Chemotherapy For Solid Tumors Research Articles

Recombinant human thrombopoietin treatment in patients with chronic liver disease-related thrombocytopenia undergoing invasive procedures: A retrospective study.

Chronic liver disease (CLD) related thrombocytopenia increases the risk of bleeding and poor prognosis. Many liver disease patients require invasive procedures or surgeries, such as liver biopsy or endoscopic variceal ligation, and most of them have lower platelet counts, which could aggravate the risk of bleeding due to liver dysfunction and coagulation disorders. Unfortunately, there is no defined treatment modality for CLD-induced thrombocytopenia. Recombinant human thrombopoietin (rhTPO) is commonly used to treat primary immune thrombocytopenic purpura and thrombocytopenia caused by solid tumor chemotherapy; however, there are few reports on the use of rhTPO in the treatment of CLD-related thrombocytopenia. To evaluate the efficacy of rhTPO in the treatment of patients with CLD-associated thrombocytopenia undergoing invasive procedures. All analyses were based on the retrospective collection of clinical data of patients with CLD who were treated in the Department of Infectious Diseases at The First Affiliated Hospital of Soochow University between June 2020 and December 2021. Fifty-nine male and 41 female patients with liver disease were enrolled in this study to assess the changes in platelet counts and parameters before and after the use of rhTPO for thrombocytopenia. Adverse events related to treatment, such as bleeding, thrombosis, and disseminated intravascular coagulation, were also investigated. Among the enrolled patients, 78 (78%) showed a platelet count increase after rhTPO use, while 22 (22%) showed no significant change in platelet count. The mean platelet count after rhTPO treatment in all patients was 101.53 ± 81.81 × 109/L, which was significantly improved compared to that at baseline (42.88 ± 16.72 × 109/L), and this difference was statistically significant (P < 0.001). In addition, patients were further divided into three subgroups according to their baseline platelet counts (< 30 × 109/L, 30-50 × 109/L, > 50 × 109/L). Subgroup analyses showed that the median platelet counts after treatment were significantly higher (P < 0.001, all). Ninety (90%) patients did not require platelet transfusion partially due to an increase in platelet count after treatment with rhTPO. No serious adverse events related to rhTPO treatment were observed. Overall, rhTPO demonstrated good clinical efficacy for treating CLD-associated thrombocytopenia. rhTPO can improve platelet count, reduce the risk of bleeding, and decrease the platelet transfusion rate, which may promote the safety of invasive procedures and improve overall survival of patients with CLD.

492TiP A phase I study of synthetic lethal, IDE397 (MAT2A inhibitor) as a monotherapy and in combination with chemotherapy in advanced solid tumors harboring MTAP deletion

Methylthioadenosine phosphorylase (MTAP) deletion occurs in ∼15% of solid tumors in the setting of 9p21 loss and is associated with poor survival (Nature Communications; 2021; 12:5606; Han G). Loss of MTAP results in methylthioadenosine (MTA) accumulation and partial inhibition of protein arginine methyltransferase-5 (PRMT5). Inhibition of methionine adenosyltransferase-2a (MAT2A) results in reduction of s-adenosyl methionine (SAM), starving PRMT5 of its methylation substrate with resulting selective sensitivity of MTAP null cancer cells. IDE397 is a novel MAT2A inhibitor being evaluated in cancer patients harboring a tumor having MTAP deletion. IDE397 has superior cellular potency, selectivity, and drug properties, including lack of liver toxicity signals and high solubility, compared to the other MAT2A inhibitors under clinical investigation. In preclinical models, including patient derived xenografts, IDE397 has been shown to exploit the synthetic lethal relationship between MTAP deletion and MAT2A with broad activity and regressions of tumors with MTAP loss as a single agent and in combination with taxanes and other chemotherapy agents across multiple solid tumor indications. Preclinically, IDE397 shows robust pharmacodynamic modulation of SAM and symmetric dimethylarginine (SDMA). (IDEAYA Data). Study IDE397-001 (NCT04794699), is a phase I, muticenter, open-label study of IDE397 as a single agent in adult participants with advanced solid tumors harboring MTAP deletion. Additional escalation, expansion and combination arms with taxanes and other agents are planned across multiple indications (NSCLC, esophagogastric and other solid tumors). All participants will receive oral daily dosing of IDE397, as monotherapy or in combination with chemotherapy, until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Primary endpoints include safety and tolerability, RP2D determination, investigator-assessed tumor response by RECIST v1.1. Enrollment in the monotherapy dose escalation is ongoing with clearance of the first 5 dose levels without DLT. NCT04794699. IDEAYA Biosciences, Inc.

The Efficacy and Mechanism of Proteasome Inhibitors in Solid Tumor Treatment.

The ubiquitin-proteasome system (UPS) is critical in cellular protein degradation and widely involved in the regulations of cancer hallmarks. Targeting the UPS pathway has emerged as a promising novel treatment in hematological malignancies and solid tumors. This review mainly focuses on the preclinical results of proteasome inhibitors in solid tumors. We analyzed the published articles associated with the anticancer results of proteasome inhibitors alone or combination chemotherapy in solid tumors. Important data presented in abstract form were also discussed in this review. Proteasome inhibitors, such as bortezomib and carfilzomib, are highly effective in treating solid tumors. The anticancer efficacy is not limited to affect the proteasomal inhibition- associated signaling pathways but also widely involves the signaling pathways related to cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT). In addition, proteasome inhibitors overcome the conventional chemo-resistance of standard chemotherapeutics by inhibiting signaling pathways, such as NF-κB or PI3K/Akt. Combination chemotherapy of proteasome inhibitors and standard chemotherapeutics are widely investigated in multiple relapsed or chemo-resistant solid tumor types, such as breast cancer and pancreatic cancer. The proteasome inhibitors re-sensitize the standard chemotherapeutic regimens and induce synergistic anticancer effects. The development of novel proteasome inhibitors and delivery systems also improves the proteasome inhibitors' anticancer efficacy in solid tumors. This review summarizes the current preclinical results of proteasome inhibitors in solid tumors and reveals the potential anticancer mechanisms.

The Potential Contribution of Dental Foci and Oral Mucositis to Febrile Neutropenia in Patients Treated With Myelosuppressive Chemotherapy for Solid Tumors and Lymphoma.

IntroductionFebrile neutropenia (FN) is a potential life-threatening complication of myelosuppressive chemotherapy, particularly when induced by infection. There is evidence that FN can originate from the oral cavity, but its contribution to FN is largely understudied in patients treated for solid tumors. The aim of this study was to assess the prevalence of FN in these patients and to evaluate its relation with dental foci and oral mucositis.Material and MethodsA prospective longitudinal observational study was conducted. Patients diagnosed with solid tumors and lymphoma scheduled to be treated with myelosuppressive chemotherapy with an intermediate risk of developing FN were included. A pre-chemotherapy dental examination was performed and patients were followed during and after chemotherapy regimen. During subsequent hospital visits for chemotherapy administration, the oral cavity was inspected and oral mucositis (OM) was scored using the CTC-AE version 3.0. When patients presented with fever, a comprehensive full body examination including laboratory/microbiological/imaging investigation was performed.ResultsEighty-eight patients were included. Pre-chemotherapy, 39 patients (44.3%) were diagnosed with a dental focus. During chemotherapy, 46 patients developed OM (53.4%), of which 15 patients had a maximum score of grade II (ulcerative mucositis). Ten patients developed FN during the follow-up period. Patients with FN more often suffered from ulcerative OM compared to patients without FN; both FN and mucositis risk was associated with the myelotoxicity of chemotherapy. However, no relation could be established between the presence of dental foci prior to chemotherapy and the development of FN (p > 0.05).ConclusionA significant relation was identified between ulcerative OM and FN, but no robust conclusions could be drawn with respect to a relationship between the presence of dental foci and FN.

Abstract 5396: DNA damage repair gene mutations predict the efficacy of immunization combined with platinum chemotherapy in advanced non-small cell lung cancer: A retrospective cohort study

Abstract Purpose: DNA damage repair (DDR) mutations are known to predict response to platinum-based chemotherapy in multiple solid tumors, as well as immunotherapy in non-small cell lung cancer (NSCLC). However, the predictive value of DDR in immunization combined with platinum chemotherapy remains unclear. Methods: We retrospectively collected information from 495 patients with advanced NSCLC whose tumors were analyzed using next-generation sequencing (NGS) and analyzed the characteristics of DDR mutations. Among them, 64 patients with NSCLC who received platinum chemotherapy and 37 patients who received immunotherapy combined with platinum chemotherapy were included in the prognostic analysis. Results: The DDR genes was commonly mutated in Chinese NSCLC population (242/495, 48.89%). In Chinese NSCLC cohort, DDR mutations showed a strong association with high tumor mutational burden (TMB-H) (DDR mutant vs DDR wild-type: 7.26 muts/Mb vs 5.15 muts/Mb, P=0.001) and higher rates of strong PD-L1 (TPS≥50%) positivity (DDR mutant vs DDR wild-type: 28.74% vs 20.69). Sixty-four advanced NSCLC patients treated with platinum-based chemotherapy were analyzed, the ORRs were 16% for the patients with DDR mutations (DDRmut) and 2.70% for the DDR wild-type (DDRwt) subgroup (P&amp;lt;0.05), and the DCRs were 88% for the DDRmut group and 48.64% for the DDRwt group (P&amp;lt;0.05). The DDRmut patients had significantly improved median PFS than the DDRwt group (7.07 months vs 4.27 months, hazard ratio (HR) =0.57, 95%CI 0.33−0.97, P= 0.0303). Median OS was also significantly better among the DDRmut patients than in the DDRwt group (29.93 vs 20.7 months, HR=0.49, 95%CI 0.25−0.97, P= 0.0359). Moreover, in thirty-Seven advanced NSCLC patients treated with immunization combined with platinum chemotherapy, the ORRs were 45% for the patients with DDR mutations (DDRmut) and 11.76% for the DDR wild-type (DDRwt) subgroup (P&amp;lt;0.05), and the DCRs were 95% for the DDRmut group and 70.59% for the DDRwt group (P&amp;lt;0.05). The DDRmut patients had significantly improved median PFS than the DDRwt group (16.83 months vs 5.83 months, hazard ratio (HR) =0.34, 95%CI 0.12−0.973, P= 0.0079). For patients in the DDRmut group, PFS receiving immunization combined with platinum chemotherapy was significantly better than those receiving platinum-based chemotherapy (16.83 months vs 7.07 months, hazard ratio (HR) =0.48, 95%CI 0.24−0.97, P= 0.046). However, for patients in the DDRwt group, there was no significant difference in PFS between those who received immunization combined with platinum chemotherapy and those who received platinum-based chemotherapy (5.8 months vs 4.2 months, hazard ratio (HR) =0.76, 95%CI 0.394−1.495, P= 0.491). Conclusions: DDR mutations may serve as a positive predictor of immunization combined with platinum chemotherapy in patients with advanced NSCLC. Citation Format: Zhiwe Xiao, Lingling Sun, Yating Zheng, Hanrui Chen, Xinting Zheng, Jiamin Luo, Chuying Gu, Ruiting Lin, Xue Hu, Mengli Huang, Lizhu Lin. DNA damage repair gene mutations predict the efficacy of immunization combined with platinum chemotherapy in advanced non-small cell lung cancer: A retrospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5396.

Abstract 5395: DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer

Abstract Background: DNA damage repair (DDR) mutations are known to predict response to platinum-based chemotherapy in multiple solid tumors. However, their predictive value remained unknown in patients with colorectal cancer. Methods: The genomic and survival datas from the TCGA-COAD and TCGA-READ cohorts of patients receiving platinum-based chemotherapy were used to analyze the predictive value of DDR mutations on platinum-based chemotherapy. Result: The DDR genes were commonly mutated (85.82%) in the TCGA-COAD and TCGA-READ cohorts. The objective response rates (ORRs) were 80% for the patients with DDR mutations (DDRmut) subgroup and 56% for the DDR wild-type (DDRwt) subgroup (P&amp;lt;0.05), and the disease control rates (DCRs) were 86% for the DDRmut subgroup and 56% for the DDRwt subgroup (P&amp;lt;0.05). In patients with stage I, II and III colorectal cancer, there was no significant difference in the overall survival (OS) between DDRmut subgroup and DDRwt subgroup (Hazard Ratio=0.48, 95%CI 0.1−2.31, log-rank P=0.35). In patients with stage IV colorectal cancer, the OS was significantly better among the DDRmut patients than in the DDRwt subgroup (Hazard Ratio=0.21, 95%CI 0.06−0.8, P= 0.011). Conclusions: DDR mutations may serve as a positive predictor of platinum-based chemotherapy therapy in patients with CRC and their clinical value warrants further investigation. Citation Format: Yan Lin, Jinyan Zhang, Xiaoli Liao, Yumei Zhang, Min Luo, Qian Li, Mingzhi Xie, Chaoyong Liang, Sina Liao, Yating Zheng, Xue Hu, Mengli Huang, Rong Liang, Yongqiang Li. DNA damage repair gene mutations predict the efficacy of platinum-based chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5395.

Ischemic Colitis of the Transverse Colon Induced by 5-Fluorouracil, Leucovorin, and Irinotecan: A Case Report

Gastrointestinal complications are common in chemotherapy patients. Although most patients’ abdominal symptoms can be due to mild chemotherapy adverse reactions, severe or life-threatening complications might occur. Typhlitis or neutropenic enterocolitis is a severe bowel wall inflammation in leukemia or solid tumor chemotherapy in neutropenic patients and may contribute to necrosis and colon perforation. Patients undergoing chemotherapy rarely experience colitis that has no standard typhlitis trait. This ischemic colitis-induced chemotherapy had conducted in patients receiving taxane-based agents. Our study presented ischemic colitis in patients receiving 5-fluorouracil, Leucovorin, and Irinotecan for sigmoid cancer that affected the transverse colon alone, unlikely for both typhlitis and chemotherapy-induced ischemic colitis. Given these findings; it is prominent to consider that life-threatening gastrointestinal complications may develop with these agents, and then surgical intervention is needed.

Safety and Efficacy of Bevacizumab in Cancer Patients with Inflammatory Bowel Disease.

Simple SummaryIn patients with inflammatory bowel disease, chronic inflammation is a risk factor for the development of digestive and nondigestive cancers. The treatment, as in patients without inflammatory bowel disease, is a combination of chemotherapy and targeted treatments, such as bevacizumab and more recently, immunotherapy. It is generally believed that the use of bevacizumab and chemotherapy could increase toxicity and lead to adverse events in this population. This study aims to evaluate the safety and efficacy of the combination of bevacizumab and chemotherapy in patients with quiescent or moderately active inflammatory bowel disease in various forms of cancer and by increasing the quality of patient care in this subgroup.Background: The safety of bevacizumab in combination with chemotherapy in patients with inflammatory bowel disease (IBD) and digestive and nondigestive cancers is poorly documented. Methods: We retrospectively evaluated patient records of all adult cancer patients with IBD at our institution from April 2007 to May 2016 with an update in November 2019. Results: Twenty-seven patients with a history of IBD (Crohn’s disease, n = 22; ulcerative colitis, n = 5) who were treated with bevacizumab and chemotherapy for metastatic solid tumors were identified. At the time of advanced cancer diagnosis, 18 patients had quiescent IBD, whereas 9 patients had moderately active IBD. Among those with moderately active IBD, five had received corticosteroids less than six months prior to cancer diagnosis and one had received infliximab. The treated cancers were colorectal cancer (n = 13), small bowel cancer (n = 4), non-small cell lung cancer (n = 3), breast cancer (n = 3), and other cancers (n = 4). Patients received bevacizumab in combination with chemotherapy and/or as maintenance for a median of 6.7 months. Grade 2 or higher bevacizumab-related complications were proteinuria in two patients and hypertension, diarrhea, rectal bleeding, and intestinal perforation in one patient each. No clinical IBD flares were observed during bevacizumab treatment. Conclusion: Bevacizumab combined with chemotherapy is safe in cancer patients with moderately active or quiescent IBD.

Phase I trial of CA-4948, an IRAK4 inhibitor, in combination with FOLFOX/PD-1 inhibitor +/- trastuzumab for untreated unresectable gastric and esophageal cancer.

TPS4168 Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple gastrointestinal cancers including gastroesophageal cancer (GEC). Preclinical studies established that: 1) Genotoxic stress incurred by chemotherapy induces TLR9, which signals through IRAK4 to drive pro-survival NFκB signaling; 2) The survival mechanism through IRAK4 is independent of cancer types and mutational profiles based on colorectal and pancreatic cancer models; and 3) IRAK4 inhibition reduces tumor desmoplasia and revitalizes intratumoral T cells, setting the stage for successful combination with immune checkpoint inhibitors in a highly aggressive autochthonous pancreatic cancer mouse model. These data combined provide a strong rationale to add CA-4948 to systemic therapy for multiple advanced gastrointestinal malignancies, where resistance to chemotherapy is inevitable and benefit of PD-1 inhibitors is limited to small population. CA-4948 is a novel, first-in-class reversible inhibitor of IRAK4. In a phase I trial, patients with relapsed/refractory hematologic malignancies tolerated CA-4948 monotherapy well with mild fatigue, neutropenia, and nausea as most common adverse events. Recommended phase 2 dose (RP2D) was determined as 300 mg orally twice daily. CA-4948 has not been tested in combination with cytotoxic chemotherapy or immune checkpoint inhibitors for solid tumors in clinic. We hypothesize that inhibition of IRAK4 with CA-4948 will potentiate the effect of immune checkpoint inhibitor while deepening the efficacy of cytotoxic chemotherapy in GEC. Methods: This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable GEC. During Dose Escalation, we will investigate CA-4948 in combination with FOLFOX/nivolumab by BOIN algorithm evaluating 4 different dose levels. Starting dose of CA-4948 for Part A will be 200 mg twice daily. Once RP2D is determined, the study will proceed to Dose Expansion, including Cohorts A and B. Cohort A will enroll up to 12 patients with HER2 negative disease at the RP2D of CA-4948 determined at the Dose Escalation phase. Cohort B will investigate CA-4948 in combination with FOLFOX/pembrolizumab and trastuzumab. The initial 6 patients in Cohort B will be considered safety lead-in to confirm the safety and tolerability at the RP2D, followed by additional patients, up to 12 patients treated at the RP2D. The primary objective is to determine the safety and RP2D of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab. Secondary objectives are to determine the preliminary efficacy of the combination. Correlative studies to evaluate pharmacodynamic effects and to identify biomarkers associated with disease response are planned. Clinical trial information: NCT05187182.

Development of a predictive model for emergency room utilization and unanticipated hospital admission in patients receiving cancer treatment for solid tumor malignancies.

e18674 Background: Unanticipated healthcare resource utilization, in the form of either emergency department utilization (EDUs) or hospital admission (HA), is an indicator of lower quality of cancer care. The objective of this study was to develop a comprehensive predictive model for emergency department utilization and hospital admission (HA) for patients with solid tumors who received chemotherapy within 30 days. Methods: We abstracted electronic health data on oncology encounters from all patients receiving systemic therapy chemotherapy for solid tumors from March 01, 2015 to August 21, 2020. Patients included in the cohort met the following criteria:1) Ages &gt; = 18 years old 2) Diagnosed with any solid tumor (3) Had any oncology treatment plan related to their solid tumor diagnosis; 4) Received at least one chemotherapy during March 01, 2015 through August 21, 2020. We defined a primary composite outcome of emergency visit or unanticipated hospitalization within 30 days after the encounter. Patient information was abstracted. We developed a predictive model for the primary outcome using LASSO logistic regression modeling. To evaluate the model, we calculated the Area Under the Receiver Operator Characteristic (AUROC) and the calibration slope. Results: 12,917 unique patients with 134,641 encounters were included. Of these, 9100 (6.7%) of encounters were ED visits or hospitalizations. 714 patients (5.5%) had at least one ED visit or hospitalization within 30 days of treatment; patients at highest risk for this outcome included those with pancreatic cancer, lung cancer and ovarian/endometrial cancer (9.1%, 7.4% and 6.8% respectively). 38 variables were identified as contributing to the LASSO model. The top predictors, in order of importance, were fever, hypernatremia, hypotension and low albumin. The model’s AUC was 0.83, indicating good model sensitivity to outcome. Conclusions: Approximately 7% of healthcare encounters in patients undergoing treatment for solid malignancies were ED visits or hospitalizations. Identifying patients at highest risk for this outcome may prevent unnecessary resource utilization and optimize patient care during cancer treatment. The model developed in this study demonstrated good sensitivity and could be implemented in clinical practice to allow for preventive outpatient interventions. Work is ongoing to integrate this model into clinical care at our institution.[Table: see text]

Factors associated to hospitalizations in older cancer patients treated with chemotherapy.

e24025 Background: Chemotherapy toxicity (CT) is higher in elderly cancer patients, mainly due to fragilities identified in this subgroup. Hospitalization can be an adverse outcome of cancer treatment, which is disruptive in older patients, leading to worse functional status and cognitive disfunction, as well as increased costs for the health system. We evaluated patients treated with chemotherapy to identify hospitalizations related to oncological treatment and factors associated with this outcome. Methods: A retrospective study was conducted in a Brazilian Oncology Center. Patients ≥65 years old who started chemotherapy for solid tumors as curative or first-line therapy in 2019 were included and data was collected of the entire treatment until suspension or change in therapy (because of progression, completion, toxicity, or death). Those treated concomitantly with immunotherapy and radiotherapy were excluded. Characteristics of patients and their treatments were analyzed as risk factors for hospitalization through univariate analysis (UVA) with Fisher’s Exact Test and Mann-Whitney Test, and those variables considered significant (p &lt; 0.05) were submitted to a multivariate analysis (MVA) with Logistic Regression. Results: We included 124 patients with a median of 70 (65-93) years old and a median of 6 (1-26) cycles of chemotherapy completed. There were 67% of women, 42.8% had Charlson Comorbidity Index (CCI) ≥1; polypharmacy (≥5 medications) was present in 38.7%; the main cancer treated were gastrointestinal (34.7%), breast (21%) and pancreas/biliary tract (20.2%). Most patients had metastatic disease (54%) and received polychemotherapy (80.6%) as primary treatment ;body index measure was ≥25 in 50.8% and 24.2% lost 5% or more of body weight during the time analyzed. Unplanned hospitalizations occurred in 40 patients and 25 were considered associated with CT (febrile neutropenia, infections, gastrointestinal adverse events, worse renal function). In UVA, age, pancreas/ biliary tract cancers, CCI≥1 and polypharmacy were factors associated to hospitalization due to CT. After MVA, only CCI≥1 (OR 3.23, CI95%1.12 – 10.05) continued as an independent factor associated to CT. Conclusions: Evaluation of comorbidities with CCI can identify older patients at higher risk of hospitalization due to toxicity during treatment with chemotherapy. Comprehensive geriatric assessment should be offered to high-risk patients in order to develop strategies to prevent this adverse outcome.

An injectable hydrogel/staple fiber composite for sustained release of CA4P and doxorubicin for combined chemotherapy of xenografted breast tumor in mice

To prepare an injectable hydrogel/staple fiber composite loaded with combretastain A-4 disodium phosphate (CA4P) and doxorubicin (DOX) and evaluate its antitumor efficacy via intratumoral injection. DOX-loaded PELA staple fibers (FDOX) were prepared using electro-spinning and cryo-cutting, and the drug distribution on the surface of the fibers was observed using a fluorescence microscope, and the encapsulation efficiency and loading capacity of FDOX were determined with a fluorospectro photometer. The fibers were then dispersed in CA4P-loaded PLGA-PEG-PLGA tri-block polymer solution at room temperature to obtain the hydrogel/staple fiber composite (GCA4P/FDOX). The thermo-sensitivity of this composite was determined by a test tube inverting method. An ultraviolet spectrophotometer and a fluorospectrophotometer were used to detect the release profile of CA4P and DOX, respectively. We observed in vivo gel formation of the composite after subcutaneous injection in mice. The in vitro cytotoxicity of GCA4P/FDOX composite in MCF-7 and 4T1 cells was assessed using cell Counting Kit-8 (CCK-8) reagent. In a mouse model bearing breast tumor 4T1 cell xenograft, we evaluated the antitumor efficacy of the composite by monitoring tumor growth within 30 days after intratumoral injection of the composite. HE staining, immunohistochemistry for Ki67 and immunofluorescence (TUNEL) assay were used for pathological examination of the tumor tissues 21 days after the treatments. The average length of FDOX was 4.0±1.3 μm, and its drug loading capacity was (2.69±0.35)% with an encapsulation efficiency of (89.70±0.12)%. DOX was well distributed on the surface of the fibers. When the temperature increased to 37 ℃, the composite rapidly solidified to form a gel in vitro. Drug release behavior test showed that CA4P was completely released from the composite in 5 days and 87% of DOX was released in 30 days. After subcutaneous injection, the composite solidified rapidly without degradation at 24 h after injection. After incubation with GCA4P/FDOX for 72 h, only 30.6% of MCF-7 cells and 28.9% of 4T1 cells were viable. In the tumor-bearing mice, the tumor volume was 771.9±76.9 mm3 in GCA4P/FDOX treatment group at 30 days. Pathological examination revealed obvious necrosis of the tumor tissues and tumor cell apoptosis induced by intratumoral injection of G4A4P/FDOX. As an efficient dual drug delivery system, this hydrogel/staple fiber composite provides a new strategy for local combined chemotherapy of solid tumors.

Immunogenicity after second and third mRNA-1273 vaccination doses in patients receiving chemotherapy, immunotherapy, or both for solid tumours.

Immunogenicity after second and third mRNA-1273 vaccination doses in patients receiving chemotherapy, immunotherapy, or both for solid tumours.

Risk of Bacterial, Viral, and Fungal Infections in Patients With Solid Malignant Tumors Treated With Curative Intent Radiation Therapy

PurposeThe incidence, etiology, and association of infections with radiation therapy (RT)–induced lymphopenia in patients with solid tumors is not well elucidated. Methods and MaterialsWe identified possible, probable, and definite infections caused by bacteria, fungi, and viruses, combining data on medication, microbiology, and diagnoses. Definite infections had either a diagnosis or a positive microbiological isolation. We analyzed the incidence and adjusted incidence-rate ratio of infections in the year after the start of RT among patients who received RT plus chemotherapy and RT monotherapy, by type of infection and according to the degree of RT-induced lymphopenia. ResultsA total of 4450 of 6334 (70.3%) patients experienced 11264 infections overall; 1424 (22.5%) patients developed 2104 definite infections in the first year after RT. Infections were more frequent among patients who received RT plus chemotherapy (2590 of 3469; incidence: 16.5 [95% confidence interval {CI}, 16.1-17.0], per 100 patient-years) compared with patients who received RT monotherapy (1860 of 2865; incidence: 12.7 [95% CI, 12.3-13.2]). The incidence of infection was highest in the first 3 months overall (28.2 vs 18.0 in patients who received RT plus chemotherapy compared with those who received RT monotherapy) and for definite infections (4.7 vs 3.8). The proportion of specific bacterial infections were similar among patients who received RT plus chemotherapy versus those who received RT monotherapy. Urinary tract infections were the most frequent (51.2% vs 56.2%), followed by pneumonias (24.1% vs 22.4%). Viral and fungal infections were more frequent among patients who received RT plus chemotherapy, but they were uncommon. In multivariable analyses, patients who received RT plus chemotherapy with a lymphopenia grade of 1-2 or ≥3 versus no lymphopenia at end of RT had an increased risk of bacterial infections 0 to 3 months after RT (incidence rate ratio, 1.45 [95% CI, 1.06-1.97] and 1.71 [95% CI, 1.26-2.34], respectively). Limiting to definite bacterial infections, the incidence rate ratio for lymphopenia grade ≥3 versus no lymphopenia was 2.66 (95% CI, 1.40-5.03). ConclusionsThe incidence of bacterial infections 0 to 3 months after RT plus chemotherapy for solid tumors was high, especially among patients with RT-induced lymphopenia grade 1-2 and ≥3.

NaAsO2 decreases GSH synthesis by inhibiting GCLC and induces apoptosis through Hela cell mitochondrial damage, mediating the activation of the NF-κB/miR-21 signaling pathway

BackgroundCervical cancer is the fourth most common cancer in women worldwide, and arsenic has a certain effect in solid tumor chemotherapy. As the rate-limiting enzyme subunit of GSH synthesis, GCLC may be an important target for arsenic to induce apoptosis through mitochondrial apoptosis pathway to exert anti-tumor effect. NF-κB plays an important role in the occurrence and development of cervical cancer and can regulate the expression of GCLC. miR-21 is a potential biomarker of cervical cancer, which can induce apoptosis through ROS regulated the mitochondrial pathway of cells. However, the role of miR-21 in the mitochondrial pathway of cervical cancer cells induced by NaAsO2 through NF-κB/GCLC and GSH synthesis regulated oxidative stress is rarely reported. Therefore, the purpose of this study was to investigate whether NaAsO2 might induce mitochondrial damage and apoptosis of cervical cancer cells through NF-κB/ miR-21 /GCLC induced oxidative stress, and play the anti-tumor role of arsenic as a potential drug for the treatment of cervical cancer. MethodsHela cells were treated with different concentrations of NaAsO2, D, L-Buthionine-(SR)-sulfoximine (BSO), IκBα inhibitor (BAY 11-7082) and miR-21 Inhibitor. CCK-8 assay, Western Blot, qRT PCR, immunofluorescence, transmission electron microscopy, mitochondrial Membrane Potential Assay Kit with JC-1,2′,7′-Dichlorofluorescin diacetate fluorescent probe and Annexin V-FITC were used to measure cell activity, GSH and ROS, mitochondrial morphology and membrane potential (ΔΨm), protein and mRNA expression of GCLC, GCLM, p65, IκBα, p-P65, p-I κBα, Bcl-2, BAX, Caspase3, cleaved-caspase3 and miR-21. ResultsCompared with the control group, with the gradual increasing dose of NaAsO2, cell viability was considerable reduced, and increased rate of apoptosis, intracellular GSH level was decreased significantly, ROS was increased, mitochondrial structure was damaged, mitochondrial membrane potential ΔΨm and Bcl2/BAX lowered, the expression of Caspase3 and cleaved-caspase3 were significantly increased, resulting in mitochondrial apoptosis. When Hela cells were treated with 15, 20, and 25 μmol/L NaAsO2, the mRNA and protein levels of GCLC and GCLM were reduced, the expression of p65 in the nucleus was increased, the expression of p-p65/p65, p-IκBα/IκBα and miR-21 were significantly increased. When BSO increased the inhibitory effect of NaAsO2 on GCLC, Compared with NaAsO2 group, the ΔΨm and protein of Bcl-2/BAX, caspase3 and cleaved-capsase3 were increased. When BAY 11–7082 combined with NaAsO2 co-treated, compared with the NaAsO2 group, the protein and mRNA expression of GCLC was increased, NaAsO2-increased expression level of miR-21 was suppressed, and the ΔΨm and cell viability were higher. In addition, compared with the combination of NaAsO2 and miR-21NC, the protein expression of GCLC was increased, the ΔΨm and cell viability reduction were alleviated by miR-21 Inhibitor combined with NaAsO2. ConclusionNaAsO2 may lead to ROS accumulation in Hela cells and trigger mitochondrial apoptosis. The mechanism may be related to the activation of NF-κB signaling pathway and the promotion of miR-21 expression which leads to the inhibition of GCLC expression and the significant decrease of intracellular reductive GSH synthesis.

Modulation of RNA splicing associated with Wnt signaling pathway using FD-895 and pladienolide B.

Alterations in RNA splicing are associated with different malignancies, including leukemia, lymphoma, and solid tumors. The RNA splicing modulators such as FD-895 and pladienolide B have been investigated in different malignancies to target/modulate spliceosome for therapeutic purpose. Different cell lines were screened using an RNA splicing modulator to test in vitro cytotoxicity and the ability to modulate RNA splicing capability via induction of intron retention (using RT-PCR and qPCR). The Cignal Finder Reporter Array evaluated [pathways affected by the splice modulators in HeLa cells. Further, the candidates associated with the pathways were validated at protein level using western blot assay, and gene-gene interaction studies were carried out using GeneMANIA. We show that FD-895 and pladienolide B induces higher apoptosis levels than conventional chemotherapy in different solid tumors. In addition, both agents modulate Wnt signaling pathways and mRNA splicing. Specifically, FD-895 and pladienolide B significantly downregulates Wnt signaling pathway-associated transcripts (GSK3β and LRP5) and both transcript and proteins including LEF1, CCND1, LRP6, and pLRP6 at the transcript, total protein, and protein phosphorylation’s levels. These results indicate FD-895 and pladienolide B inhibit Wnt signaling by decreasing LRP6 phosphorylation and modulating mRNA splicing through induction of intron retention in solid tumors.

Abstract P2-12-04: Characterization of gut microbiome composition in triple negative breast cancer patients treated with neoadjuvant chemotherapy

Abstract Background: Recent evidences showed intestinal microbiota to be implicated in carcinogenesis and response to chemotherapy and immune checkpoint inhibitors in solid tumors. Furthermore, antibiotics are known to deeply influence microbiome composition in healthy people and cancer patients. The role of gut microbiome in triple negative breast cancer (TNBC) is underexplored. Methods: In this pilot prospective study, we characterized the gut microbiome of 30 TNBC patients undergoing neoadjuvant chemotherapy at two Italian Institutions. Fecal samples were collected at 2 timepoints: at the baseline (t0) and at 1 week (t1) from CT. Microbiome was analyzed by 16S rRNA sequencing. Measures of α-diversity expressed by Richness and Simpson evenness were evaluated at the species level. β-diversity was calculated using PERMANOVA test according to UniFrac measures of dissimilarity at the species level.Tumor infiltrating lymphocytes (TILs) were assessed from diagnostic core biopsy and surgical specimen. Results: From September 2017 to March 2020, 30 TNBC patients were enrolled. Median age was 53 years, 43% were premenopausal, 43% were overweight or obese (BMI&amp;gt;25); 97% had a histologic G3 carcinoma, clinical nodal involvements was present in 57%; median TILs at diagnosis was 30%. All patients received anthracycline and taxane-based chemotherapy, including carboplatin in 23 patients (77%). A pCR was achieved in 15 (50%) patients. The overall rate of stool samples collection was 93%. With regards to t0, no differences in terms of α- and β-diversity were found.At t1, α-diversity was significantly higher in pCR group (Simpson evenness index, p=0.016). Considering clinical-pathological features, a BMI &amp;lt;24.9 was associated with higher microbiome richness (p=0.012). Measurements of β-diversity did not differ between groups.As 73% of patients during the treatment phase received antibiotics, with consequent potential microbiome impairment, we repeated analyses at t1 considering fecal samples collected &amp;gt;90 days after the end of antibiotic therapy (N=17). At this analysis, β-diversity evaluated with Unifrac measure was significantly correlated with pCR (p=0.035), with Haemophilus Influentiae being significantly enriched in non-pCR group. Conclusions: Fecal microbiome collection and analysis in this population is feasible and deserves further investigation with regards its association with response to chemotherapy. Citation Format: Grazia Maria Vernaci, Davide Massa, Ilaria Patuzzi, Alice Menichetti, Tommaso Giarratano, Gaia Griguolo, Federica Miglietta, Matteo Fassan, Edoardo Savarino, PierFranco Conte, Valentina Guarneri, Maria Vittoria Dieci. Characterization of gut microbiome composition in triple negative breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-04.

Classical mathematical models for prediction of response to chemotherapy and immunotherapy.

Classical mathematical models of tumor growth have shaped our understanding of cancer and have broad practical implications for treatment scheduling and dosage. However, even the simplest textbook models have been barely validated in real world-data of human patients. In this study, we fitted a range of differential equation models to tumor volume measurements of patients undergoing chemotherapy or cancer immunotherapy for solid tumors. We used a large dataset of 1472 patients with three or more measurements per target lesion, of which 652 patients had six or more data points. We show that the early treatment response shows only moderate correlation with the final treatment response, demonstrating the need for nuanced models. We then perform a head-to-head comparison of six classical models which are widely used in the field: the Exponential, Logistic, Classic Bertalanffy, General Bertalanffy, Classic Gompertz and General Gompertz model. Several models provide a good fit to tumor volume measurements, with the Gompertz model providing the best balance between goodness of fit and number of parameters. Similarly, when fitting to early treatment data, the general Bertalanffy and Gompertz models yield the lowest mean absolute error to forecasted data, indicating that these models could potentially be effective at predicting treatment outcome. In summary, we provide a quantitative benchmark for classical textbook models and state-of-the art models of human tumor growth. We publicly release an anonymized version of our original data, providing the first benchmark set of human tumor growth data for evaluation of mathematical models.

Light-responsive nanodrugs co-self-assembled from a PEG-Pt(IV) prodrug and doxorubicin for reversing multidrug resistance in the chemotherapy process of hypoxic solid tumors.

Hypoxia-induced multi-drug resistance (MDR) often develops in the chemotherapy process of most anticancer drugs (e.g., doxorubicin, DOX) and results in treatment failure in the clinic. Herein, a PEG-Pt(IV) prodrug was co-self-assembled with DOX into nanodrugs (PEG-Pt(IV)@DOX NPs). They can accumulate in tumor sites due to their longer blood retention half-life. Under light irradiation, the PEG-Pt(IV) prodrug can in situ self-generate oxygen (O2) to reduce the hypoxic zone in tumor tissue effectively and simultaneously release active cis-Pt(II) and DOX. The increasing O2 concentration in the tumor tissue can raise the level of reactive oxygen species (ROS) produced from DOX and significantly enhance the cytotoxicity of DOX to inhibit tumor proliferation by combining with active cis-Pt(II). Finally, the hypoxia-induced MDR of DOX can be alleviated. More importantly, the enhanced cytotoxicity of DOX is limited to the tumor site, which can effectively reduce its side effects on normal tissues. In summary, this would be a promising platform for the combination chemotherapy of hypoxia solid tumors in the clinic.

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.