Combination Chemotherapy Agents Research Articles

Effects of adipocyte-conditioned cell culture media on S1P treatment of human triple-negative breast cancer cells.

Sphingosine-1-phosphate (S1P) is a potent sphingolipid metabolite that regulates a wide range of biological functions such as cell proliferation, cell apoptosis and angiogenesis. Its cellular level is elevated in breast cancer, which, in turn, would promote cancer cell proliferation, survival, growth and metastasis. However, the cellular concentration of S1P is normally in the low nanomolar range, and our previous studies showed that S1P selectively induced apoptosis of breast cancer cells at high concentrations (high nanomolar to low micromolar). Thus, local administration of high-concentration S1P alone or in combination of chemotherapy agents could be used to treat breast cancer. The breast mainly consists of mammary gland and connective tissue stroma (adipose), which are dynamically interacting each other. Thus, in the current study, we evaluated how normal adipocyte-conditioned cell culture media (AD-CM) and cancer-associated adipocyte-conditioned cell culture media (CAA-CM) would affect high-concentration S1P treatment of triple-negative breast cancer (TNBC) cells. Both AD-CM and CAA-CM may suppress the anti-proliferative effect and reduce nuclear alteration/apoptosis caused by high-concentration S1P. This implicates that adipose tissue is likely to be detrimental to local high-concentration S1P treatment of TNBC. Because the interstitial concentration of S1P is about 10 times higher than its cellular level, we undertook a secretome analysis to understand how S1P would affect the secreted protein profile of differentiated SGBS adipocytes. At 100 nM S1P treatment, we identified 36 upregulated and 21 downregulated secretome genes. Most of these genes are involved in multiple biological processes. Further studies are warranted to identify the most important secretome targets of S1P in adipocytes and illustrate the mechanism on how these target proteins affect S1P treatment of TNBC.

Multiomics Study of a Novel Naturally Derived Small Molecule, NSC772864, as a Potential Inhibitor of Proto-Oncogenes Regulating Cell Cycle Progression in Colorectal Cancer

Colorectal cancer (CRC) is one of the most prevalent malignant tumors, and it contributes to high numbers of deaths globally. Although advances in understanding CRC molecular mechanisms have shed significant light on its pathogenicity, current treatment options, including combined chemotherapy and molecular-targeted agents, are still limited due to resistance, with almost 25% of patients developing distant metastasis. Therefore, identifying novel biomarkers for early diagnosis is crucial, as they will also influence strategies for new targeted therapies. The proto-oncogene, c-Met, a tyrosine kinase that promotes cell proliferation, motility, and invasion; c-MYC, a transcription factor associated with the modulation of the cell cycle, proliferation, apoptosis; and cyclin D1 (CCND1), an essential regulatory protein in the cell cycle, all play crucial roles in cancer progression. In the present study, we explored computational simulations through bioinformatics analysis and identified the overexpression of c-Met/GSK3β/MYC/CCND1 oncogenic signatures that were associated with cancer progression, drug resistance, metastasis, and poor clinical outcomes in CRC. We further demonstrated the anticancer activities of our newly synthesized quinoline-derived compound, NSC772864, against panels of the National Cancer Institute's human CRC cell lines. The compound exhibited cytotoxic activities against various CRC cell lines. Using target prediction tools, we found that c-Met/GSK3β/MYC/CCND1 were target genes for the NSC772864 compound. Subsequently, we performed in silico molecular docking to investigate protein-ligand interactions and discovered that NSC772864 exhibited higher binding affinities with these oncogenes compared to FDA-approved drugs. These findings strongly suggest that NSC772864 is a novel and potential antiCRC agent.

Cutaneous Manifestations of Breast Cancer Patients in Combination with Capecitabine and Lapatinib Chemotherapy

The combination of chemotherapy with lapatinib and capecitabine in human epidermal growth factor receptor 2 (HER2) positive breast cancer is quite effective. The combination of these two agents increases the risk of dermatological toxicities. A woman, 38 years old, HER2 positive breast cancer with a combination of chemotherapy agents between lapatinib and capecitabine gives an overview of skin toxicities such as acneiform eruptions, palmar-plantar erythrodysesthesia (PPE), and paronychia. Therapy, in this case, aims at clinical improvement. The combination of lapatinib and capecitabine has a side effect profile like each drug. Combined use of the two agents increases the incidence of skin side effects, including acneiform eruptions, PPE, and paronychia, compared to monotherapy. Early awareness of the side effects of chemotherapeutic agents is needed for early treatment to prevent the worsening of the condition and discontinuation of chemotherapeutic agents due to drug side effects.

Evaluation of single and combination chemotherapy agents in patients with metastatic breast cancer

Background: There are several ways to treat breast cancer, one of which is administering chemotherapy agents. Chemotherapy agents have activity in inhibiting the cell cycle. That will affect the effectiveness of therapy and the side effects of chemotherapy agents. Objective: This study aimed to evaluate single and combination chemotherapy agent therapeutic efficacy and side effects Method: The design of this study used an observational cohort study with retrospective data collection from January to December 2019. Patients obtained from medical records were diagnosed with metastatic stage of breast cancer at Panti Nirmala Hospital, Malang. The effectiveness of the chemotherapy agent was seen from the carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3), which were carried out in the first and third cycles, then analyzed using the Wilcoxon and U-Mann Whitney tests. Side effects of chemotherapy agents were analyzed descriptively. Results: Analysis of the Wilcoxon test showed differences between the two groups of chemotherapeutic agents in CEA and CA15-3 (p<0.05). U-Mann Whitney test analysis showed no difference after administration of the two groups of chemotherapy agents at CEA (p>0.05). However, there was a difference in CA15-3 (p<0.05). Both chemotherapy agents showed most common side effects such as pain, nausea, vomiting, and alopecia. Conclusion: Patients who received a combination of chemotherapy agents had lower CA15-3 levels than single chemotherapy agents.

Lymphocyte Exhaustion in AML Patients and Impacts of HMA/Venetoclax or Intensive Chemotherapy on Their Biology.

Simple SummaryPatients with acute myeloid leukemia (AML) are routinely treated with either intensive chemotherapy or DNA hypomethylating agents (HMA) in combination with the Bcl-2 inhibitor, venetoclax. While both treatment regimens are highly cytotoxic to the aggressive AML tumor cells, they are also toxic to immune cells. Therefore, we sought to establish the detrimental impacts of these therapies on lymphocytes and their recovery over time in AML patients. Even prior to treatment initiation, the patients were found to have exhausted lymphocytes in peripheral blood, and additional signs of exhaustion were noted after treatment with HMA/venetoclax. In fact, the lymphocytes were still suppressed for two to three months after the initiation of induction therapy. Furthermore, T cells in a subset of patients subsequently found to be resistant to venetoclax therapy exhibited a higher expression of perforin and CD39 and more pronounced IFN-γ production.Acute myeloid leukemia (AML) is an aggressive malignancy that requires rapid treatment with chemotherapies to reduce tumor burden. However, these chemotherapies can compromise lymphocyte function, thereby hindering normal anti-tumor immune responses and likely limiting the efficacy of subsequent immunotherapy. To better understand these negative impacts, we assessed the immunological effects of standard-of-care AML therapies on lymphocyte phenotype and function over time. When compared to healthy donors, untreated AML patients showed evidence of lymphocyte activation and exhaustion and had more prevalent CD57+NKG2C+ adaptive NK cells, which was independent of human cytomegalovirus (HCMV) status. HMA/venetoclax treatment resulted in a greater fraction of T cells with effector memory phenotype, inhibited IFN-γ secretion by CD8+ T cells, upregulated perforin expression in NK cells, downregulated PD-1 and 2B4 expression on CD4+ T cells, and stimulated Treg proliferation and CTLA-4 expression. Additionally, we showed increased expression of perforin and CD39 and enhanced IFN-γ production by T cells from pre-treatment blood samples of venetoclax-resistant AML patients. Our results provide insight into the lymphocyte status in previously untreated AML patients and the effects of standard-of-care treatments on their biology and functions. We also found novel pre-treatment characteristics of T cells that could potentially predict venetoclax resistance.

Caffeic Acid Phenethyl Ester as a DHODH Inhibitor and Its Synergistic Anticancer Properties in Combination with 5-Fluorouracil in a Breast Cancer Cell Line.

IntroductionA combination of chemotherapy agents is the best choice in breast cancer treatment to increase the patient survival rate. 5-fluorouracil (5-FU) is one of the drugs applied in combination with other drugs to control and delay development of cancer cells. Nevertheless, the occurrence of multidrug resistance and dose-limiting cytotoxicity have limited the efficacy of 5-FU treatment. Therefore, the discovery of new anti-breast cancer drugs should be pursued.ObjectiveTo study potency of a promising naturally derived compound, caffeic acid phenethyl ester (CAPE), for breast cancer treatment in single and combination with 5-FU.MethodsCytotoxicity of CAPE, 5-FU, and 5-FU+CAPE was studied by in vitro MTT experiment in MCF-7 cell line, and RT-PCR analysis was used to evaluate the change in gene expression due to the treatment. Moreover, an enzymatic assay and molecular docking analysis were applied to evaluate the possible mechanism of substance-induced apoptosis.ResultsThe study revealed that a single treatment of CAPE showed cytotoxicity with IC50 6.6 ± 1.0 µM and 6.5 ± 2.9 µM at 24 h and 48 h, respectively. Meanwhile, 5-FU showed cytostatic activity. The 5-FU + CAPE has a synergistic effect at 24 h treatment with a CI = 0.5 and an additive effect at 48 h treatment with CI = 1.0. CAPE was also found to enhances the mRNA expression of caspase-8 and BAX within 6 hours in combination with 5-FU compared to 5-FU treatment alone. Our study reveals a new mechanism of CAPE which is related to the inhibition of human dihydroorotate dehydrogenase (HsDHODH) with an IC50 of 120.7 ± 6.8 µM, by bound to the ubiquinone-binding site of the enzyme and could be responsible for inducing extrinsic and intrinsic apoptosis.ConclusionThis study demonstrated the cytotoxicity of CAPE potential to induce apoptosis of breast cancer MCF-7 cell line single and cytotoxic–cytostatic combination with 5-FU. Therefore, further studies to develop CAPE and its derivatives will be required to discover new candidates for breast cancer agents.

Cutaneous reaction to ifosfamide plus mesna treated with desensitization challenge: a case report

BackgroundIfosfamide is an alkylating agent used in the treatment of a wide range of tumours. Because of known side effects it is usually administered in combination with mesna, a thiol agent with uroprotective activity, to reduce them and increase the therapeutic dose. The most frequently administered regimens for ifosfamide are fractionated doses for 3 to 5 days, high-dose intravenous bolus, and continuous infusion over 24 to 72 h. Hypersensitivity reactions to ifosfamide plus mesna are not frequently described in the literature. Moreover, no reports exist concerning desensitization for this chemotherapy combination.Case presentationA 47-year-old man with stage IV renal sarcoma was treated with the combination of ifosfamide and mesna every 3 weeks in a 4-consecutive-day infusion protocol. During the second cycle of chemotherapy, he presented acute cutaneous symptoms. A 12-step desensitization protocol was proposed in view of the lack of knowledge of the possible hypersensitivity reactions to this combination of chemotherapy agents, and the multiple difficulties found during the study of the case.ConclusionsThe 12-step desensitization protocol was well tolerated. Therefore, it is an appropriate and safe option in the case of suspected allergy to ifosfamide plus mesna.

Ginsenoside Rh2 mitigates doxorubicin-induced cardiotoxicity by inhibiting apoptotic and inflammatory damage and weakening pathological remodelling in breast cancer-bearing mice.

ObjectivesThere are presently a few viable ways to reduce cardiotoxicity of doxorubicin (Dox). The combination of chemotherapy agents with natural compounds delivers greater efficacy and reduces adverse effects in recent researches for cancer treatment. Here, we examined the potential effect of ginsenoside Rh2 on a Dox‐based regimen in chemotherapy treatment.Materials and MethodsHuman breast tumour (MDA‐MB‐231) xenograft nude mice, human cardiac ventricle fibroblasts, and human umbilical vein endothelial cells (HUVEC) were employed in the present study. Histology, immunohistochemistry, immunofluorescence, western blot, antibody array, and RNA‐sequencing analyses were utilized to assess the protective effect of Rh2 on cardiotoxicity induced by Dox and the underlying mechanisms.ResultsRh2‐reduced cardiotoxicity by inhibiting the cardiac histopathological changes, apoptosis and necrosis, and consequent inflammation. Pathological remodelling was attenuated by reducing fibroblast to myofibroblast transition (FMT) and endothelial–mesenchymal transition (EndMT) in hearts. RNA‐sequencing analysis showed that Dox treatment predominantly targets cell cycle and attachment of microtubules and boosted tumour necrosis, chemokine and interferon‐gamma production, response to cytokine and chemokine, and T cell activation, whereas Rh2 regulated these effects. Intriguingly, Rh2 also attenuated fibrosis via promoting senescence in myofibroblasts and reversing established myofibroblast differentiation in EndMT.ConclusionsRh2 regulates multiple pathways in the Dox‐provoked heart, proposing a potential candidate for cancer supplement and therapy‐associated cardiotoxicity.

Evaluation of oral mucositis in pediatric cancer patients in Hiwa Hospital in Sulaymaniyah city, Kurdistan Region, Iraq

Background and objective: Oral mucositis is caused by the destruction of the oral mucosal epithelium and suppression of its growth secondary to antineoplastic treatment in the form of chemotherapeutic drugs, substances, or radiotherapy. This study aimed to evaluate oral mucositis in pediatric cancer patients because it is one of the common side effects of cancer therapy that influences the outcome. Methods: This is a cross-sectional study that enrolled 100 pediatric patients with both hematological and non-hematological cancer. The age of the patients ranged from 1-18 years, involving both genders. Cases admitted to Hiwa hospital were clinically evaluated for oral mucositis, and ethical permission was taken from parents. Risk factors were assessed, including age, sex, cancer type, type of chemotherapy, radiotherapy, number of cycles, complete blood count, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and tumor necrosis factor-beta. Results: Baseline serum cytokines levels showed significant correlation between Interleukin-6 and intensity of the oral mucositis (P = 0.003, rho = 0.314) and no correlation between severity of oral mucositis with tumor necrosis factor-alpha, tumor necrosis factor-beta nor interleukin-1 beta (P = 0.140 and rho = 0.258, P = 0.463 and rho = -0.079, and P = 0.706 and rho = -0.041, respectively). There was significant relationship between Hemoglobin level, neutropenia and type of non-hematological cancer with the intensity of oral mucositis respectively (P ≤0.001 and rho = -0.352, P = 0.027 and rho = -0.221, and P = 0.035 and rho = 0.095, respectively). Correlation between age, gender, white blood cell count, platelet count, type of hematological malignancy and past history with the intensity of the oral mucositis did not show significant result. Conclusion: Intensity of oral mucositis increased with anemia, neutropenia, high interleukin-6 level, and the type of non-hematological cancer. It is recommended to treat anemic, neutropenic patients as soon as possible before exacerbating the mucositis. Methotrexate is the most aggressive drug alone and in combined chemotherapy agents, which may cause mucositis and needs prophylaxis like topical nystatin suspension or other methods. Keywords: Oral mucositis; Pediatric cancer; Non-hematological; Hematological; Sulaymaniyah.

O02 Cancer, Covid and control of RA – a toxic combination?

Case report - IntroductionThis case highlights the dilemma of keeping rheumatoid arthritis disease under control in active cancer cases and establishing a consistent multidisciplinary dialogue during a pandemic and staffing crises.During chemotherapy and active cancer treatment, disease-modifying therapies (conventional and biologic) are often stopped. In some cases, the potential benefits versus risks of restarting usual therapies have to be balanced against risks of suppressing disease activity with high-dose steroids. Risks of infection (common and atypical) need to be considered.Case report - Case descriptionA is a 67-year-old female non-smoker diagnosed with seropositive rheumatoid arthritis (RF, anti –CCP positive) in 2008. Other conditions include type 2 diabetes, atrial fibrillation (on warfarin), hypothyroidism and obstructive sleep apnoea. Due to active disease, despite triple therapy (methotrexate, sulphasalazine and hydroxychloroquine), anti-TNF therapy (etanercept) commenced in 2009 with primary non-response. However, she responded well to B-cell therapy (rituximab) in conjunction with oral methotrexate (25mg weekly) receiving annual infusions from 2010 to 2016.In 2017, an elective sleeve gastrectomy procedure for high BMI was abandoned after peritoneal deposits of concern were noted. Histology and CT imaging were consistent with a primary peritoneal malignancy (Stage 3c low-grade serous adenocarcinoma). Treatment involved debulking surgery (total abdominal hysterectomy, bilateral salpinoophorectomy, omentectomy) and tamoxifen.Treatment for rheumatoid arthritis stalled during this period but as frequent steroids were required for active joint inflammation, in agreement with the oncologists, she had a rituximab cycle in 2018.Unfortunately, in 2019 she had signs of cancer progression (elevated tumour markers, CT imaging) and has subsequently started carboplatin chemotherapy. She has been unable to continue methotrexate or rituximab pending completion of the chemotherapy cycles (ongoing). However, her arthritis is now uncontrolled without increased steroids. Due to recurrent flares, her maintenance dose has been increased from 5mg to 7.5—10mg prednisolone daily until we can establish if it is safe and appropriate to recommence her usual arthritis regime.Even without disease-modifying therapy like methotrexate and rituximab, risk of infection (including atypical ones) is still significant with the combination of chemotherapy and steroids. Risk of progressive joint damage and adverse quality of life with active arthritis also needs to be considered. Staffing crises, exacerbated by COVID pandemic issues, have added to complexity of decision making and coordination of regular multidisciplinary discussions regarding treatment.Case report - DiscussionCancer is a known association in rheumatoid arthritis patients with a twofold higher risk of lymphoma compared to the general population. Whether condition or treatment affects risk remains unclear as immune dysregulation is relevant in both autoimmunity and cancer. Paraneoplastic, recent onset arthritis, chemotherapy- or immunotherapy-induced arthralgia/arthritis are also well documented. This case had a seropositive rheumatoid arthritis phenotype quite a few years prior to cancer diagnosis. Primary peritoneal cancer is uncommon, often presenting as in this case as an incidental finding. It is usually treated like ovarian cancerWhilst methotrexate has been implicated in lung cancer, melanoma and non-Hodgkin lymphoma, overall safety data suggest any risk is quite low (e.g., EBV-associated lymphoproliferative disorders usually resolve with drug discontinuation). It is also a known chemotherapeutic agent. Anti-TNF treatment algorithms generally exclude patients with recent cancer. Rituximab, originally developed as a cancer drug, is not thought to affect risk of cancer development or progression.Treatment with disease-modifying therapy (conventional and biologics) is often withheld in patients with active malignancy undergoing chemotherapy due to a theoretical risk of potentiated immunosuppression and toxicity, particularly cytopaenias. However, maintaining arthritis control with glucocorticoids also has short- and long-term risks. Combining chemotherapy agents like carboplatin with methotrexate has been used for urothelial carcinoma and can be well tolerated with close monitoring of haematological parameters.Thus, it could be argued this patient is at risk of infections whichever treatment approach is taken and regaining control of arthritis with recommencement of methotrexate and rituximab is much better for her quality of life.Regular multidisciplinary discussions are important to outline risks versus benefits of combined treatment. This may be difficult in practice during staffing crises. Covid risk in patients receiving rituximab and/or chemotherapy, timing and response to COVID vaccination are also important considerations.Case report - Key learning pointsPrimary peritoneal cancer is uncommon and can present as an incidental findingWhilst treatment for progressive cancer is important, withholding rheumatoid arthritis treatment can have a significant adverse impact on quality of lifeMorbidity and mortality risks of stopping treatment versus combined treatment (cancer therapy and disease-modifying therapy) ideally needs to be fully discussed and agreed with the patient and all care providers – lack of “named” providers, restructuring, redeployment, multi-specialty care and a global pandemic can make coordination of this difficult

Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study

BackgroundThe safety and efficacy outcome of elderly metastatic colorectal cancer (mCRC) patients fit enough to receive combination chemotherapy plus biological agents is an issue of growing interest. Also, gender-specific differential toxicity and efficacy of anti-epidermal growth factor receptor (EGFR)-based upfront treatments need to be explored.Patients and methodsValentino was a multicenter, randomized, phase II trial, investigating two panitumumab-based maintenance strategies following first-line panitumumab plus FOLFOX in RAS wild-type mCRC patients. We carried out a subgroup analysis, aimed at assessing the differences in efficacy, safety and quality of life (QoL) according to age (<70 versus ≥70 years) and gender (male versus female). Efficacy endpoints were progression-free survival (PFS), overall survival (OS) and overall response rate (ORR); safety endpoints were rates of any grade and grade 3/4 adverse events (AEs).ResultsNo significant differences in terms of PFS, OS and ORR were observed between patients aged <70 or ≥70 years and the effect of the maintenance treatment arm on survival outcomes was similar in the two subgroups. The safety profile of both induction and maintenance treatment and the impact on QoL were similar in elderly and younger patients. No significant differences in PFS, OS, ORR or clinical benefit rate were observed according to gender. A significantly higher rate of overall grade 3/4 AEs (P = 0.008) and of grade 3/4 thrombocytopenia (P = 0.017), any grade and grade 3/4 neutropenia (P < 0.0001) and any grade conjunctivitis (P = 0.033) was reported in female as compared to male patients. Conversely, we reported a significantly higher incidence of any grade skin rash (P = 0.0007) and hypomagnesemia (P = 0.029) in male patients.ConclusionsThe upfront choice of an anti-EGFR-based doublet chemotherapy followed by a maintenance strategy represents a valuable option in RAS wild-type mCRC irrespective of gender and age, though a careful evaluation of patients to maximize the risk/benefit ratio is warranted.

Role of autophagy in cholangiocarcinoma: Pathophysiology and implications for therapy.

Cholangiocarcinoma (CCA) is a malignant tumour of the biliary system that originates from the neoplastic transformation of cholangiocytes. CCA is characterized by late diagnosis and poor outcome, with surgery considered as the last option for management. Autophagy is a physiological lysosomal degradation process, essential for cellular homeostasis and ubiquitous in all eukaryotic cells. Several studies have reported a potential involvement of autophagy in cancer, but it remains unclear whether activation of this process represents a survival mechanism of cancer cells. In the present review, we examine the autophagic process and summarize the current knowledge about the involvement of autophagy in the progression of cancer. The link between autophagy and chemoresistance and the use of autophagic markers in diagnosis are also considered in detail. Preliminary evidence shows that the combination of autophagy modulators (activators or inhibitors) with conventional chemotherapeutic agents offers a possible treatment option against signalling pathways that are hyperactivated or altered in CCA. In vitro evidence suggests that combination of chemotherapy agents, such as cisplatin, under activation or inhibition of autophagic processes, in two different CCA cell lines, may improve chemosensitivity and reduce cell survival, respectively. A deeper understanding of these pathways, in both cancer and non-cancer cells, could unveil possible therapeutic targets to treat CCA patients.

RARE-17. HIGH-THROUGHPUT SCREEN IDENTIFIES POTENTIAL CHEMOTHERAPIES FOR CHOROID PLEXUS CARCINOMA TREATMENT USING INTRAARTERIAL STRATEGY

Choroid plexus carcinoma is a rare infantile brain tumor with an aggressive clinical course.1 There is no optimal treatment and survival is poor. Gross total surgical removal is the single most important predictor of survival.1 Gross total surgical removal rates are inconsistent and associated with significant morbidity owing to the hemorrhagic nature of these tumors compounded by a small circulating blood volume. Neoadjuvant systemic chemotherapy with “second look surgery” helps to achieve gross total surgical removal2 but has an inefficient pharmacokinetic profile and exposes children to dose- limiting toxic side effects. Hence, there is a strong need to identify and develop new agents and strategies to improve current choroid plexus carcinoma (CPC) treatment. Here, we report a high-throughput drug screening using a CPC cancer tissue-originated from a 7-year-old male patient and procured (Children’s Cancer Hospital Egypt) to identify new potent drugs. The selected candidates have been used as single agent and combination agent chemotherapy to propose a relevant study (e.g pharmacokinetics, toxicity, biodistribution, anticancer efficacy) for improving CPC treatment using a pre-existing intraarterial chemotherapy. A genetically engineered model has been developed by Shannon et al by breeding RosamTmG with Nestin-Cre to generate Nestin-cre/Rosa mTmG reporter mice overexpressing c-Myc, which provides a fully penetrant model of CPC in the lateral ventricle CP and 4th ventricle CP.3 This mice model will be used to explore in vivo the newly discovered drug combinations to treat the CPC tumor. 1. Hosmann, A. et al. Management of choroid plexus tumors—an institutional experience. Acta Neurochir. (Wien). 161, 745–754 (2019) 2. Schneider, C. et al. Neoadjuvant chemotherapy reduces blood loss during the resection of pediatric choroid plexus carcinomas *christian. J. Neurosurg. Pediatr. Pediatr. 16, 126–133 (2015) 3. Shannon, M. L. et al. Mice Expressing Myc in Neural Precursors Develop Choroid Plexus and Ciliary Body Tumors. Am. J. Pathol. 188, 1334–1344 (2018)

The impact of multi-agent chemotherapy in metastatic pancreatic adenocarcinoma: A population-based study utilizing the SEER database.

416 Background: Over the last decade, various landmark trials have demonstrated the impact of multi-agent chemotherapy in the treatment of PDAC. However, the impact in the ‘real world’ has been less clear. The ACCORD trial (2011) was a phase III trial comparing combination chemotherapy (FOLFIRINOX) and single agent (gemcitabine) for advanced disease. The MPACT trial introduced another beneficial regimen (nab-paclitaxel and gemcitabine) in 2013. Subsequently, multi-agent chemotherapy became standard of care for medically appropriate patients. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with PDAC between 1998 and 2017. The cohort was divided into two groups: 1998-2011 (pre-ACCORD) and 2012-2017 (post-ACCORD). We analyzed all patients with metastatic PDAC for overall survival and compared results in the two groups using Kaplan Meier analysis and multivariate Cox proportional hazards models. An interrupted time series analysis was also used to compare the temporal trends in 2-year survival between 1998 and 2017. Results: A total of 47,134 patients were diagnosed with PDAC between 1998 and 2017. Nearly two-third of patients (26,438; 57%) had distant disease. On univariate survival analysis, there was a significant increased overall survival probability in the 2012-17 group compared to the 1998-2011 group (p&lt;0.05). The one- and two-year survival rates were 11% and 3% in the pre-ACCORD period compared to 14% and 4 % after the ACCORD trial respectively. This difference remained significant on multivariate analysis while adjusting for covariates (HR=0.08, 0.78-0.92, p=0.05). On interrupted time series analysis, we observed a steady rise in 2- year survival between 1998 and 2017. There was a significant jump in the two-year survival probability from 16% at 2011 to 20% at 2012 in metastatic PDAC (β=0.02, 0.009-0.03, p&lt;0.0001, Table). Conclusions: Beyond the randomized clinical trial arena, overall survival has increased over time, with a statistically significant jump around the time of the ACCORD trial. However, the absolute increase in the ‘real world’ is smaller than the gains observed in prospective clinical trials. [Table: see text]

PD-1 Systematic review and meta-analysis of the efficacy of chemotherapeutic regimens in advanced gallbladder cancer: Assessing current practice and treatment benefit

Biliary tract cancers (BTC) are a heterogeneous group of malignancies, including gallbladder cancer (GBC). Treatment for GBC is based on studies recruiting patients with all BTC primary sites rather than GBC alone. GBC represents a different molecular entity to other BTCs, which may impact the response to treatment. The benefit of chemotherapeutic regimens specifically for the treatment of patients with GBC, including the current standard first- and second-line regimens for BTC, is poorly understood. This study explored the benefit derived from palliative cytotoxic chemotherapeutic regimens in GBC. A systematic review and meta-analysis were designed and registered with the PROSPERO database prior to commencement (CRD42019155745). A systematic search was conducted on MEDLINE; key bibliographies were reviewed and selected annual conferences were used to identify articles. Eligible studies reported data on patients with advanced GBC treated with systemic chemotherapeutic regimens. Phase II and III trials, case series, and cohort studies were eligible; phase I studies and small cohorts (< 10 in the first line, < 5 in second/third line) were excluded. Data were pooled using random effects models. 3,035 studies were identified; 58 studies with 66 study arms (n= 1,986 patients with GBC) were eligible for meta-analysis. In patients with GBC, estimated pooled radiological overall response rates (ORR), mean progression-free survival (PFS) and overall survival (OS) were 23.2% [95% confidence interval (CI), 20.0-26.5], 4.8 months (95% CI, 4.3-5.2) and 8.3 months (95% CI, 7.6-8.9), respectively. In patients with GBC, the use of ≥3 chemotherapy agents in combination was associated with increased ORR [35.8% (95% CI, 25.4-46.8)], mean PFS [5.9 months (95% CI 5.2-6.7)] and OS [9.9 months (95% CI, 8.5-11.3). There was a significant improvement in ORR, disease-free survival (DFS), mean PFS and OS with increasing numbers of chemotherapeutic agents (all spearman rho coefficients=1; P< 0.001). Patients with GBC had a lower ORR than non-GBC BTC [odds ratio (OR) 0.65 (95% CI, 0.50-0.84)]; specifically, patients with GBC have lower ORR when compared with the individual subgroups of BTC: cholangiocarcinoma (not otherwise specified) [OR 0.63 (95% CI, 0.48-0.83)], intrahepatic cholangiocarcinoma [OR 0.51 (95% CI 0.32-0.83)] and extrahepatic cholangiocarcinoma [OR 0.64 (95% CI, 0.40-1.00)]. Patients with GBC respond differently to systemic therapy compared with other BTC primary sites; they achieve lower ORR. In GBC, increasing numbers of chemotherapy agents are associated with better outcomes. Although differences may be due to selection bias, intensification of chemotherapy in fitter patients may be investigated either in a GBC-specific trial or (with a planned statistical and reporting approach) within a large randomised BTC trial.

The role of chemotherapy in treatment of advanced breast cancer: an overview for clinical practice

This review aims to evaluate the role of chemotherapy-containing regimens in the treatment of advanced breast cancer (ABC), with the purpose to optimize selection, sequencing and duration of treatment with the currently available agents for clinical practice. Data from observational as well as randomized phase II and III studies were included. Chemotherapy yielded a median overall survival (OS) of 2 years in registration studies, with comparable efficacy of different agents. Combining chemotherapy agents did not yield OS improvement and caused greater toxicity compared with single-agent chemotherapy. Continuing chemotherapy till progression or unacceptable toxicity generated greater efficacy without detrimental impact on quality of life compared with a limited amount of cycles. In real-world studies, benefits after third-line chemotherapy were modest compared with first- and second-line. Furthermore, effects of previous chemotherapy predicted effects of next-line therapy in real-world. Physicians increasingly prescribed capecitabine or taxanes as first- or second-line chemotherapy over time.

Real-world treatment patterns among metastatic breast cancer patients by BRCA status and phenotype.

e13046 Background: BRCA1/2 mutations account for 5-10% of breast cancer (BC) patients. BRCA1 mutations are associated with aggressive tumors, often triple negative (TNBC) (HER2, estrogen-receptor [ER], progesterone-receptor [PR] negative) and are mainly treated with combination chemotherapy or platinum agents. This study aimed to compare real world treatment patterns in breast cancer patients who were BRCA-mutation positive (BRCA+) and those who were BRCA-mutation negative (BRCA-), focusing on hormone-receptor positive (HR+) and TNBC subgroups. Methods: Optum’s Humedica electronic health records (EHR) database was used to identify a cohort of women with 1) confirmed BC ICD-9/ICD-10 diagnosis between 2008 and 2018, 2) at least 12 months of history in EHR, 3) at least one distant metastasis diagnosis (per ICD-9/ICD-10 or physician notes), and 4) no previous diagnosis of other primary cancers in previous 12 months. HR and HER2 test results were used to create relevant subgroups. Distinct lines of therapy (LOT) in the post-metastatic period were established using business rules. Treatment patterns and duration of treatment were analyzed. Results: Among 65,934 metastatic BC patients identified, 7941 were BRCA+, of whom 5366 (68%) were HR+ and 1323 (17%) had TNBC phenotype, while 4027 were BRCA-, of whom 2859 (71%) were HR+ and 561 (14%) had TNBC phenotype. Seventy-one percent of BRCA+ women underwent drug treatment, compared to 65% of BRCA- women. Drug treatments included hormonal treatment (+/-other agents), targeted therapy, and chemotherapy only, and varied across the different cohorts (Table). Mean (median) duration of treatment in LOT1 in the BRCA+ and BRCA- cohorts was 117 (73) and 117 (72) days, respectively. Conclusions: Real-world evidence on treatment patterns in BC patients revealed substantial differences across important biomarker and hormonal status BC phenotypes. As a preponderance of women with TNBC are still being treated exclusively with chemotherapy, these data highlight how the need for development of effective treatment options for TNBC remains high. [Table: see text]

Development of Ethanolic Extract of Pinang Masak Jambi (Areca Catechu L.) as A Modulator of Doxorubicin Cytotoxic Effect in Breast Cancer Therapy

Doxorubicin is one of the chemotherapy agents that is often used in breast cancer therapy. Phenomenon of breast cancer cell resistance to chemotherapy agents has been traced to the molecular level. The development of compounds that can overcome drug resistance chemotherapy needs to be continuously developed, especially agents with specific molecular targets, namely P-glycoprotein (Pgp), NFkB, cyclin, and cyclin-dependent kinase (CDK). Another alternative is the combination of chemotherapy agents with chemopreventive agents (co-chemotherapy) to reduce side effects and increase sensitivity of cancer cells. Doxorubicin is often used in breast cancer therapy. This study was performed to determine the effect of ethanolic extract of Pinang Masak Jambi (Areca catechu L.) (EEPMJ) and doxorubicin combination on MCF-7 breast cancer cells. Cytotoxic assay of EEPMJ and doxorubicin, alone, or in combination, was done using MTT test method to determine the IC50 and CI (Combination Index) values. The results indicated that EEPMJ and doxorubicin had IC50 values of 75.1 μg/ml and 22 μg/ml, respectively. Based on CI values, all combination concentration showed varying CI values. The concentration of 1/8 IC50 of EEPMJ with 1/2, 1/4, and 1/8 IC50 of doxorubicin showed a strong synergistic effect (CI 0.1 - 0.3), with the inhibition of cell viability up to 67.39%. This synergistic effect occurs because EEPMJ potentially could increases the cytotoxicity of doxorubicin.

Development and Validation of HPLC and HPTLC Methods for Therapeutic Drug Monitoring of Capecitabine in Colorectal Cancer Patients.

Capecitabine is a prodrug of 5-fluorouracil, employed as a monotherapy or combination chemotherapy agent for treatment of colorectal cancer. Combination therapy of capecitabine consists of oxaliplatin, and hence, it becomes essential to determine that co-administration does not affect its metabolism. High-performance liquid chromatography and high-performance thin-layer chromatography methods were developed and validated to determine the plasma concentration of capecitabine. In this study, blood samples from 12 patients with colorectal cancer were collected and analyzed by both methods with a reference internal standard. Two groups consisting of six patients each were formed: the first group was treated with capecitabine monotherapy, the second group with capecitabine + oxaliplatin combination therapy. The results of analysis from both the methods indicated that there is no significant drug-drug interaction. The co-administration of oxaliplatin did not affect the metabolism of capecitabine. Both assay methods were compared for their sensitivity, robustness and specificity. It was found that both the assay methods were suitable for therapeutic drug monitoring of capecitabine.

How does chemotherapy treatment damage the prepubertal testis?

Chemotherapy treatment is a mainstay of anticancer regimens, significantly contributing to the recent increase in childhood cancer survival rates. Conventional cancer therapy targets not only malignant but also healthy cells resulting in side effects including infertility. For prepubertal boys, there are currently no fertility preservation strategies in use, although several potential methods are under investigation. Most of the current knowledge in relation to prepubertal gonadotoxicity has been deduced from adult studies; however, the prepubertal testis is relatively quiescent in comparison to the adult. This review provides an overview of research to date in humans and animals describing chemotherapy-induced prepubertal gonadotoxicity, focusing on direct gonadal damage. Testicular damage is dependent upon the agent, dosage, administration schedule and age/pubertal status at time of treatment. The chemotherapy agents investigated so far target the germ cell population activating apoptotic pathways and may also impair Sertoli cell function. Due to use of combined chemotherapy agents for patients, the impact of individual drugs is hard to define, however, use of in vivo and in vitro animal models can overcome this problem. Furthering our understanding of how chemotherapy agents target the prepubertal testis will provide clarity to patients on the gonadotoxicity of different drugs and aid in the development of cytoprotective agents.