Chemotherapy For Solid Tumors Research Articles

Recovery of lymphocyte subpopulations is incomplete in the long-term setting in pediatric solid tumor survivors.

Childhood cancer survivors (CCSs) may have comorbidities including a long-term abnormality in the immune system. Immune reconstitution in CCSs after treatment for acute leukemia has been reported previously, while analyses of immune reconstitution in CCSs with solid tumors have been limited. Childhood cancer survivors who received chemotherapy for solid tumors and who visited University of Tsukuba Hospital between November 2019 and March 2021 were included the study. Peripheral blood was collected for flow cytometry analysis. Forty-nine samples from 35 CCSs (18 male, 17 female) were included in the study. High-dose chemotherapy and cerebral spinal irradiation were conducted in 14 CCSs (40%) and in five CCSs (14%), respectively. The median time between the completion of chemotherapy and the collection of the present samples was 15.0 months (range, 0-286 months). The total lymphocyte count, B cells, and CD8-positive T cells recovered to the normal range of controls (NR-CTLs) in 0 (0%), four (66.7%), and four (66.7%) of six samples at 0-3 months after the completion of chemotherapy, and in three (60%), four (80%), and three (60%) of five samples at 3-12 months after the completion of chemotherapy, respectively. Meanwhile, CD4-positive T cells remained lower than NR-CTLs in 0 (0%) of six samples, one (20%) of five samples, and seven (63.7%) of 11 samples at 0-3, 3-12 and 12-60 months after the completion of chemotherapy, respectively. Recovery to the NR-CTLs was rapidly achieved in B cells and CD8-positive T cells, while the recovery was slower and incomplete in CD4-positive T cells. Careful observation of infection in long-term follow-up clinics is needed.

Erythrocyte Membrane Camouflaged Metal–Organic Framework Nanodrugs for Remodeled Tumor Microenvironment and Enhanced Tumor Chemotherapy

AbstractThe abundant extracellular matrix (ECM) in solid tumors causes limited drug penetration and hypoxia‐mediated chemoresistance, which lead to poor chemotherapy outcomes. To solve this problem, a biomimetic metal–organic framework nanodrug (ZIF‐8‐DOX‐LY‐RM) is developed with red blood cell membrane (RM) camouflage and encapsulation of type 1 transforming growth factor β receptor (TGFBR1) inhibitor and doxorubicin (DOX) for efficient chemotherapy. Based on the biomimetic properties of the erythrocyte membrane, ZIF‐8‐DOX‐LY‐RM can effectively accumulate in tumor tissues with immune escape and prolonged blood circulation. Then, the enriched nanodrug ZIF‐8‐DOX‐LY‐RM releases the TGFBR1 to remove collagen, subsequently leading to enhanced nanodrug penetration and increased oxygen supply. The abundant oxygen supply then relieves hypoxia‐mediated chemoresistance of DOX through increased cellular uptake and elevated reactive oxygen species production. The in vivo studies demonstrate the outstanding performance of ZIF‐8‐DOX‐LY‐RM nanoparticles in chemotherapy of cancer. This work presents an ECM normalization strategy for the synergistic collagen depletion and hypoxia alleviation and opens a promising avenue for effective chemotherapy of solid tumors.

Analysis of Secondary Leukemia and Myelodysplastic Syndrome After Chemotherapy for Solid Organ Tumors Using the Food and Drug Administration Adverse Event Reporting System (FAERS)

Purpose: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers. Methods: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used. Results: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy. Conclusions: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

Laser Therapy as a Preventive Approach for Oral Mucositis in Cancer Patients Undergoing Chemotherapy: The Potential Role of Superoxide Dismutase.

Purpose:Oral mucositis is a painful condition that occurs in patients who undergo chemotherapy. Due to the worsening of oral mucositis, the patient may progress to a worse clinical condition and interrupt antineoplastic treatment. There is little literature on low-power laser therapy in chemotherapy for other solid tumors. The purpose of this study was to investigate whether low-level laser therapy (LLLT) applied before chemotherapy could prevent oral mucositis in patients with solid tumors. Methods:Laser therapy was applied at a frequency of 630nm, with a dose of 2J / cm2, for the prevention of oral mucositis induced by chemotherapy specifically for non-hematological tumors. Epidemiological data, total neutrophils, general side effects, development of oral mucositis and degree, and the performance of low-power laser therapy to prevent oral mucositis were collected. The involvement of oxidative stress was evaluated by the enzyme superoxide dismutase (SOD) through blood samples, before and after chemotherapy treatments. Results:LLLT in the proposed protocol is efficient in reducing the development of oral mucositis (only at grade I/II) in patients under chemotherapy and able to reduce the severity of oral mucosal lesions, in patients who developed mucositis after the use of the laser for prevention. All individuals who underwent LLLT protocol did not show a significant reduction of SOD activity after the last chemotherapy cycle. Conclusions:The prophylactic laser therapy protocol proposed by the study, defined at a frequency of 630nm, a dose of 2J / cm2, demonstrated the ability to decrease the occurrence of oral mucositis in patients undergoing chemotherapy protocols to solid tumors. This effect could be related to preserved SOD activity, as it was observed that oral mucositis is related to leukopenia and reduced SOD activity and LLLT protocol prevented the decrease of SOD activity.

Cryptosporidium spp. during chemotherapy: a cross-sectional study of 94 patients with malignant solid tumor.

BACKGROUND: Cryptosporidium spp. is a protozoan parasite that infects many vertebrate animals, including humans. Since Cryptosporidium spp. can cause chronic life-threatening diarrhea and severe malabsorption in immunocompromised patients, we investigated the prevalence of this parasite among patients undergoing chemotherapy for malignant solid tumors.OBJECTIVE: Investigate the prevalence of Cryptosporidium spp. in stool samples.DESIGN: Cross-sectional.SETTING: Tertiary care.PATIENTS AND METHODS: Stool samples were collected from adult patients with malignant solid tumors receiving chemotherapy and diarrhea. Cryptosporidium spp. prevalence was determined using Ziehl–Neelsen staining, ELISA, and real-time PCR targeting of the COWP gene.MAIN OUTCOME MEASURE: The prevalence of Cryptosporidium spp. in patients undergoing chemotherapy for malignant solid tumors.SAMPLE SIZE: 94RESULTS: The prevalence was 2.1% (2/94), 5.3% (5/94), and 5.3% (5/94) as detected by Ziehl–Neelsen staining, real-time PCR and ELISA, respectively. The prevalence reached 8.5% (8/94) using all results obtained from the three methods. Among eight positive stool samples, four were positive by at least two different methods (Ziehl–Neelsen staining-ELISA or ELISA-real-time PCR) whereas the remaining four were positive by either ELISA or real-time PCR.CONCLUSION: These findings show the risk of cryptosporidiosis in cancer patients and the necessity to use at least two diagnostic methods during the diagnosis of cryptosporidiosis to reach more accurate and trustworthy results.LIMITATIONS: Further studies with a larger sample size are recommended.CONFLICT OF INTEREST: None.

LBA8 Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors

Patients with cancer have an increased risk of complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Vaccination is recommended, but the impact of chemotherapy and immunotherapy on immunogenicity and safety is still unclear.

The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application

Chemotherapy for human solid tumors in clinical practice is far from satisfactory. Despite the discovery and synthesis of hundreds of thousands of anticancer compounds targeting various crucial units in cancer cell proliferation and metabolism, the fundamental problem is the lack of targeting delivery of these compounds selectively into solid tumor tissue to maintain an effective concentration level for a certain length of time for drug-tumor interaction to execute anticancer activities. The enhanced permeability and retention effect (EPR effect) describes a universal pathophysiological phenomenon and mechanism in which macromolecular compounds such as albumin and other polymer-conjugated drugs beyond certain sizes (above 40 kDa) can progressively accumulate in the tumor vascularized area and thus achieve targeting delivery and retention of anticancer compounds into solid tumor tissue. Targeting therapy via the EPR effect in clinical practice is not always successful since the strength of the EPR effect varies depending on the type and location of tumors, status of blood perfusion in tumors, and the physical-chemical properties of macromolecular anticancer agents. This review highlights the significance of the concept and mechanism of the EPR effect and discusses methods for better utilizing the EPR effect in developing smarter macromolecular nanomedicine to achieve a satisfactory outcome in clinical applications.

Prognostic value of platelet-to-lymphocyte ratio in neoadjuvant chemotherapy for solid tumors: A PRISMA-compliant meta-analysis.

Introduction:Previous research indicates that the platelet-to-lymphocyte ratio (PLR) may be an indicator of poor prognosis in many tumor types. However, the PLR is rarely described in patients undergoing neoadjuvant chemotherapy (NAC) for solid tumors. Thus, we performed a meta-analysis to investigate the prognostic value of this ratio for patients with solid tumors treated by NAC.Methods:A comprehensive search of the literature was conducted using the PubMed, EMBASE, Cochrane Library, and Web of Science databases, followed by a manual search of references from the retrieved articles. Pooled hazard ratios (HRs) with 95% confidence interval (CIs) were used to evaluate the association between PLR and 3 outcomes, namely, overall survival, disease-free survival, and pathological complete response rate after NAC.Results:Eighteen studies published no earlier than 2014 were included in our study. A lower PLR was associated with better overall survival (HR = 1.46, 95% CI, 1.11–1.92) and favorable disease-free survival (HR = 1.81, 95% CI, 1.27–2.59). A PLR that was higher than a certain cutoff was associated with a lower pathological complete response rate in patients with cancer who received NAC (Odds ratio = 1.93, 95% CI, 1.40–2.87).Conclusion:Elevated PLR is associated with poor prognosis in various solid tumors. PLR may be a useful biomarker in delineating those patients with poorer prognoses who may benefit from neoadjuvant therapies.

Risk factors for dysgeusia during chemotherapy for solid tumors: a retrospective cross-sectional study.

This study retrospectively analyzed the risk factors for transchemotherapy dysgeusia. Before each chemotherapy cycle, patients were routinely evaluated for the presence/severity of dysgeusia based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale for adverse effects and graded as follows: 0, no change in taste; 1, altered taste with no impact on eating habits; or 2, altered taste with an impact on eating habits. Information from 2 years of evaluations was collected and patient medical records were reviewed to obtain data on chemotherapy cycle, sex, age, body mass index, body surface area, primary tumor, chemotherapy protocol, and history of head and neck radiotherapy. The X2 test and multinomial logistic regression were used for statistical analysis (SPSS 20.0, p < 0.05). Among 7425 total patients, 3047, 2447, and 1931 were evaluated after the first, second, and third chemotherapy cycles, respectively. One-fifth of the patients (19.0%) presented a significant loss of taste, with 1118 (15.0%) showing grade 1 dysgeusia and 442 (6.0%) showing grade 2 dysgeusia. The chemotherapy duration (p < 0.001), female sex (p < 0.001), location of the primary tumor in the uterus (p = 0.008), head and neck (p = 0.012), and testicles (p = 0.011), and use of ifosfamide (p = 0.009), docetaxel (p = 0.001), paclitaxel (p < 0.001), pertuzumab (p = 0.005), bevacizumab (p < 0.001), and dacarbazine (p = 0.002) independently increased the risk of dysgeusia. In head and neck tumors, a previous history of radiotherapy significantly increased the prevalence of dysgeusia (p = 0.017), and the use of cisplatin (p = 0.001) increased this prevalence. Cycles of chemotherapy, sex, uterine cancer, head and neck tumors, testicular cancer, ifosfamide, docetaxel, paclitaxel, pertuzumab, bevacizumab, and dacarbazine increase the risk of dysgeusia.

Abstract CT211: Personalized, rational, efficacy-driven chemotherapy dosing via an artificial intelligence system (PRECISE): A protocol for the PRECISE CURATE.AI pilot clinical trial

Abstract Background: Faced with a trade-off between efficacy and toxicity, oncologists have conventionally administered the maximum tolerated doses in chemotherapy on an assumption that higher doses increase efficacy. However, multiple studies have shown that this method of toxicity-guided dosing may result in more frequent toxicities and potentially suboptimal efficacy. With the advent of artificial intelligence (AI), personalized dosing in chemotherapy may be considered to optimize patient care. CURATE.AI is an efficacy-driven, indication-agnostic and mechanism-independent personalized dosing platform that may offer an optimal solution. In contrast to traditional AI approaches based on massive volumes of population data, CURATE.AI requires only the individual patient's medical profile for dose recommendations. Based on the observation that the relationship between a drug dose and a phenotypic response in a human system can be modelled by a dynamic quadratic surface, CURATE.AI continually guides dosing throughout the treatment duration to optimize efficacy. While CURATE.AI has been used in various clinical settings, there are no prior randomized controlled trials (RCTs) on CURATE.AI-guided chemotherapy dosing for solid tumors. Therefore, we are conducting a pilot study to assess the technical and logistical feasibility of an RCT for CURATE.AI-guided solid tumor chemotherapy dosing. We aim to collect exploratory data on efficacy and toxicity, and on the use of longitudinal blood tumor marker measurements, including ctDNA, to inform dose guidance decision. Methods: PRECISE is an open-label, single-arm, multi-centre, prospective pilot clinical trial on using CURATE.AI to achieve personalized, efficacy-driven and dynamically optimized chemotherapy dosing for solid tumors (NCT04522284). Adults with metastatic solid tumors and raised baseline tumor marker levels who are planned for palliative-intent, capecitabine-based chemotherapy will be recruited. CURATE.AI will guide drug dosing for each participant based only on their own tumor marker levels and drug doses as input data. The primary outcome is the proportion of participants in whom CURATE.AI is successfully applied. Secondary outcomes include the timeliness of dose recommendations, participant and physician adherence to CURATE.AI-recommended doses, and the proportion of clinically significant dose changes. As an exploratory outcome, we will analyze the utility of tumor markers including CEA, CA19-9 and ctDNA in high frequency serial measurements. We aim to initially enroll 10 participants from 2 hospitals in Singapore, perform an interim analysis, and consider either cohort expansion or a RCT based on initial pilot data. Recruitment of patients began in August 2020. As of December 2020, 2 participants have been enrolled with recruitment planned for 1 year. Citation Format: Chong Boon Teo, Benjamin Kye Jyn Tan, Xavier Tadeo, Siyu Peng, Hazel Pei Lin Soh, Sherry De Xuan Du, Vilianty Wen Ya Luo, Aishwarya Bandla, Raghav Sundar, Dean Ho, Theodore Kee, Agata Blasiak. Personalized, rational, efficacy-driven chemotherapy dosing via an artificial intelligence system (PRECISE): A protocol for the PRECISE CURATE.AI pilot clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT211.

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

A Systematic Literature Review of Overall Survival and Delivered Dose Intensity in Cancer Patients Receiving Chemotherapy and G-CSF in Randomized Control Trials

IntroductionAdvances in cancer diagnosis, treatment and supportive care have contributed to improvements in overall survival (OS) in recent decades. Granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenic complications associated with chemotherapy. G-CSF support may improve disease control and survival by minimizing dose reductions and treatment delays as well as enabling administration of dose-dense regimens, dose escalation and additional chemotherapeutic agents when indicated. With the introduction of biosimilar G-CSFs, the impact of G-CSF on OS reported in recent randomized clinical trials is of considerable interest. We undertook an updatedsystematic literature review to determine the impact of G-CSFon delivered dose intensity and OS in cancer patients receiving chemotherapy for solid tumors or malignant lymphoma.MethodsFollowing our previous review (Lyman G et al, Ann Oncol 2013;24:2475-84), relevant publications between September 1, 2012 and March 20, 2017 were identified according to best-practice principles and reported in compliance with PRISMA requirements. Randomized, controlled trials comparing primary G-CSF support vs no initial G-CSF and reporting survival measures or occurrence of secondary tumors including acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) with a minimum follow-up of 24 months were identified. Following the initial treatment cycle, control subjects may have received no G-CSFs, G-CSFs at the discretion of the treating physician, or secondary use of G-CSFs. Exclusion criteria included non-random assignment to the treatment group; G-CSF administered from the start in all study arms; use of granulocyte macrophage colony-stimulating factor; patients receiving stem cell or bone marrow transplantation, or a prior diagnosis of leukemia of any type.Full electronic search was undertaken of of Embase, Medline In-Process and Cochrane libraries. No language restrictions were imposed on the literature search. Abstracts of papers initially identified were evaluated independently by two investigators for eligibility using specified inclusion/exclusion criteria. All potentially relevant papers were evaluated in detail. Bibliographies of all identified relevant studies were used to perform a recursive search. Full papers were assessed independently by two investigators according to the predefined eligibility criteria. Any disagreement between investigators was resolved by discussion.A meta-analysis was conducted to estimate the relative risk (RR) and risk difference for OS between patients who did or did not receive primary G-CSF support. As previously reported, four prospectively-defined study designs reflecting differing dosing schedules were evaluated for impact of primary G-CSF support.Statistical software R was utilized for these analyses.ResultsA total of2604 publications were identified. After removing duplicate reports and further screening, 14 recent studies met the inclusion criteria. Nine studies reported OS and 2 reported incidence of AML/MDS. Sample sizes ranged from 85 to 2091 patients with solid tumors or lymphoma at various stages.The updated meta-analysis showed that OS was significantly improved in patients receiving primary G-CSF vs patients who did not (relative risk [RR] of death during follow-up = 0.92; 95% confidence intervals [CI]: 0.90, 0.95; p<0.0001) [Table]. Study design groups 2, 3 and 4 also had significant RRs favoring G-CSF (see table). Based on the reported and extracted data, it was not possible to make any conclusions regarding OS differences between originator and biosimilar G-CSF formulations.Of the 2 studies evaluating AML/MDS, 1 reported no cases during follow-up in either arm and the other reported 9 occurrences in the G-CSF arm and 2 in the control arm: RR = 1.85; 95% CI: 1.19, 2.88; p=0.0064.ConclusionsResults of this systematic literature review and meta-analysis confirm a modest but statistically significant increase in OS in patients undergoing chemotherapy with primary G-CSF support for solid tumors and lymphoma. [Display omitted] DisclosuresYau:Hexal: Employment. Nakov:Hexal: Employment. Krendyukov:Hexal: Employment.

Genome-Wide Analysis Reveals Hypoxic Microenvironment Is Associated With Immunosuppression in Poor Survival of Stage II/III Colorectal Cancer Patients.

Background: Hypoxia is associated with a poorer clinical outcome and resistance to chemotherapy in solid tumors; identifying hypoxic-related colorectal cancer (CRC) and revealing its mechanism are important. The aim of this study was to assess hypoxia signature for predicting prognosis and analyze relevant mechanism.Methods: Patients without chemotherapy were selected for the identification of hypoxia-related genes (HRGs). A total of six independent datasets that included 1,877 CRC patients were divided into a training cohort and two validation cohorts. Functional annotation and analysis were performed to reveal relevant mechanism.Results: A 12-gene signature was derived, which was prognostic for stage II/III CRC patients in two validation cohorts [TCGA, n = 509, hazard ratio (HR) = 2.14, 95% confidence interval (CI) = 1.18 – 3.89, P = 0.01; metavalidation, n = 590, HR = 2.46, 95% CI = 1.59 – 3.81, P < 0.001]. High hypoxic risk was correlated with worse prognosis in CRC patients without adjuvant chemotherapy (HR = 5.1, 95% CI = 2.51 – 10.35, P < 0.001). After integration with clinical characteristics, hypoxia-related gene signature (HRGS) remained as an independent prognostic factor in multivariate analysis. Furthermore, enrichment analysis found that antitumor immune response was suppressed in the high hypoxic group.Conclusions: HRGS is a promising system for estimating disease-free survival of stage II/III CRC patients. Hypoxia tumor microenvironment may be via inhibiting immune response to promote chemoresistance in stage II/III CRC patients.

Personalised, Rational, Efficacy-Driven Cancer Drug Dosing via an Artificial Intelligence SystEm (PRECISE): A Protocol for the PRECISE CURATE.AI Pilot Clinical Trial.

Introduction: Oncologists have traditionally administered the maximum tolerated doses of drugs in chemotherapy. However, these toxicity-guided doses may lead to suboptimal efficacy. CURATE.AI is an indication-agnostic, mechanism-independent and efficacy-driven personalised dosing platform that may offer a more optimal solution. While CURATE.AI has already been applied in a variety of clinical settings, there are no prior randomised controlled trials (RCTs) on CURATE.AI-guided chemotherapy dosing for solid tumours. Therefore, we aim to assess the technical and logistical feasibility of a future RCT for CURATE.AI-guided solid tumour chemotherapy dosing. We will also collect exploratory data on efficacy and toxicity, which will inform RCT power calculations.Methods and analysis: This is an open-label, single-arm, two-centre, prospective pilot clinical trial, recruiting adults with metastatic solid tumours and raised baseline tumour marker levels who are planned for palliative-intent, capecitabine-based chemotherapy. As CURATE.AI is a small data platform, it will guide drug dosing for each participant based only on their own tumour marker levels and drug doses as input data. The primary outcome is the proportion of participants in whom CURATE.AI is successfully applied to provide efficacy-driven personalised dosing, as judged based on predefined considerations. Secondary outcomes include the timeliness of dose recommendations, participant and physician adherence to CURATE.AI-recommended doses, and the proportion of clinically significant dose changes. We aim to initially enrol 10 participants from two hospitals in Singapore, perform an interim analysis, and consider either cohort expansion or an RCT. Recruitment began in August 2020. This pilot clinical trial will provide key data for a future RCT of CURATE.AI-guided personalised dosing for precision oncology.Ethics and dissemination: The National Healthcare Group (NHG) Domain Specific Review Board has granted ethical approval for this study (DSRB 2020/00334). We will distribute our findings at scientific conferences and publish them in peer-reviewed journals.Trial registration number: NCT04522284

Honoring Emil J. Freireich: A Visionary Medical Cancer Researcher-March 21, 1927-February 1, 2021.

![][1] Dr. Emil Freireich at MD Anderson in 2018, in conversation with Lauren Gobert, a leukemia physician assistant who had childhood acute lymphoblastic leukemia cured by combination therapy developed as a result of Dr. Freireich's research. Emil J, Freireich, a founding father of

Evaluation of TFR-1 Expression in Feline Mammary Cancer and In Vitro Antitumor Efficacy Study of Doxorubicin-Loaded H-Ferritin Nanocages.

Simple SummaryTransferrin receptor one (TFR-1), recognized by ferritin, is overexpressed in many tumor cells. This feature has been exploited to produce a selective overload of drugs within tumor cells by creating an engineered ferritin nanocage loaded with doxorubicin (HFn(DOX)). This bionanotechnology has been tested in human cancer, but there are no studies in veterinary oncology. This work, after evaluating the expression of TFR-1 in feline tumors, demonstrated for the first time the effectiveness in vitro of this nanocage in animals. These results confirm that engineered bionanocages also offer unprecedented opportunities for animal cancer to be applied in veterinary medicine and in comparative studies including spontaneous animal models of cancer.The transferrin receptor 1 (TFR-1) has been found overexpressed in a broad range of solid tumors in humans and is, therefore, attracting great interest in clinical oncology for innovative targeted therapies, including nanomedicine. TFR-1 is recognized by H-Ferritin (HFn) and has been exploited to allow selective binding and drug internalization, applying an HFn nanocage loaded with doxorubicin (HFn(DOX)). In veterinary medicine, the role of TFR-1 in animal cancers remains poorly explored, and no attempts to use TFR-1 as a target for drug delivery have been conducted so far. In this study, we determined the TFR-1 expression both in feline mammary carcinomas during tumor progression, as compared to healthy tissue, and, in vitro, in a feline metastatic mammary cancer cell line. The efficacy of HFn(DOX) was compared to treatment with conventional doxorubicin in feline mammary cancer cells. Our results highlighted an increased TFR-1 expression associated with tumor metastatic progression, indicating a more aggressive behavior. Furthermore, it was demonstrated that the use of HFn(DOX) resulted in less proliferation of cells and increased apoptosis when compared to the drug alone. The results of this preliminary study suggest that the use of engineered bionanocages also offers unprecedented opportunities for selective targeted chemotherapy of solid tumors in veterinary medicine.

Neoadjuvant Chemotherapy Induces IL34 Signaling and Promotes Chemoresistance via Tumor-Associated Macrophage Polarization in Esophageal Squamous Cell Carcinoma.

The tumor microenvironment (TME) plays a key role in the efficacy of neoadjuvant chemotherapy (NAC) in solid tumors including esophageal squamous cell carcinoma (ESCC). However, the TME profile of ESCC treated with NAC is not fully understood. In this study, we investigated the effect of NAC on the TME especially tumor-associated macrophages (TAM), the important immunosuppressive components of the TME, in ESCC. We quantified the expression of CD163, a crucial marker of TAM, in pretherapeutic biopsy and surgically resected ESCC specimens from patients who received NAC (n = 33) or did not receive NAC (n = 12). We found that NAC dramatically increased the expression of CD163 on TAMs in ESCC. Colony-stimulating factor 1 (CSF-1) and IL34 are crucial cytokines that recruit monocytes into tumor sites and differentiate them into TAMs. Interestingly, NAC significantly upregulated the expression of IL34 but not CSF-1 on tumor cells, and the frequencies of CD163+ TAMs were significantly correlated with IL34 expression in ESCC after NAC. The expression of IL34 in NAC-nonresponsive patients was significantly higher than that in NAC-responsive patients, and patients with IL34-high ESCC exhibited worse prognosis as compared with patients with IL34-low ESCC. We also demonstrated that 5-fluorouracil (5-FU)/cisplatin preferentially increased mRNA expression of IL34 on human ESCC cell lines. Human peripheral blood monocytes co-cultured with ESCC cells treated with 5-FU/cisplatin increased the expression of CD163, which was attenuated by the treatment with CSF-1R inhibitors. These data suggest that IL34 expression by NAC shifts the TME toward CD163+ TAM-rich immunosuppressive and chemo-insensitive microenvironment in ESCC. IMPLICATIONS: The blockade of IL34 signaling may offer a novel therapeutic strategy against chemoresistance in ESCC by inhibiting M2-TAM polarization.

Galaxy and MEAN Stack to Create a User-Friendly Workflow for the Rational Optimization of Cancer Chemotherapy.

One aspect of personalized medicine is aiming at identifying specific targets for therapy considering the gene expression profile of each patient individually. The real-world implementation of this approach is better achieved by user-friendly bioinformatics systems for healthcare professionals. In this report, we present an online platform that endows users with an interface designed using MEAN stack supported by a Galaxy pipeline. This pipeline targets connection hubs in the subnetworks formed by the interactions between the proteins of genes that are up-regulated in tumors. This strategy has been proved to be suitable for the inhibition of tumor growth and metastasis in vitro. Therefore, Perl and Python scripts were enclosed in Galaxy for translating RNA-seq data into protein targets suitable for the chemotherapy of solid tumors. Consequently, we validated the process of target diagnosis by (i) reference to subnetwork entropy, (ii) the critical value of density probability of differential gene expression, and (iii) the inhibition of the most relevant targets according to TCGA and GDC data. Finally, the most relevant targets identified by the pipeline are stored in MongoDB and can be accessed through the aforementioned internet portal designed to be compatible with mobile or small devices through Angular libraries.

The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies.

ObjectivesTo estimate the risk of thrombocytopenia in various cancers and chemotherapy regimens.MethodsStructured patient‐level data from the Flatiron Health Electronic Health Record database were used to identify adult patients who received chemotherapy for a solid tumor or hematologic malignancy from 2012 to 2017. Three‐month cumulative incidence of thrombocytopenia was assessed based on platelet counts, overall and by grade of thrombocytopenia. Co‐occurrence of anemia, neutropenia, and leukopenia was evaluated.ResultsOf 15,521 patients with solid tumors, 13% had thrombocytopenia within 3 months (platelet count < 100 × 109/L); 4% had grade 3 (25 to < 50 × 109/L), and 2% grade 4 (<25 × 109/L) thrombocytopenia. Of 2537 patients with hematologic malignancies, 28% had any thrombocytopenia, 16% with grade 3, and 12% with grade 4. Among patients with thrombocytopenia, it occurred without another cytopenia in 18% of solid tumors and 7% of hematologic malignancies.ConclusionsIn a large, US‐representative sample of patients undergoing chemotherapy in clinical practice, thrombocytopenia incidence varied across tumor and regimen types. Despite recommendations to alter chemotherapy to avoid severe thrombocytopenia, 4% of patients with solid tumors and 16% with hematologic malignancies experienced grade 3 thrombocytopenia. Prediction and prevention of thrombocytopenia may help oncologists avoid dose modifications and their adverse effects on survival.

Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death

Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.