 24-hour ECG monitoring. Anxiety levels were assessed using the HADS scale and scale CH. D. Spielberger -Yu.L. Khanin. The study was conducted before the start of treatment, after the completion of the doxorubicin course and after the completion of the course of radiotherapy. Results with discussion. In middle-aged patients, moderate Score risk was found in 21.9%, in the elderly at 58.6% (p = 0.0043, RR 2.68, 95% CI 1.301-5.520). A high Score risk was found in 15.6% of middle-aged patients and 41.4% of elderly patients (p = 0.0438, RR 2.648, 95% CI 1061-6.607). The most common risk factors in the patients studied in addition to age were heredity, overweight, hypercholesterolemia and diabetes mellitus. All examined patients had moderate reactive anxiety. Patients of middle age have moderate personal anxiety, in elderly patients high personal anxiety. After treatment with doxorubicin in a cumulative dose not exceeding 360 mg/m2 , a reduction in the ejection fraction below 50% was found in 6 middle-aged patients and 17.2% in elderly patients. Asymptomatic diastolic dysfunction was detected in 31.3% of middle-aged patients and 55.2% of the elderly. In patients of both groups, after arranging treatment, arrhythmia was detected. The obtained data indicate to the need for in-depth examination of middle-aged and especially elderly patients with left breast cancer with an assessment of risk factors and conducting an in-depth examination using Echocardiography, 24-hour ECG monitoring and psychological testing to prevent and early detection of cardiovascular complications.

Diffuse large B-cell lymphoma in Southeast Asian cohort: expression patterns of B-cell receptor (BCR) repertoire and its linkage with molecular subtypes and response to R-CHOP therapy

AimsHeightened B-cell receptor (BCR) activity in diffuse large B-cell lymphoma (DLBCL) is well established, and a subset of patients with relapsed DLBCL can benefit from BCR-targeted therapies. Universal outreach of...

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

The long‐term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty‐eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty‐four mice (n = 6 per group) underwent pre‐ and post‐treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor‐associated macrophages (TAM) density were compared between different groups using a one‐way ANOVA. Twenty‐four additional NSG mice underwent survival analyses with Kaplan–Meier curves and a log‐rank (Mantel–Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor‐bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.

Dedifferentiated Endometrial Carcinoma Could be A Target for Immune Checkpoint Inhibitors (Anti PD-1/PD-L1 Antibodies).

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.