Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length.

BACKGROUND: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL. RESULTS: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ ß ≤ 0.8) with large intertumor variation and overall low hypermethylation (ß > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (ß < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499-31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286-18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239-21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319-27.397) and PFS (HR 4.689, 95% CI 1.102-19.963) in LBCL treated with R-CHOP-like regimens. CONCLUSION: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.

Evaluating the Outcome and Patient Safety of Methotrexate, Doxorubicin, and Cisplatin Regimen for Chemotherapy in Osteosarcoma: A Meta-Analysis.

BACKGROUND: Several studies of multi-drug regimens for osteosarcoma have shown different efficacies and are still controversial. Meanwhile, chemotherapy options have remained largely unchanged over a couple of decades. This study is designed to ascertain the outcome and safety of Methotrexate, Doxorubicin, and Cisplatin regimen for chemotherapy in osteosarcoma patients through the utilization of meta-analysis. METHODS: We interrogated trials that compared the MAP regimen with other regimens as chemotherapy for osteosarcoma from several databases encompassing PubMed, Science Direct, and grey literature (Google Scholar) until December 2022. The analyzed outcomes including Event-Free Survival (EFS), Overall Survival (OS), Tumor Necrosis (TN) rate, and Adverse Event (AE) were then analyzed using RevMan 5.4 software in fixed or random effect models. RESULTS: Our meta-analysis comprised 8 prospective articles that evaluated a cumulative number of 2920 OS patients. The analysis results indicated no meaningful difference in 5-year EFS (OR=0.99, 95% CI=0.77-1.27, [P = 0.91]) and neoadjuvant chemotherapy response (TN) (OR=0.76, 95% CI=0.49-1.17, [P = 0.22]) between the MAP and control groups. Furthermore, 5-year OS analysis revealed a significant association in the control group (OR=0.82, 95% CI=0.68-0.99, [P = 0.04]). However, the control group was associated with statistically meaningful AE compared to the MAP group, particularly in thrombocytopenia (OR=0.46, 95% CI=0.23-0.90, [P = 0.02]) and fever (OR=0.34, 95% CI=0.26-0.46, [P < 0.00001]). CONCLUSION: The present meta-analysis showed that the MAP regimen remains preferable in treating osteosarcoma patients despite no significant outcome compared to the other regimens considering the less frequent AE in the MAP regimen.

Digital Gangrene as a Paraneoplastic Manifestation of Peripheral T-cell Lymphoma Not Otherwise Specified Type.

BACKGROUND: Peripheral T cell lymphoma (PTCL), not otherwise specified (NOS) is a heterogenous group of predominantly nodal T cell lymphomas that generally presents with lymphadenopathy with or without extra nodal involvement. Acral vascular syndrome clinically presents as digital ischemia with Raynaud's phenomenon and acral cyanosis. Although, this condition is commonly associated with connective tissue disorder, smoking and vasculitis, its association with lymphoid malignancy is very rare. Here, we present a case report of a patient with digital gangrene of all toes and fingers as a presenting symptom of PTCL-NOS. CASE DESCRIPTION: A 62 year old male presented with digital ischemia associated with pain, low grade fever, loss of appetite and significant weight loss of 6 kilograms over a period of 3 months. On examination, he was found to have bilateral inguinal and axillary lymph nodes with gangrenous changes over toes and fingers but peripheral pulses were palpable. On evaluation he had anemia, elevated ESR and CRP. CT angiogram revealed thinned out digital arteries with multifocal areas of narrowing. Patient was screened for other causes of digital gangrene and was tested negative for ANCA, ANA, cryoglobulins and viral markers. Lymph node biopsy with IHC was suggestive of peripheral T-cell lymphoma-NOS and was started on CHOP regimen. Lymph nodes size decreased and gangrenous changes resolved. CONCLUSION: Though digital ischemia is a rare paraneoplastic presentation of lymphoma, it should be considered if there is a rapid progression of gangrene. Early initiation of chemotherapy may result in the reduction of further progression of digital gangrene and thus prevent permanent disability. In our patient, progression of gangrene was prevented even though it was an aggressive variant of T cell lymphoma.

Ultrasmall Fe3O4 nanoparticles self-assembly induced dual-mode T1/T2-weighted magnetic resonance imaging and enhanced tumor synergetic theranostics.

Individual theranostic agents with dual-mode MRI responses and therapeutic efficacy have attracted extensive interest due to the real-time monitor and high effective treatment, which endow the providential treatment and avoid the repeated medication with side effects. However, it is difficult to achieve the integrated strategy of MRI and therapeutic drug due to complicated synthesis route, low efficiency and potential biosafety issues. In this study, novel self-assembled ultrasmall Fe3O4 nanoclusters were developed for tumor-targeted dual-mode T1/T2-weighted magnetic resonance imaging (MRI) guided synergetic chemodynamic therapy (CDT) and chemotherapy. The self-assembled ultrasmall Fe3O4 nanoclusters synthesized by facilely modifying ultrasmall Fe3O4 nanoparticles with 2,3-dimercaptosuccinic acid (DMSA) molecule possess long-term stability and mass production ability. The proposed ultrasmall Fe3O4 nanoclusters shows excellent dual-mode T1 and T2 MRI capacities as well as favorable CDT ability due to the appropriate size effect and the abundant Fe ion on the surface of ultrasmall Fe3O4 nanoclusters. After conjugation with the tumor targeting ligand Arg-Gly-Asp (RGD) and chemotherapy drug doxorubicin (Dox), the functionalized Fe3O4 nanoclusters achieve enhanced tumor accumulation and retention effects and synergetic CDT and chemotherapy function, which serve as a powerful integrated theranostic platform for cancer treatment.

Comparison of anthracycline-containing and anthracycline-free regimens in neoadjuvant HER-2 positive breast cancer treatment.

While some clinics have adopted abbreviated neoadjuvant treatment for HER2-positive breast cancer, there remains a shortage of comprehensive clinical data to support this practice. This is a retrospective, multicenter study. A total of 142 patients were included in the study who are HER2-positive breast cancer, aged ≤ 65 years, with left ventricular ejection fraction ≥ 50%, received neoadjuvant chemotherapy and underwent surgery at 10 different oncology centers in Türkiye between October 2016 and December 2022. The treatment arms were divided into 4-6 cycles of docetaxel/trastuzumab/pertuzumab for arm A, 4 cycles of adriamycin/cyclophosphamide followed by 4 cycles of taxane/TP for arm B. There were 50 patients (35.2%) in arm A and 92 patients (64.8%) in arm B. The median follow-up of all of the patients was 19.9 months (95% CI 17.5-22.3). The 3-year DFS rates for treatment arms A and B were 90.0% and 83.8%, respectively, and the survival outcomes between the groups were similar (p = 0.34). Furthermore, the pathologic complete response rates were similar in both treatment arms, at 50.0% and 51.1%, respectively (p = 0.90). This study supports shortened neoadjuvant treatment of HER2-positive breast cancer, a common practice in some clinics.

GZ17-6.02 kills PDX isolates of uveal melanoma.

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.

Diffuse large B-cell lymphoma as an extra-hepatic manifestation of hepatitis C and co-infection of helicobacter pylori: A case report.

Along with infecting hepatocytes, the Hepatitis C virus (HCV) is also a lymphotropic virus. Chronic HCV infection can mutate the Bcl2, a proto-oncogene that inhibits apoptosis. This causes continuous stimulation of B lymphocytes, which results in clonal growth of these immunoglobulin-producing cells. In Western countries, there is a well-documented link between HCV and lymphoproliferative illness. HCV and Non-Hodgkin lymphoma (NHL) have been found to be significantly correlated in Europe, Japan, and the southern United States. There, however, has been no association found in central and northern Europe, the northwestern United States, and some Asian countries. A literature deficit exists in South Asia about the incidence of HCV infection in lymphoma patients. Here, the first documented instance of Diffuse Large B-cell NHL (germinal center type) is reported in a 35-year-old patient. The patient presented to the outpatient department at Ruth KM Pfau, Civil Hospital Karachi, in July of 2022, with the chief complaints of altered bowel habits due to involvement of the anorectal junction and concomitant infection by Helicobacter pylori with a prior history of HCV infection.

Vanishing bile duct syndrome as a presentation of Hodgkin's lymphoma.

Vanishing bile duct syndrome is an uncommon condition characterised by the progressive loss and disappearance of bile ducts. It is an acquired form of cholestatic liver disease presenting with hepatic ductopenia (loss of >50% bile ducts in the portal areas). We present a case of vanishing bile duct syndrome as a presentation of Hodgkin's lymphoma who was treated with standard-of-care chemotherapy-doxorubicin, bleomycin, vinblastine and dacarbazine (along with brief administration of rituximab), which led to complete response and normalisation of liver function.

The Effect of Therapy Regimen on Antitumor Efficacy of the Nanosomal Doxorubicin against Rat Glioblastoma 101.8.

One of the key problems of glioblastoma treatment is the low effectiveness of chemotherapeutic drugs. Incorporation of doxorubicin into PLGA nanoparticles allows increasing the antitumor effect of the cytostatics against experimental rat glioblastoma 101.8. Animal survival, tumor volume, and oncogene expression in tumor cells were compared after early (days 2, 5, and 8 after tumor implantation) and late (days 8, 11, and 14) start of the therapy. At late start, a significant increase in the expression of oncogenes Gdnf, Pdgfra, and Melk and genes determining the development of multidrug resistance Abcb1b and Mgmt was revealed. At early start of therapy, only the expression of oncogenes Gdnf, Pdgfra, and Melk was enhanced. Early start of treatment prolonged the survival time and increased tumor growth inhibition by 141.4 and 95.7%, respectively, in comparison with the untreated group; these differences were not observed in the group with late start of therapy. The results indicate that the time of initiation of therapy is a critical parameter affecting the antitumor efficacy of DOX-PLGA.

Diffuse Large B-Cell Lymphoma With Cardiac Invasion Presented as Acute Myocardial Infarction and Left Ventricular Hypertrophy: A Case Report.

Primary cardiac lymphoma is an exceedingly rare malignant tumor, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histological subtype. This disease has non-specific clinical manifestations, making early diagnosis crucial. However, DLBCL diagnosis is commonly delayed, and its prognosis is typically poor. Herein, we report the case of a 51-year-old male patient with DLBCL who presented with recurrent chest tightness for 4 months as the primary clinical symptom. The patient was admitted to the hospital and diagnosed with acute myocardial infarction and left ventricular hypertrophy with heart failure. Echocardiography revealed a progression from left ventricular thickening to local pericardial thickening and adhesion in the inferior and lateral walls of the left ventricle. Finally, pathological analysis of myocardial biopsy confirmed the diagnosis of DLBCL. After treatment with the R-CHOP chemotherapy regimen, the patient's chest tightness improved, and he was discharged. After 2 months, the patient succumbed to death owing to sudden ventricular tachycardia, ventricular fibrillation, and decreased blood pressure despite rescue efforts. Transthoracic echocardiography is inevitable for the early diagnosis of DLBCL, as it can narrow the differential and guide further investigations and interventions, thereby improving the survival of these patients.

Evaluation of some proinflammatory cytokines and biochemical parameters in pre and postmenopausal breast cancer women.

The study was planned to evaluate the differences in certain proinflammatory cytokines(IL-6, TNF-α) with CRP and biochemical parameters (E2, D3, LDH, GGT, TSB, Ca, Ph, uric acid), between women with pre- and postmenopausal breast cancer and seemingly healthy women in Iraqi women as controls; at medical city in teaching Oncology hospital,70 breast cancer patients women their ages ranged (47.51 ± 1.18) and 20 healthy women with age (44.45 ± 2.66) begun from September (2020) to February (2021). The aims of this study to investigate the evaluation of chemotherapy effects especially doxorubicin and cyclophosphamide only use in this study in pre and postmenopausal breast cancer women on proinflammatory cytokines(IL-6, TNF-α) with CRP and on biochemical parameters(E2, D3, LDH, GGT, TSB, Ca, Ph, uric acid) in pre and postmenapausal breast cancer women. The patients were divided into five groups and each group contains 14 patients women with breast cancer during pre and postmenopausal periods. The control groups were divided into 10 pre and 10 postmenopausal women(Fig. 1). The results of proinflammatory cytokines of and biochemical parameters in premenopausal groups were as the levels of IL-6 (pg/ml),TNF-α(pg/ml) and CRP (ng/ml) showed significant increase differences (P < 0.01)among breast cancer treated (BCT) groups in comparison with control groups,While the Liver enzymes GGT,LDH and TSB showed highly significant increase (P < 0.01) in BCT groups, Estrogen levels (pg/ml) and D3(ng/ml) increased significantly (P < 0.01)among BCT groups. Blood serum calcium and phosphorus with uric acid levels (mg/dl) showed significant difference (P < 0.01); While the result in postmenopausal of IL-6(pg/ml), TNF-α (pg/ml) and CRP (ng/ml) showed highly significant differences (P < 0.01)among BCT groups.While GGT(IU/L), LDH(IU/L) and TSB (mg/dl) enzymes were increased significantly (p < 0.01), Estrogen (pg/ml) and D3(ng/ml) levels showed significant increase (P < 0.01) among BCT groups.Blood calcium and phosphorus showed significant increase (P < 0.01) while uric acid was non-significant increase (P > 0.05).

Biomimetic Dual-Target Theranostic Nanovaccine Enables Magnetic Resonance Imaging and Chemo/Chemodynamic/Immune Therapy of Glioma.

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.

A20 promoted the phagocytosis of lymphoma cells by dendritic cells from activated B-cell-like non-Hodgkin lymphoma.

Non-Hodgkin lymphoma (NHL) is a lymphoproliferative disorder derived from either B or T lymphocytes. Among NHL, activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) and T cell non-Hodgkin lymphomas (T-NHL) are poor prognosis and aggressive subtypes. Macrophages are professional phagocytic cells and dendritic cells (DCs) are professional antigen-presenting cells in immune system. Doxorubicin (Dox) and Etoposide (ET) are the most effective anti-cancer drugs. A20 and CYLD are negative regulators of NF-κB-dependent functions in many cell types. Little is known about the roles of A20 and CYLD in regulating functions of DCs and macrophages from NHL. The present study, therefore, explored whether A20/CYLD expression contributes to functions of DCs and macrophages from NHL. To this end, blood samples of seventy-nine patients with ABC DLBCL and T-NHL were examined. Gene expression profile was determined by quantitative RT-PCR and immunophenotype, cell apoptosis and phagocytosis by flow cytometry. As a result, immunophenotypic analysis showed that the numbers of CD13+CD117-, CD56+CD40+ and CD23+CD40+ expressing cells were significantly elevated in ABC DLBCL cases compared to healthy individuals and T-NHL patients. Interestingly, upon treatment of Dox and ET, the phagocytosis of lymphoma cells was significantly reduced by CD11c+CD123- DCs and the percentage of CD56+ mature DCs was significantly enhanced in ABC DLBCL patients only in the presence of A20 siRNA, but not CYLD siRNA. In conclusion, ABC DLBCL patients with low A20 expression were defective in elimination of lymphoma cells by DCs and linked to killer DC expansion in circulation.

Peposertib, a DNA-PK Inhibitor, Enhances the Anti-Tumor Efficacy of Topoisomerase II Inhibitors in Triple-Negative Breast Cancer Models.

Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.

Intelligent Biogenic Missile for Two-Photon Fluorescence Imaging-Guided Combined Photodynamic Therapy and Chemotherapy in Tumors.

Photodynamic therapy (PDT) is a significant noninvasive therapeutic modality, but it is often limited in its application due to the restricted tissue penetration depth caused by the wavelength limitations of the light source. Two-photon (TP) fluorescence techniques are capable of having an excitation wavelength in the NIR region by absorbing two NIR photons simultaneously, which offers the potential to achieve higher spatial resolution for deep tissue imaging. Thus, the adoption of TP fluorescence techniques affords several discernible benefits for photodynamic therapy. Organic TP dyes possess a high fluorescence quantum yield. However, the biocompatibility of organic TP dyes is poor, and the method of coating organic TP dyes with silica can effectively overcome the limitations. Herein, based on the TP silica nanoparticles, a functionalized intelligent biogenic missile TP-SiNPs-G4(TMPyP4)-dsDNA(DOX)-Aptamer (TGTDDA) was developed for effective TP bioimaging and synergistic targeted photodynamic therapy and chemotherapy in tumors. First, the Sgc8 aptamer was used to target the PTK7 receptor on the surface of tumor cells. Under two-photon light irradiation, the intelligent biogenic missile can be activated for TP fluorescence imaging to identify tumor cells and the photosensitizer assembled on the nanoparticle surface can be activated for photodynamic therapy. Additionally, this intelligent biogenic missile enables the controlled release of doxorubicin (DOX). The innovative strategy substantially enhances the targeted therapeutic effectiveness of cancer cells. The intelligent biogenic missile provides an effective method for the early detection and treatment of tumors, which has a good application prospect in the real-time high-sensitivity diagnosis and treatment of tumors.

Real-life study on the use of response adapted therapy in patients with Hodgkin Lymphoma: Results from a multicenter experience.

Few data are known regarding the use of interim positron emission tomography (iPET) after the first two cycles (iPET2) of chemotherapy in treatment-naïve classical Hodgkin lymphoma (cHL) in routine clinical practice, and about the real-life adoption of intensification strategies for iPET positive patients. We conducted a multicenter retrospective study on cHL to investigate the use of iPET in the real-life setting, its prognostic role and outcomes of patients early shifted to intensification. Six hundreds and forty-one patients were enrolled (62% had advanced stage). iPET2 was positive in 89 patients (14%) including 8.7% and 17% early and advanced stage patients, respectively (p = 0.003). Among iPET 2 positive cases treatment was immediately modified in 19 cases; in 14 cases treatment was modified after an additional positive iPET4. Overall 56 iPET2 positive patients never received intensified therapies. Most frequently used intensified therapy was autologous stem cell transplantation followed by BEACOPP. After a median follow-up of 72 months, the 5-year progression-free survival (PFS) was 82% with iPET2 positive patients showing a worse PFS compared with iPET2 negative cases: 31% versus 85%. Focusing on advanced stage patients with a positive iPET2, the 5-year PFS was 59% for patients shifted to intensified therapy at any time point versus 61% for patients who never received intensified therapy. Our study confirmed the higher curability of naïve cHL patients in a real-world setting, and the prognostic role of iPET2 in this setting. A poor adherence to response-adapted strategy which however did not translate into a difference in patient outcomes.

Investigation of efficacy of two different chemotherapy protocols used in neoadjuvant chemotherapy in clinical stages II-IV canine malignant mammary tumours.

The first aim of this study is to demonstrate the clinical efficacy and reliability of two different neoadjuvant chemotherapy (NAC) protocols consisting of doxorubicin/cyclophosphamide (AC) and paclitaxel in dogs with clinical stages II-IV canine malignant mammary tumours (CMTs). Secondly, to determine the Luminal A, Luminal B, HER2-positive and triple-negative molecular subtypes and their value in predicting clinical response to NAC in biopsy samples, and thirdly, to reveal the changes in Ki-67, human epidermal growth factor receptor type 2 (HER2), oestrogen receptor (ER), and progesterone receptor (PgR) expression levels induced by NAC. Thirty dogs with clinical stages II-IV CMTs (T1-3N0-1M0) according to the modified TNM system were included in the study. Dogs in group-1 (n = 15) AC combination and dogs in group-2 (n = 15) were administered paclitaxel. Partial response (PR) was the most common clinical response in both treatment groups (66.66% and 86.66%, respectively). There was no difference between the groups regarding clinical response parameters (p = .001). The rate of treatment responders was higher than the rate of non-responders in both groups (p < .001). The adverse effects observed in both groups were mostly limited to grades 1 and 2 and all were easy to manage. The most frequently detected molecular subtype was Luminal A (59.25%). Complete response (CR) was achieved in 33.33% of dogs with triple-negative CMT in the AC group and 14.29% of the Luminal A subtype in the paclitaxel group. Alterations in Ki-67, HER2, ER, and PgR expressions after chemotherapy were not statistically significant (p > .05). As a result, we have shown that these neoadjuvant chemotherapy protocols are effective and safe alternative treatment options for CMTs.

Coiled-Coil Protein Hydrogels Engineered with Minimized Fiber Diameters for Sustained Release of Doxorubicin in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) lacks expressed protein targets, making therapy development challenging. Hydrogels offer a promising new route in this regard by improving the chemotherapeutic efficacy through increased solubility and sustained release. Moreover, subcutaneous hydrogel administration reduces patient burden by requiring less therapy and shorter treatment times. We recently established the design principles for the supramolecular assembly of single-domain coiled-coils into hydrogels. Using a modified computational design algorithm, we designed Q8, a hydrogel with rapid assembly for faster therapeutic hydrogel preparation. Q8 encapsulates and releases doxorubicin (Dox), enabling localized sustained release via subcutaneous injection. Remarkably, a single subcutaneous injection of Dox-laden Q8 (Q8•Dox) significantly suppresses tumors within just 1 week. This work showcases the bottom-up engineering of a fully protein-based drug delivery vehicle for improved TBNC treatment via noninvasive localized therapy.

A Pioglitazone Nanoformulation Designed for Cancer-Associated Fibroblast Reprogramming and Cancer Treatment.

The recent focus of cancer therapeutics research revolves around modulating the immunosuppressive tumor microenvironment (TME) to enhance efficacy. The tumor stroma, primarily composed of cancer-associated fibroblasts (CAFs), poses significant obstacles to therapeutic penetration, influencing resistance and tumor progression. Reprogramming CAFs into an inactivated state has emerged as a promising strategy, necessitating innovative approaches. This study pioneers the design of a nanoformulation using pioglitazone, a Food and Drug Administration-approved anti-diabetic drug, to reprogram CAFs in the breast cancer TME. Glutathione (GSH)-responsive dendritic mesoporous organosilica nanoparticles loaded with pioglitazone (DMON-P) are designed for the delivery of cargo to the GSH-rich cytosol of CAFs. DMON-P facilitates pioglitazone-mediated CAF reprogramming, enhancing the penetration of doxorubicin (Dox), a therapeutic drug. Treatment with DMON-P results in the downregulation of CAF biomarkers and inhibits tumor growth through the effective delivery of Dox. This innovative approach holds promise as an alternative strategy for enhancing therapeutic outcomes in CAF-abundant tumors, particularly in breast cancer.

Real-World Challenges of Managing Diffuse Large B-Cell Lymphoma in a Developing Country.

PURPOSE: To highlight challenges and cancer care disparities in patients of diffuse large B-cell lymphoma management in resource-constrained settings. MATERIALS AND METHODS: This multicenter retrospective study included 738 patients from 12 public and private sector hematology-oncology centers across Pakistan. Patients were divided into limited-resource and enhanced-resource settings as per national diffuse large B-cell lymphoma (DLBCL) guidelines. RESULTS: The median age at diagnosis was 47 years (range, 14-89). Male:female ratio was 2.5:1. Majority of the patients (69.3%) were treated in limited-resource settings. Computed tomography was used as a staging modality in 442 (60%) patients. Limited-stage DLBCL was present in 13.5% of patients, while 86.3% had advanced-stage disease at diagnosis. First-line regimens included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in 56% and cyclophosphamide, doxorubicin, vincristine, prednisone in 34% of patients, while 10% of patients received palliative regimens upfront. Of evaluable data, complete remission was documented in 299 (74.4%) patients, 39 (9.8%) had partial response and 63 (13.5%) had progressive disease. Disease-free survival (DFS) and overall survival (OS) status were not available for 345 (46.8%) patients at the time of data collection. Overall study cohort had a median follow-up of 2.2 years with a median OS of 3.6 years (95% CI, 3.1 to 4.1), median DFS of 3.1 years (95% CI, 2.6 to 3.6), and a 5-year OS of 40% and DFS of 36%. CONCLUSION: Patients from low- and middle-income countries present at an earlier age and have more advanced disease. Patients were frequently lost to follow-up, and record keeping was inadequate more so in patients treated in limited-resource settings. There is a need to establish a national lymphoma registry, improve record keeping, and standardize treatments to ensure improvement in treatment outcomes.