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Abstract: Cancer, a crucial global health problem, is characterized by abnormal cell division and uncontrolled growth. According to WHO, cancer is the second leading cause of global deaths and accounted for approximately 9.6 million deaths or one in six deaths in 2018. The National Cancer Registry Programme Report 2020, released by the ICMRIndia, estimated that there would be 13,90,000 cases of cancer in India in 2020 and that this number is likely to rise to 15,70,000 by 2025. In spite of several anti-cancer drugs, cancer cannot be cured completely, especially at late stages. In the current era, almost every person is suffering from some kind of disease. Thus, it is the necessity of time to develop novel, potent bioactive molecules. Many researchers are working on the development of new lead molecules or finding a new biological target for the betterment of human beings. However, heterocycles are constantly being used for the discovery of new lead molecules. Many of the clinically approved drugs contain the heterocyclic core as these molecules show exhilarating pharmaceutical properties, including anti-cancer agents such as methotrexate, vinblastine, vincristine, daunorubicin, 5-fluorouracil, doxorubicin, etc. Thus, heterocyclic compounds provide a fascinating research area for the design and development of anti-cancer drug(s). Herein, we focused on the natural as well as synthetic anti-cancer heterocyclic compounds. Furthermore, efforts have been made toward the mechanism of action of selected heterocyclic anti-cancer compounds.

Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody-drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.We randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed.A total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P = 0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up.Patients who received A+AVD for the treatment of stage III or IV Hodgkin's lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.).

The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients.Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed.A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation.A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients.

The objective of this article is to summarize new treatment strategies of desmoid tumors.Desmoid tumor has an unpredictable evolution that may spontaneously regress or stabilize. A shift toward an initial frontline active surveillance has been acknowledged by experts. Surveillance monitoring should be performed frequently after the diagnosis to avoid missing a significant progression and then spaced in case of stabilization. Treatment is based on significant tumor growth or symptoms. Recent guidelines recommend commencing medical treatment. Kinase inhibitors and cytotoxic agents are the two classes of drugs where studies included progressive desmoid tumors and should be selected to guide medical practice. In a randomized trial, 2 years progression-free survival (PFS) was significantly better in the sorafenib group (81 versus 36% in the placebo group). In another randomized phase 2, 6 months PFS was 83.7% with pazopanib versus 45% with methotrexate and vinblastine. In a retrospective study, including progressive desmoid tumors, methotrexate + vinca alkaloids achieved 75 months median PFS. Cryotherapy is an alternative option in desmoid tumors with compatible locations and tumor sizes. Following medical treatment or cryotherapy failure, superficial sites represent the best indications for surgery in cases of continuous progression. In the event of a contra-indication or failure of medical treatment, in locations where surgery would be mutilating and incomplete, radiotherapy is an effective option.Active surveillance with planned imaging has become the first-line management in desmoid tumor.

Hodgkin variant Richter transformation (HvRT) is a rare and challenging complication of chronic lymphocytic leukaemia (CLL) for which information on prognostic factors and treatment approaches remain limited. We analysed characteristics and survival outcomes of a population-based cohort of 32 patients with HvRT identified in British Columbia over a 40-year period. Median interval from CLL diagnosis to HvRT was 5.6 years (range, 0-33.6), with five cases diagnosed concurrently. Most patients (80%) had treatment for CLL prior to HvRT. Median age at HvRT was 71 years (range, 51-86) and the majority of patients had high-risk disease, including stage 3-4 in 87% and International Prognostic Score (IPS) ≥ 4 in 65%. Two-year progression-free (PFS) and overall survival (OS) from HvRT were 47% (95% CI: 29%-64%) and 57% (95% CI: 38%-72%), respectively. OS from HvRT was significantly worse in those with anaemia (p = 0.02), elevated lactate dehydrogenase (p = 0.04), high IPS (p = 0.04), and worse performance status (p = 0.001). For those treated with curative-intent ABVD/ABVD-like therapy, 2-year PFS and OS were 70% (95% CI: 45%-85%) and 74% (95% CI: 49%-89%), respectively. In this real-world population-based cohort, HvRT was associated with poor clinical outcomes overall; however, those able to tolerate curative-intent therapy had similar survival to older patients with de novo HL.

A novel in vitro 3D micronucleus assay was developed in China using the EpiSkin™ 3D human skin model. This EpiSkin™ Micronucleus Assay showed good predictivity and reproducibility during internal validation and is expected to contribute to in vitro genotoxicity testing as a follow-up for positive results from 2D micronucleus assay. Having developed the assay in one laboratory, further work focused on the transferability and inter-laboratory reproducibility in two additional Chinese authority laboratories (Guangdong Provincial Center for Disease Control and Prevention and Zhejiang Institute for Food and Drug Control). Formal training was provided for both laboratories, which resulted in good transferability based on the results of two positive compounds, such as mitomycin C and vinblastine. Independent experiments were then performed, and inter-laboratory reproducibility was checked using 2-acetylaminofluorene, 5-fluorouracil, 2,4-dichlorophenol, and d-limonene. The dose-responses of the positive control chemical, mitomycin C, were similar to those of the developing laboratory, and all test chemicals were correctly classified by all laboratories. Overall, there was a good transferability as well as intra- and inter-laboratory reproducibility of the EpiSkin™ Micronucleus Assay. This study further confirmed the assay’s robustness and provided confidence to enter following validation stages for scientific acceptance.

PURPOSE The AHL2011 study (ClinicalTrials.gov identifier: NCT01358747 ) demonstrated that a positron emission tomography (PET)-driven de-escalation strategy after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) provides similar progression-free survival (PFS) and overall survival (OS) and reduces early toxicity compared with a nonmonitored standard treatment. Here, we report, with a prolonged follow-up, the final study results. METHODS Patients with advanced Hodgkin lymphoma (stage III, IV, or IIB with mediastinum/thorax ratio > 0.33 or extranodal involvement) age 16-60 years were prospectively randomly assigned between 6 × BEACOPP and a PET-driven arm after 2 × BEACOPP delivering 4 × ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in PET2– and 4 × BEACOPP in PET2+ patients. PET performed after four cycles of chemotherapy had to be negative to complete the planned treatment. RESULTS In total, 823 patients were enrolled including 413 in the standard arm and 410 in the PET-driven arm. With a 67.2-month median follow-up, 5-year PFS (87.5% v 86.7%; hazard ratio [HR] = 1.07; 95% CI, 0.74 to 1.57; P = .67) and OS (97.7% in both arms; HR = 1.012; 95% CI, 0.50 to 2.10; P = .53) were similar in both randomization arms. In the whole cohort, full interim PET assessment predicted patients' 5-year PFS (92.3% in PET2–/PET4–, 75.4% [HR = 3.26; 95% CI, 18.3 to 5.77] in PET2+/PET4– and 46.5% [HR = 12.4; 95% CI, 7.31 to 19.51] in PET4+ patients, respectively; P < .0001) independent of international prognosis score. Five-year OS was also affected by interim PET results, and PET2+/PET4– patients (93.5%; HR = 3.3; 95% CI, 1.07 to 10.1; P = .036) and PET4+ patients (91.9%; HR = 3.756; 95% CI, 1.07 to 13.18; P = .038) had a significant lower OS than PET2–/PET4– patients (98.2%). Twenty-two patients (2.7%) developed a second primary malignancy, 13 (3.2%) and 9 (2.2%) in the standard and experimental arms, respectively. CONCLUSION The extended follow-up confirms the continued efficacy and favorable safety of AHL2011 PET-driven strategy, which is noninferior to standard six cycles of BEACOPP. PET4 provides additional prognostic information to PET2 and allows identifying patients with particularly poor prognosis.

Despite multiple randomized trials, variation in practice remains regarding the most effective treatment for early-stage, favorable-risk Hodgkin lymphoma. With increasing emphasis on alternative payment models, we investigate the cost-effectiveness of chemotherapy alone versus combined modality therapy (CMT).A Markov model was formed to compared 2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) to 2 cycles of ABVD followed by 20 Gy in 10 fractions involved-site radiation therapy. Modalities were compared using the incremental cost-effectiveness ratio, with effectiveness measured in quality-adjusted life years (QALYs) and evaluated with a willingness to pay a threshold of $100,000 per QALY gained.The base case analysis showed that CMT is cost-effective compared with ABVD alone, with an incremental cost-effectiveness ratio of $8028 per QALY gained and an incremental cost of $236 gaining 0.029 QALYs. On sensitivity analyses, the results were the most sensitive to changes in recurrence rates. If the recurrence rate differences were ≥6%, CMT was cost-effective.CMT is a cost-effective strategy for early-stage, favorable-risk Hodgkin lymphoma based on currently available evidence. However, small variations in recurrence-rate estimates dramatically affect strategy cost-effectiveness.

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties, a high incidence of pulmonary metastasis and a poor prognosis. Chemotherapy is the mainstay of treatment for osteosarcoma. Currently, there are no molecular targeted drugs approved for osteosarcoma treatment, particularly effective drugs for osteosarcoma with pulmonary metastases. It has been reported that fibroblast activation protein alpha (FAPα) is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis, demonstrating that FAPα-targeted agents might be a promising therapeutic strategy for osteosarcoma. In the present study, we reported that the FAPα-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPα-positive osteosarcoma cells in vitro and in vivo. Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells. Importantly, it also decreased the migration and invasion capacities and reversed epithelial–mesenchymal transition (EMT) of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo. Mechanistically, Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway, leading to inhibition of the growth and metastatic spread of osteosarcoma cells. These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPα-positive osteosarcoma, particularly osteosarcoma with pulmonary metastases.

BACKGROUND: Targeted cancer therapy is an alternative to standard chemotherapy for a better prognosis. Although its incompetency for triple-negative breast cancer (TNBC), treatment still relies on classical chemotherapy. Increasing evidence suggest that chemotherapeutic drug-induced toxic effect could be minimised by combinatorial therapy. Profilin’s familiar anti-tumorigenic activity can be utilised in combination with the drug to improve efficacy, which could be promising therapeutics to treat TNBC. METHODS: All-trans retinoic acid (ATRA) in combination with vinblastine was tested on human MDA MB-231 cell line (MB-231) (in vitro) and MB-231 borne breast cancer in nude mice (in vivo). Effects of combination treatment on tumour growth inhibition and apoptosis were examined by tumour volume, histology and PARP cleavage. ATRA-induced transcriptional regulation of profilin had been evaluated by gel-shift and reporter gene assays. Profilin’s role in ATRA-induced vinblastine efficacy was validated in profilin-stable and profilin-silenced cells. RESULTS: ATRA binds with RAR/RXR to increase the profilin expression that potentiated cell death by chemotherapeutics. ATRA priming led to vinblastine-mediated potentiation of G2–M phase cell cycle arrest in MB-231 cells and regression of breast cancer in xenograft mice at very low concentration without any adverse effects. Moreover, increased p53 and PTEN but downregulated p65 in the tumour tissues further supported the involvement of profilin for tumour regression. CONCLUSIONS: Vinblastine at very low concentration (20 times lesser than the recommended dose for breast cancer therapeutic) significantly regress tumour growth in ATRA-primed mice without any toxic effects suggesting potential combinatorial therapeutics for TNBC.

A powerful tris(4-bromophenyl)aminium hexachloroantimonate (BAHA) mediated regioselective intermolecular coupling reaction of vindoline with a wide range of substrates that include β-ketoesters, β-diketones, β-ketoaldehydes, β-ketonitriles, β-ketolactones, β-ketolactams, β-cyanoesters, and malononitriles is detailed. The BAHA-promoted intermolecular sp(3)/cp(2) coupling, representing a special class of selective C–H functionalization reactions with direct carbon–carbon bond formation, proceeds with generation of a quaternary center bound to the aryl C15 center of vindoline capable of accommodating of the vinblastine C16’ methyl ester and functionalized for subsequent divergent heterocycle introduction. A comprehensive examination of the reaction scope, optimization of subtle reaction parameters, and key insights into the reaction mechanism are described. Contrary to what might be prevailing expectations, studies suggest the plausible mechanism entails initial single-electron oxidation of the substrate enolate, not vindoline, and subsequent regiospecific addition of the resulting electrophilic radical to vindoline. As such and beyond the new arylation reaction with vindoline, the studies define a host of new, previously unrecognized, applications of BAHA and related triarylaminium radical cations that arises from their ability to generate stabilized electrophilic radicals from β-ketoesters and related substrates under non-reducing and metal-free conditions. Those exemplified herein include mediating stabilized enolate free radical arylation, dimerization, allylation, alkene addition, and α-oxidation reactions.

Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

Whether alterations in the microtubule cytoskeleton affect the ability of endothelial cells (ECs) to sprout and form branching networks of tubes was investigated in this study. Bioassays of human EC tubulogenesis, where both sprouting behavior and lumen formation can be rigorously evaluated, were used to demonstrate that addition of the microtubule-stabilizing drugs, paclitaxel, docetaxel, ixabepilone, and epothilone B, completely interferes with EC tip cells and sprouting behavior, while allowing for EC lumen formation. In bioassays mimicking vasculogenesis using single or aggregated ECs, these drugs induce ring-like lumens from single cells or cyst-like spherical lumens from multicellular aggregates with no evidence of EC sprouting behavior. Remarkably, treatment of these cultures with a low dose of the microtubule-destabilizing drug, vinblastine, led to an identical result, with complete blockade of EC sprouting, but allowing for EC lumen formation. Administration of paclitaxel in vivo markedly interfered with angiogenic sprouting behavior in developing mouse retina, providing corroboration. These findings reveal novel biological activities for pharmacologic agents that are widely utilized in multidrug chemotherapeutic regimens for the treatment of human malignant cancers. Overall, this work demonstrates that manipulation of microtubule stability selectively interferes with the ability of ECs to sprout, a necessary step to initiate and form branched capillary tube networks.

Introduction: In both developing and developed countries, cancer is among the leading causes of millions of deaths. The incidence of cancer is increasing due to environmental changes and modernization of life style. Lung and breast cancer deaths lead in number compared to other cancer deaths. Although the cause of cancer due to external factors like tobacco use, chemicals, radiation, infectious organisms and internal factors like immune conditions and genetic modification are known, the occurrence and deaths due to cancer cannot be controlled. Methods: It is expected that the incidence of cancer after two decades will increase by 70% and death rate will also increase by 50%, which is an alarming situation globally. Although synthetic compounds are being used in the control of cancer as chemopreventive agents, about 50% of these are related to natural products as the origin. There is an emerging evidence to show that in the past 50 years, natural products derived from plants and marine sources had beneficial effects in the treatment and prevention of cancer. Taxol, vincristine, vinblastine, cytarabine, eribulin mesylate and trabectidine are some of the anticancer compounds isolated from terrestrial and marine sources. Results: This review highlights mainly the role of natural compounds isolated from terrestrial and marine sources as anticancer agents through the docking of these compounds with the related macromolecular targets. Conclusion: Cell line studies for some of the compounds isolated from natural products are also reported.

Cancer stem cells (CSCs) in breast cancers are considered to be a major cause of tumor recurrence and metastasis, which lead to chemotherapeutic failures and poor survival rates among breast cancer patients. Hence, this study attempted to evaluate the anti-tumor potential of a bioactive withanolide compound, withaferin A (WFA), against the molecular targets that maintain the stemness of breast cancer stem cells, using in silico molecular modeling approach. The crystal structures of potential breast cancer stem cell targets—HSP70, HSP90, NFκB, and BRCA1 were retrieved from PDB. The 2D structures of WFA, its analogs, along with doxorubicin and vinblastine were retrieved from the PubChem database. WFA and withaferin A diacetate exhibited strong receptor-ligand interactions for the target macromolecules. Their binding energy values ranged between –55.241 and –40.250 kcal/mol. Compared to doxorubicin, WFA markedly inhibited the growth and decreased the viability of MCF-7-derived breast cancer stem cells, with an IC50 value of 1.476 μM for 48 h. Therefore, our results indicate that WFA and its derivatives could be promising anti-tumor agents against breast cancer stem cells. Further in vitro studies are warranted in order to gain a greater understanding of the action of this compound in a physiological setting.

Thymus and activation-regulated chemokine (TARC) is expressed on Reed-Sternberg cells of patients with classical Hodgkin lymphoma (HL) and may serve as a marker in response assessment. In our study, we correlated serum TARC levels with early response to treatment measured by PET/CT in 19 newly diagnosed patients with HL who received ABVD (Adriblastin, Bleomycin, Vinblastine, Dacarbazine) regimen. Finally, 17 patients were analyzed and six of them (35%) achieved PET/CT negativity defined as Deauville (D) 1 or 2 after 2 cycles of ABVD; 11 pts (65%) had D3 on PET/CT. None of the patients presented D 4/5. Median serum TARC levels at diagnosis were significantly higher when compared with healthy controls: 5718 pg/ml vs 76.1 pg/ml (p p = 0.049. There was a tendency to higher baseline serum TARC levels in patients with an increased LDH (lactate dehydrogenase) activity (p = 0.08) and in those who progressed when compared with those who maintained response (p = 0.09). Serum TARC levels decrease after chemotherapy and may serve as a marker of response assessment.

Catharanthus roseus is a very rich source of medically important alkaloids. However, since their concentrations are extremely low in plant tissues, many efforts have been made to increase the alkaloids level - among them are the application of various elicitors. Since the alkaloids are synthetized by a complex pathway, the detailed knowledge of the molecular background of the system is essential. The current job aimed to study the effect of two elicitor, methyl jasmonate (MeJa) and UV-B irradiation, and also their simultaneous effect, on the expression patterns of two key synthesis-involved genes, namely tryptophan decarboxylase and strictosidine synthase through quantitative RT-PCR. Estimation of vinblastine, vincristine and ajmalicine, was carried out using high performance liquid chromatography (HPLC) in the elicited plant leaves. From the obtained results, it was concluded, that these two elicitors act on different way, and also their combined application induces the tryptophan decarboxylase but in less for the strictosidine synthase gene expression in the treated Catharanthus roseus leaves. The results showed that the combination of MeJa and UV-B light (MU) induces higher accumulation of vinblastine,vincristine and ajmalicine than other treatments. Vinblastine content with MU60 treatment showed higher level during the third day of exposure to the combined elicitors (methyl jasmonate and UV-B). Vincristine accumulation was the highest after one day of exposure to MU60 treatment. Its content was increased 6-fold than control after one day exposure to the combined elicitors. Additionally, it could be observed that MU60 treatment, was the best for ajmalicine accumulation. Ajmalicine content was increased 8-fold than control at 60 min exposure to the combined elicitors. As a final outcome, we also conclude that the effect of the different elicitations is highly dependent on the experimental parameters.

Background More than 90% of the adult population globally is chronically infected by the Epstein–Barr virus (EBV). It is well established that EBV is associated with a number of malignancies, and advances in knowledge of EBV-related malignancies are being made every year. Several studies have analysed the global epidemiology and geographic distribution of EBV-related cancers. However, most have only described a single cancer type or subtype in isolation or limited their study to the three or four most common EBV-related cancers. This review will present an overview on the spectrum of cancers linked to EBV based on observations of associations and proportions in the published literature while also using these observations to estimate the incidence and mortality burden of some of these cancers. Method We have reviewed the literature on defining features, distribution and outcomes across six cancers with a relatively large EBV-related case burden: Nasopharyngeal carcinoma (NPC), Gastric carcinoma (GC), Hodgkin lymphoma (HL), Burkitt lymphoma (BL), Diffuse large B-cell lymphoma (DLBCL) and Extranodal NK/T-cell lymphoma, Nasal type (ENKTL-NT). We retrieved published region-specific EBV-related case proportions for NPC, GC, HL and BL and performed meta-analyses on pooled region-specific studies of EBV-related case proportions for DLBCL and ENKTL-NT. We match these pooled proportions with their respective regional incidence and mortality numbers retrieved from a publicly available cancer database. Additionally, we also reviewed the literature on several other less common EBV-related cancers to summarize their key characteristics herein. Conclusion We estimated that EBV-related cases from these six cancers accounted for 239,700–357,900 new cases and 137,900–208,700 deaths in 2020. This review highlights the significant global impact of EBV-related cancers and extends the spectrum of disease that could benefit from an EBV-specific therapeutic.

Lung lesions of Hodgkin's lymphoma (HL) are rare and difficult to diagnose by nonsurgical biopsy. We herein present the case of a 72‐year‐old Japanese male who presented with accumulation of lung infiltrates and masses bilaterally on the lungs for 3 years. Although transbronchial lung biopsy (TBB) and computed tomography‐guided biopsy were conducted several times, his diagnosis remained inconclusive. On further deterioration of lung lesions, the patient was transferred to our hospital. Positron emission tomography revealed increased accumulation in the bilateral lungs and right supraclavicular lymph nodes. Surgical biopsy of the lymph node was performed. He was finally diagnosed with HL and underwent chemotherapy with doxorubicin, vinblastine, dacarbazine, and brentuximab vedotin. After chemotherapy, the lung lesion showed significant regression. A literature review indicated that the diagnostic success rate of TBB was low (18.5%) in cases of lung lesions in HL., Here, we report a case of undiagnosed HL with lung lesions despite multiple TBBs. Our literature review indicated that the diagnostic success rate of TBB was low (18.5%) in cases of lung lesions in HL. Surgical biopsy should be considered early to avoid a delay in diagnosis because the diagnostic ability of TBB for HL patients with lung lesions is limited.

Background We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. Methods Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming–A’Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of 40% being probable. Results Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. Conclusions Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease. Trial registration NCT02057913.

Introduction Hodgkin lymphoma is a highly curable lymphoproliferative malignancy with an overall relative survival rate of 87.4%. It is characterized by multinucleated Reed–Sternberg cells which are mostly derived from B cells in the germinal center. Case report We present a case of a 40-year-old gentleman with acquired immunodeficiency syndrome who presented with Stage 4b Hodgkin lymphoma complicated with fulminant hepatic failure and direct hyperbilirubinemia. The initial presentation of Hodgkin lymphoma as cholestatic jaundice is extremely rare. Management and outcome Though the survival rate with chemotherapy is high, the fulminant hepatic failure made the situation challenging with the use of chemotherapeutic regimens that require hepatic excretion. He received dose reduced adriamycin-bleomycin-vinblastine-dacarbazine regimen [doxorubicin 12.5 mg (6.75 mg/m2), bleomycin 18 units (10 units/m2), vinblastine 3 mg (1.5 mg/m2), dacarbazine 380 mg (190 mg/m2)] as well as bictegravir/emtricitabine/tenofovir alafenamide since admission for treatment of human immunodeficiency virus and hepatitis B. He started responding with the first cycle of dose reduced adriamycin-bleomycin-vinblastine-dacarbazine regimen with bilirubin levels trended down and normalized as well as his clinical condition improved. He received the full dose of adriamycin-bleomycin-vinblastine-dacarbazine on day 15. Discussion Our case report emphasizes that the early usage of dose reduced adriamycin-bleomycin-vinblastine-dacarbazine regimen can restore hepatic function and can achieve improvement in hepatic function allowing the delivery of full-dose chemotherapy.

A 26-year-old man with limited-stage classic Hodgkin lymphoma (cHL) achieved complete response after standard treatment with combined modality treatment of involved-field radiation and four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. Fourteen years later, enlarged mediastinal lymph nodes were revealed by computed tomography, and based on identical histological findings, he was diagnosed with cHL, considered to be a recurrence of the initial disease. HL is a rare subtype of malignant lymphoma in Japan, and there are limited data on well-documented cases in Japanese, especially very late recurrence. Our case has shown that CR could be achieved again with the use of brentuximab vedotin (BV) followed by autologous stem cell transplantation (ASCT) for such late recurrence. Although the possible risk factors for relapse of cHL remain uncertain, patients with late-relapse cHL that occurs 5 or more years after the end of initial therapy show better survival after additional treatment than that in patients with early-relapse cHL. Due to the possible occurrence of very late relapse, as described in the present case report, a reconsideration of strategies for long-term follow-up after chemoradiotherapy for limited-stage cHL is warranted.

Introduction The popularity of robot‐assisted radical cystectomy over open radical cystectomy has been increasing because the former, a minimally invasive surgery, contributes to earlier recovery and shorter hospitalization. However, atypical recurrences may be more frequent after robot‐assisted radical cystectomy than after open radical cystectomy. We report a case of an atypical early recurrence of bladder cancer including the descending colon. Case presentation A 70‐year‐old Japanese man underwent robot‐assisted radical cystectomy for muscle‐invasive bladder cancer. Four months later, he was hospitalized for severe anemia (hemoglobin, 5.1 g/dL). Colonoscopy revealed a 4‐cm submucosal oozing tumor in the descending colon. Computed tomography revealed multiple recurrent lesions including recurrence in the descending colon, all of which disappeared completely after chemotherapy with six cycles of dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin. Conclusion We encountered a rare case of an atypical recurrence of bladder cancer in the colon after robot‐assisted radical cystectomy.

BackgroundHodgkin lymphoma (HL) is a treatable tumor affecting children, adolescents and young adults (AYAs; 15-39 years old). Population-based studies report worse survival for non-White children and AYAs but have limited data on individual therapeutic exposures. This study examined overall and HL-specific survival in a population-based cohort of patients while adjusting for sociodemographic factors and treatment.MethodsData for 4807 patients younger than 40 years with HL (2007-2017) were obtained from the California Cancer Registry. Individual treatment information was extracted from text fields; chemotherapy regimens were defined by standard approaches for pediatric and adult HL. Multivariable Cox models examined the influence of patient and treatment factors on survival.ResultsAt a median follow-up of 4.4 years, 95% of the patients were alive. Chemotherapy differed by age, with 70% of 22- to 39-year-olds and 41% of

The InPOG-HL-15-01, a multicentric prospective study, used a risk-stratified and response-based approach with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) backbone to treat children and adolescents with newly diagnosed Hodgkin lymphoma (HL) and reduce the use of radiation therapy (RT). Children/adolescents with bulky disease or inadequate response at early response assessment (ERA) after two cycles of chemotherapy were assigned to receive RT. For ERA, positron emission tomography computed tomography (PET-CT) was recommended but not mandatory in view of limited access. This study aimed to compare the impact of using contrast-enhanced computed tomography (CECT) and PET-CT on treatment decisions and outcomes.396 patients were enrolled and 382 had an ERA at the assigned time point. Satisfactory response was defined as Deauville score 3 or less for patients undergoing PET-CT and complete response (CR)/very good partial response (VGPR) for patients undergoing CECT. Outcomes of interest incorporate 5 year event-free survival (EFS), EFS including abandonment (EFSa), and overall survival (OS).At ERA, satisfactory response was documented in 277 out of 382 (72.5%) participants and this was significantly higher in PET-CT (151 out of 186, 81.2%) as compared with CECT-based assessments (126 out of 196, 64.3%) respectively (p value .001). Amongst the 203 patients with nonbulky disease (wherein the indication for RT was entirely dependent on ERA), 96 out of 114 (84.2%) and 61 out of 89 (68.5%) patients achieved a satisfactory response according to the PET-CT and CECT (p value = .008) respectively and hence a lesser proportion of patients in the PET-CT arm received RT. Despite a lower usage of RT the 5 year OS of both groups, ERA based on CECT (91.8%) versus PET-CT (94.1%) was comparable (p value = .391) and so was the 5 year EFS (86.7 vs. 85.5%, p value = .724).Use of PET-CT as the modality for ERA is more likely to indicate a satisfactory response as compared with CECT and thereby decreases the need for RT in response-based treatment algorithm for HL-afflicted children. The reduction in the application of RT did not impact the overall outcome and plausibly would lower the risk of delayed toxic effects.

The anti-cancer vinblastine and vincristine alkaloids can only be naturally found in periwinkle (Catharanthus roseus). Both of these alkaloids' accumulations are known to be influenced by salicylic acid (SA). The transcriptome data to reveal the induction effect (s) of SA, however, seem restricted at this time. In this study, the de novo approach of transcriptome assembly was performed on the RNA-Sequencing (RNA-Seq) data in C. roseus. The outcome demonstrated that SA treatment boosted the expression of all the genes in the Terpenoid Indole Alkaloids (TIAs) pathway that produces the vinblastine and vincristine alkaloids. These outcomes supported the time-course measurements of vincristine alkaloid, the end product of the TIAs pathway, and demonstrated that SA spray had a positive impact on transcription and alkaloid synthesis. Additionally, the abundance of transcription factor families including bHLH, C3H, C2H2, MYB, MYB-related, AP2/ ERF, NAC, bZIP, and WRKY suggests a role for a variety of transcription families in response to the SA stimuli. Di-nucleotide and tri-nucleotide SSRs were the most prevalent SSR markers in microsatellite analyses, making up 39% and 34% of all SSR markers, respectively, out of the 77,192 total SSRs discovered.

Background In male dogs, uroepithelial cancers include invasive urothelial carcinoma (iUC) and prostate carcinoma (PCA). The inability to distinguish iUC involving the prostate from PCA results in indiscriminate clinical management strategies that could be suboptimal as first-line chemotherapy for iUC (cisplatin) and PCA (docetaxel) differ in people. Prostate specific membrane antigen (PSMA) is a transmembrane protein, and its overexpression has been identified in human prostate carcinoma and neovasculature associated with solid tumor growth. This study investigates whether differential PSMA expression exists between presumptive canine iUC and PCA among cell lines and archived patient samples, which might allow for improved accuracy in disease-based stratification and optimal chemotherapy selection. Additionally, in vitro sensitivities of reported canine iUC and PCA cell lines to uroepithelial directed chemotherapeutic agents were characterized. Results Normalized PSMA gene and protein expressions were not significantly different between 5 iUC and 4 PCA cell lines. PSMA protein expression was uniformly observed in uroepithelial cancers regardless of anatomic origin from archived patient samples, further confirming that PSMA cannot differentiate iUC from PCA. In vitro sensitivity of cell lines to uroepithelial directed chemotherapeutics revealed that vinblastine exerted the broadest cytotoxic activity. Conclusions Differential expression of PSMA was not identified between canine iUC and PCA cell lines or archived patient samples, and PSMA alone cannot be used for disease stratification. Nonetheless given its conserved overexpression, PSMA may be a targetable surface marker for both canine iUC and PCA. Lastly, in uroepithelial carcinomas, vinblastine might exert the broadest anticancer activity regardless of cellular origin.

Introduction While Hodgkin lymphoma (HL) is mostly curable, outcomes for advanced-stage HL remain unsatisfactory. The International Prognostic Score and its modifications were developed to predict HL prognosis; however, more straightforward prognostic factors are needed. This study aimed to identify simpler prognostic factors for advanced-stage newly diagnosed HL (NDHL). Methods This retrospective study used the Taiwan National Health Insurance Research Database and the Taiwan Cancer Registry. Patients with advanced-stage NDHL receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or ABVD-like regimens between 2009 and 2016 were enrolled. Cox proportional hazards models were used to identify prognostic factors for the time to next treatment (TTNT) and overall survival (OS). We used the time-dependent area under the receiver operating characteristic curve (AUROC) to evaluate model performance. Results The study included 459 patients with advanced-stage NDHL. A bimodal age distribution (peaks 20-44 and >65 years) was observed. Over a median follow-up of 4.7 years, the complete remission and OS rates were 52% and 76%, respectively. Age ≥60 years (adjusted hazard ratio [aHR]: 1.73, 95% confidence interval [CI]: 1.23-2.43), extranodal involvement (1.40, 1.05-1.87), B symptoms (1.53, 1.13-2.06), and Charlson Comorbidity Index (CCI) ≥1 (1.49, 1.08-2.06) were significantly associated with a shorter TTNT. The time-dependent AUROC was .65. With a time-dependent AUROC of .81, age ≥60 years (4.55, 2.90-7.15) and CCI ≥1 (1.86, 1.18-2.91) were risk factors for worse OS. Conclusion Older age and more comorbidities were risk factors for an inferior OS in advanced-stage NDHL, while older age, extranodal involvement, B-symptoms, and higher CCI were significantly associated with disease relapse.

Primary CNS involvement is very rare in Hodgkin lymphoma. Here we present two cases of spinal cord dissemination. Two women of 40 and 65 years of age presented symptoms of spinal cord injury; imaging showed an intramedullary mass in T10 and T2, respectively, without vertebral involvement and upper diaphragmatic lymph nodes. Lymph-node biopsy confirmed the diagnosis of classical Hodgkin lymphoma in both patients. The first patient received four cycles of chemotherapy (escalated BEACOPP and ABVD) with intrathecal therapy, and the second four cycles of doxorubicin, vinblastine, dacarbazine (AVD) and local irradiation after surgery decompression. Complete metabolic response was obtained at the end of treatment. After 5 and 7 years of follow-up respectively, neurological deficits persisted in both.Lymph-node infiltration is the most common presentation in Hodgkin lymphoma at diagnosis. Primary extranodal involvement is rare and spinal cord infiltration exceptional. Back pain, tingling and vesico-sphincter dysfunctions are the main symptoms. 18F-fluorodeoxyglucose (FDG) PET and MRI can detect the location and extension of neurological involvement. We present here two cases of tumoral myelitis and a review of the literature. Local treatment (surgery/radiotherapy) is often administered together with chemotherapy to optimize local control and to avoid long-term sequelae.

Background:: Oral cancer is a significant health problem worldwide. Oral squamous cell carcinoma (OSCC) is a malignant neoplasm of epithelial cells that mostly affects different anatomical sites in the head and neck and derives from the squamous epithelium or displays similar morphological characteristics. Generally, OSCC is often the end stage of several changes in the stratified squamous epithelium, which begin as epithelial dysplasia and progress by breaking the basement membrane and invading adjacent tissues. Several plant-based drugs with potent anti-cancer effects are considered inexpensive treatments with limited side effects for cancer and other diseases. Objective:: The aim of this review is to explore whether some Brazilian plant extracts or constituents exhibit anti-tumorigenic activity or have a cytotoxic effect on human oral carcinoma cells. Methods:: Briefly, OSCC and several metabolites derived from Brazilian plants (i.e., flavonoids, vinblastine, irinotecan, etoposide and paclitaxel) were used as keywords to search the literature on PubMed, GenBank and GeneCards. Results:: The results showed that these five chemical compounds found in Cerrado Biome plants exhibit anti-neoplastic effects. Evaluating the compounds revealed that they play a main role in the regulation of cell proliferation. Conclusion:: Preserving and utilising the biodiversity of our planet, especially in unique ecosystems, such as the Cerrado Biome, may prove essential to preserving and promoting human health in modern contexts.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients and Methods: Patients with advanced, treatment-naive, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

PURPOSE To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4–negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering–defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4–negative patients.

Introduction Most Indian centers use Adriamycin/Bleomycin/Vinblastine/Dacarba-zine (ABVD) chemotherapy for pediatric Hodgkin lymphoma (pHL). To reduce the late toxicity, robust predictive markers are needed to risk stratify pHL patients, thereby limiting the number of chemotherapy cycles and omitting radiation for low-risk and intensifying treatment for high-risk children. Objective This study was conducted to analyze the outcome of pHL patients treated with ABVD and various factors predicting the outcome. Materials and Methods This retrospective study analyzed the outcome of 113 consecutive pHL children treated with ABVD chemotherapy from 11 tertiary care centers in South India from 2009 to 2019. Results The median duration of follow-up was 2.73 years. The median age was 13 years. B symptoms are seen in 50.5% patients, bulky disease in 23%, and stage IV in 28.3%. Of 113 pHL, 69% had a positron emission tomography (PET) and 31% had computed tomography (CT)-based staging. Stage IV (37.1%) and extranodal involvement (31.2%) were seen more often with PET than with CT staging (8.5 and 2.8%, respectively). Among 64 patients with interim PET scan after two cycles (iPET2), 20.3% did not achieve complete remission (CR) and no factors were significantly associated. The 4-year event-free survival (EFS) rate of the entire cohort was 86%. The 4-year EFS rate was 93% for patients with CR in iPET2 and 52% for patients not achieving CR. The only independent predictor of low EFS was iPET2 response (p < 0.05). Conclusion Our study confirms the prognostic role of PET scan staging and response assessment. Not achieving CR on the iPET2 scan indicates poor prognosis and warrants clinical trial enrollment for a better outcome.

Aims Several fungal endophytes were isolated from some medicinal plants and screened for their ability to produce the anticancer drug vinblastine. Methods and results An isolate was found to produce vinblastine (205·38 μg l-1 ), and the identity of the fungal vinblastine was confirmed by UV spectroscopic, high-performance liquid chromatography and electrospray ionization mass spectrometry analyses. Based on both morphological and molecular studies, the vinblastine-producing strain was identified as Alternaria alternata. Cytotoxic activities of the fungal vinblastine were evaluated against CHO-K1, MCF-7 and HepG-2 cell lines by the MTT assay. The proliferation of these cell lines was inhibited after treatment with fungal vinblastine and the recorded IC50 values of the respective cell lines were 12·15, 8·55 and 7·48 μg ml-1 . A strain improvement programme for improving vinblastine productivity by the fungal strain was also used. In addition, 10 broth media were evaluated for further increasing the production of vinblastine. The yield of vinblastine was intensified by 3·98-fold following gamma irradiation at 1000 Gy, and a stable mutant strain was isolated. Among the screened media, M1D broth (pH 6·0) stimulated the highest vinblastine production of 1553·62 μg l-1 by the isolated mutant strain. Conclusions The present study is the first report on the production and yield improvement of the anticancer drug vinblastine by A. alternata. Significance and impact of the study These findings suggest A. alternata as a viable and potent source with excellent biotechnological potential for the production of vinblastine.

Catharanthus roseus is known for its scarce and expensive anticancer bisindole alkaloids, vincristine and vinblastine, which are derived from the coupling of monomeric terpenoid indole alkaloids, catharanthine and vindoline. Vindoline represents the bottleneck in bisindole semi-synthesis as unlike catharanthine, its biosynthesis is restricted to the plant leaves, which are the only commercially-viable source for it. For reducing the exorbitant cost of bisindoles, identification of C. roseus genotypes accumulating higher-than-usual amount of vindoline is urgently required. Here, one such vindoline-rich genotype (CIMAP866) was identified and characterized. It was comparatively analyzed with elite varieties, Dhawal and Nirmal, for morphology, genetic profile, leaf vindoline content (% dry weight), elemental composition, and expression pattern of alkaloid biosynthetic genes. Its vindoline content (~0.20%) was significantly higher than that of Dhawal (~0.09%) and Nirmal (~0.04%). CIMAP866 possesses dwarf character, spreading/bushy growth, wider canopy, shorter petiole and internodes, more laticifers, higher chlorophyll content, altered content of certain elements and distinct genetic profile, as compared to the other genotypes. Significantly higher dat expression in CIMAP866 was a key determinant for its vindoline-rich nature. Vindoline content was a direct function of dat expression and laticifer number. This study has provided a lead towards developing an industrially-useful C. roseus variety.

Effective and tolerable treatments are needed for older patients with classical Hodgkin lymphoma. We report results for older patients with classical Hodgkin lymphoma treated in the large phase III ECHELON-1 study of frontline brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Modified progression-free survival per independent review facility for older versus younger patients (aged ≥60 vs.

Shuai Ping,1 Siyuan Wang,1 Jinbing He,1 Jianghai Chen2 1Department of Orthopaedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, People’s Republic of China; 2Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of ChinaCorrespondence: Jianghai Chen Email chenjianghai@hust.edu.cnPurpose: Skin cutaneous melanoma (SKCM) is the most aggressive skin cancer that results in high morbidity and mortality rate worldwide. Immune-related long non-coding RNAs (IRlncRs) play an important role in regulating gene expression in tumors. Therefore, in this study, we aimed to identify IRlncRs signature that could predict prognosis and therapeutic targets for melanoma irrespective of the gene expression levels.Methods: RNA-sequencing data were obtained from The Cancer Genome Atlas (TCGA). IRlncRs were identified using co-expression analysis and recognized using univariate analysis. The impact of IRlncRs on survival was analyzed using a modified least absolute shrinkage and selection operator (Lasso) regression model. A 1-year survival receiver operating characteristic curve was constructed, and the area under the curve was calculated to identify the optimal cut-off point to distinguish between high and low-risk groups in patients with SKCM. Furthermore, integrative analysis was performed to identify the impact of clinicopathological features, chemotherapeutic treatment, tumor-infiltrating immune cells, and mutant genes on survival.Results: A total of 28 IRlncRs significantly associated with survival were identified. Seventeen IRlncRs pairs were used to build a survival risk model that could be used to distinguish between low and high-risk groups. The high-risk group was negatively associated with tumor-infiltrating immune cells and had a higher half inhibitory centration for chemotherapeutic agents such as cisplatin and vinblastine. Additionally, the high-risk group had a positive correlation with the expression of specific mutant genes such as BRAF and KIT.Conclusion: Our findings demonstrate that some IRlncRs have a significant correlation with survival and therapeutic targets for SKCM patients and may provide new insight into the clinical diagnosis and treatment strategies for SKCM patients.Keywords: melanoma, immune-related gene, long non-coding RNA signature, prognosis, the cancer genome atlas

Structural information about drug-receptor interactions is paramount in drug discovery and subsequent optimization processes. Drugs can bind to multiple potential targets as they contain common chemical entities in their structures. Understanding the details of such interactions offer possibilities for repurposing and developing potent inhibitors of disease pathways. Vinblastine (VLB) is a potent anticancer molecule showing multiple receptor interactions with different affinities and degrees of structural perturbations. We have investigated the multi-target binding profile of VLB with DNA and human serum albumin (HSA) in a dynamic physiological environment using spectroscopic, molecular dynamics simulations, and quantum mechanical calculations to evaluate the structural features, mode, ligand and receptor flexibility, and energetics of complexation. These results confirm that VLB prefers to bind in the major groove of DNA with some inclination toward Thymidine residue and the TR-5 binding site in HSA with its catharanthine half making important contacts with both the receptors. Spectroscopic investigation at multiple temperatures has also proved that VLB binding is entropy driven indicating the major groove and TR-5 binding site of interaction. Finally, the overall binding is facilitated by van der Waals contacts and a few conventional H-bonds. VLB portrays reasonable conformational diversity on binding with multiple receptors.

The VESPER trial demonstrated improved progression-free (PFS) and (preliminarily) overall survival (OS) with six cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVACx6) versus four cycles of gemcitabine and cisplatin (GCx4) before radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), but with increased toxicity. This study compares the cost-effectiveness of these regimens.A cost-effectiveness analysis of neoadjuvant ddMVACx6 and GCx4 was performed using a decision-analytic Markov model with 5-year, 10-year, and lifetime horizons. Probabilities were derived from reported VESPER data. Utility values were obtained from the literature. Primary outcomes were effectiveness measured in quality-adjusted life years (QALY) and incremental cost-effectiveness ratio (ICER) with a willingness to pay threshold of $100,000 per QALY. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model.At 5 years, ddMVACx6 improved QALYs by 0.30 at an additional cost of $16,100, rendering it cost-effective relative to GCx4 (ICER: $53,284/QALY). Additionally, probabilistic sensitivity analysis found ddMVACx6 to be cost-effective in 79% and 81% of microsimulations at10-year and lifetime horizons, respectively. One-way sensitivity analysis demonstrated a minimum difference in 5-year progression of 0.9% and progression mortality of 0.7% between ddMVACx6 and GCx4 was necessary for ddMVACx6 to remain cost-effective.Neoadjuvant ddMVACx6 was more cost-effective than GCx4 for MIBC. These data, together with the improved PFS and (albeit preliminary) OS noted in VESPER, support use of this regimen in appropriate candidates for neoadjuvant chemotherapy before RC.We performed a benefit-to-cost analysis using evidence from a randomized controlled trial that compared two different chemotherapy treatments before bladder removal for bladder cancer that had invaded into the bladder muscle. Despite being more expensive and having a greater likelihood of toxicity, six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin was more cost-effective (or had higher value) than four cycles of gemcitabine and cisplatin.

Intestinal inflammation and intestinal barrier damage are important pathological changes in Crohn's disease (CD). Vindoline is a natural monomer with anti-inflammatory effects. We employed CD model mice to explore the effect of Vindoline on CD-like colitis and the possible mechanism. Il-10-deficient (Il-10

The goal of this study was to develop a method for the simultaneous quantification of 23 commonly used antineoplastic drugs in a hospital pharmacy, using ultra-high pressure liquid chromatography separation coupled to tandem mass spectrometry detection (UHPLC-MS/MS). The following drugs were investigated: 5-fluorouracil, cytarabine, ganciclovir, gemcitabine, dacarbazine, methotrexate, pemetrexed, busulfan, topotecan, rentitrexed, ifosfamide, cyclophosphamide, etoposide, irinotecan, doxorubicin/epirubicin, vincristine, docetaxel, paclitaxel, daunorubicin, idarubicin, vinblastine, oxaliplatin and carboplatin. The chromatographic separation was performed on a phenyl-hexyl column (2.1 ×100 mm, 1.7 µm) with a gradient elution of methanol and water containing 10 mM ammonium formate adjusted to pH 4.9. All compounds were analyzed in less than 13 min and detected with a triple quadrupole mass spectrometer operating in MRM mode. Limits of detection (LODs) and limits of quantification (LOQs) were comprised between 0.01 and 5 ng.mL

Infantile myofibroma is a rare, benign tumour of infancy typically managed surgically. In a minority of cases, more aggressive disease is seen and chemotherapy with vinblastine and methotrexate may be used, although evidence for this is limited. Chemotherapy dosing in infants is challenging, and vinblastine disposition in infants is unknown. We describe the use of vinblastine therapeutic drug monitoring in four cases of infantile myofibroma. Marked inter- and intrapatient variability was observed, highlighting the poorly understood pharmacokinetics of vinblastine in children, the challenges inherent in treating neonates, and the role of adaptive dosing in optimising drug exposure in challenging situations.

Madagascar periwinkle (Catharanthus roseus, family Apocynaceae) is a reservoir of more than 130 monoterpene indole alkaloids (MIAs) including the famous anti-neoplastic dimeric MIAs vinblastine and vincristine, and anti-hypertensive monomeric MIAs ajmalicine and serpentine. Understanding the biosynthetic steps and regulatory factors leading to the formation of MIAs is crucial for rational engineering to achieve targeted enhancement of different MIAs. Due to its highly recalcitrant nature, C. roseus is considered genetically non-tractable for transformation at the whole-plant level. Though few reports have demonstrated tissue culture-mediated regeneration and transformation of C. roseus at whole-plant level recently, the efficiency and reproducibility of these protocols have been a major challenge. To overcome this, we have developed a tissue-culture-independent Agrobacterium-mediated in planta transformation method in C. roseus. Using this method, we were able to efficiently generate stable transgenic plants without relying on the cumbersome methods of tissue-culture regeneration and transformation. Moreover, the transformed plants obtained through this in planta method exhibited stability in subsequent generations. Our method is useful not only for the elucidation of biosynthetic and regulatory steps involved in MIA formation through transgenic plant approach but also for metabolic engineering at the whole-plant level in C. roseus.

Catharanthus roseus is a medicinal plant that produces an abundance of monoterpenoid indole alkaloids (MIAs), notably including the anticancer compounds vinblastine and vincristine. While the canonical pathway leading to these drugs has been resolved, the regulatory and catalytic mechanisms controlling many lateral branches of MIA biosynthesis remain largely unknown. Here, we describe an ethyl methanesulfonate (EMS) C. roseus mutant (M

Cancer chemotherapeutic drugs acts in different manner to kill malignant cells. Most of the anticancer drugs available in clinical practice to treat cancer patients, are natural products including whole plant extract, crude plant extracts, isolated constituents, plant –based drug formulations etc. These natural compounds have been a basis for the development of several drugs against cancer. Agents such as topotecan, taxol, vinca alkaloids (vincristine, vinblastine, vinorelbine and vindesine), are important anticancer agents in widespread clinical use. Other agents, such as combretastatin, flavopiridol, betulinic acid were shown to have anti-tumor effects in both in vitro and in vivo experiments. In this review, we aim to make a brief description of classical plant-derived chemotherapeutics drugs and also to highlight the importance of these natural compounds in the development of new potential drugs in cancer treatment.