bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety, efficacy, pharmacokinetics, and pharmacodynamics of the illudofulvene drug CAP-0121.
Authors: Suhandynata Raymond T. , Nguyen TK , Kotamraju Venkata R. , Momper Jeremiah D , Kelner Michael J.
Published: June 2024

e15120

Background: Irofulven is an anticancer agent derived from illudin S initially investigated due to its unique mechanism of action and potential to overcome multi-drug resistance. This study investigates the pharmacokinetics/pharmacodynamics (PK/PD) and efficacy and safety of the second-generation drug, CAP-0121 (Califia Pharma). Methods: 24-hour comprehensive PK was performed at two different intravenous (IV) doses in canines for irofulven (0.2 mg/kg and 1 mg/kg; MTD) and CAP-0121 (1 mg/kg and 3 mg/kg). Plasma concentrations were measured by LC-MS/MS and PK parameters were calculated for both drugs using noncompartmental methods (Phoenix WinNonlin, version 8.4). PK parameters included area under the concentration vs time curve (AUC), maximum observed concentration (Cmax), clearance (CL), volume of distribution (Vd), and elimination half-life (t1/2). Canine chemistry/hematology/coagulation/urine panels, were measured across 28 days to ascertain the maximum tolerated dose (MTD). Both platelet and neutrophil count reversibility was also assessed. Mice xenograft models implanted with a drug resistant human ovarian cancer (A2870), or a drug-resistant human metastatic lung cancer (MV522), were dosed with irofulven (9 mg/kg; MTD) and CAP-0121 (15, 20, and 25 mg/kg) and resulting tumor mass, % change in body weight, and platelet counts were compared relative to vehicle only. Results: Systemic exposure, CL, Vd, and t1/2 were similar between irofulven and CAP-0121 at a 1 mg/kg IV dose. For irofulven, AUC increased approximately proportionally at doses of 0.2 mg/kg and 1 mg/kg. For CAP-0121, exposure also increased proportionally at doses of 1 mg/kg and 3 mg/kg. MTD of CAP-0121 was found to be 3-fold higher in canines compared to irofulven as 3-fold more CAP-0121 was required to match the platelet reduction observed with irofulven; platelet and neutrophil nadir was rapidly reversible for CAP-0121. Canine nadir platelets and neutrophil counts were 3-fold higher for CAP-0121 vs irofulven at the same dose (1 mg/kg). There was no evidence of any canine systemic organ toxicity (gross, histologic, blood and urine analysis) for CAP-0121 at either dose. CAP-0121 was superior to irofulven (p < 0.02) with regards to final tumor weights in mice xenograft models, even though MTD was not reached for CAP-0121; a change in body weight and platelet loss was not observed for CAP-0121 at up 25 mg/kg in mice. With regards to in vitro anticancer cytotoxic activity, the two drug-resistant xenograft models confirm the superiority of CAP-0121 over irofulven. This study demonstrates that CAP-0121 has favorable PK parameters and a wider therapeutic window in humans compared to irofulven, emphasizing the potential anticancer utility of CAP-0121 for solid cancers without prolonged thrombocytopenia. Conclusions: Further investigation in clinical trials is warranted to confirm these preclinical observations.
Characterization of novel compounds that directly bind to and inactivate the HPV E6 protein for treatment of HPV-associated cervical and oropharyngeal cancers.
Authors: Nichols William Garrett , Rietz Anne , Kumari Lokesh , Lu Zhijian , Androphy Elliot
Published: June 2024

e15122

Background: The human papillomavirus (HPV) E6 protein is necessary for viral genome replication and is always expressed in HPV-induced malignancies. We performed in silico screening of chemical libraries for molecules that bind to a pocket on the cancer associated HPV-16 E6 protein. We focused on the protein-protein interaction of E6 with one of its cellular binding partners, the ubiquitin ligase E6AP. In a trimolecular complex with E6, E6AP ubiquitinates p53, leading to its destruction by the proteasome. We designed, synthesized, and characterized >300 compounds that 1) bind to the E6AP interaction surface of the HPV-16 E6 protein; 2) are armed with a ‘warhead’ to make an irreversible bond with a specific cysteine in this HPV-16 E6 binding pocket; 3) and restore levels of p53 and selectively decrease viability of HPV-16 expressing tumor derived cells. Methods: E6 inhibitor optimization was guided by in silico docking strategies, co-crystallization, and medicinal chemistry, followed by biochemical and cellular assays to iteratively design and synthesize molecules with increased E6 inhibitory activities. Results: We used whole protein mass spectrometry to interrogate covalent bonding to E6, showing irreversible binding to the cysteine in the targeted E6 binding pocket without the other 13 cysteines in E6, with Ki in the range of seconds. Biolayer interferometry and fluorescence polarimetry measured blockade of E6 with E6AP, with IC50 in the range of 400-600 nM. To establish in cell inactivation of E6, human cervical cancer derived SiHa cells that express HPV-16 E6 were incubated with compounds, showing dose dependent increase of p53 levels up to 8-fold after 24 hrs, an effect that was not observed in the HPV-16- cell line RPE-1 expressing wild-type p53. Viability of two cervical (SiHa, CaSki) and two oropharyngeal HPV-16+ cancer cell lines (UM-SC-47, UM-SCC-104) was reduced with an IC50 of ~2-3 µM, with an IC50>30µM in RPE-1 cells and telomerase immortalized human keratinocytes. These in vitro and cell-based experiments revealed dependence on the cysteine residue in the E6AP binding pocket of E6. For in vivo proof-of-concept studies, we developed mouse xenograft models, performed by engrafting SiHa, UM-SC-47 and UM-SCC-104 cancer derived cells subcutaneously into the flank of immunodeficient mice. Lead compounds were administered by intraperitoneal injection and demonstrated nearly complete inhibition (> 70% tumor reduction) in HPV-16 tumor growth compared to vehicle. Anti-tumor activity was not observed with the HPV-negative tumor cell line C33A. Conclusions: HPV-16 is identified in about 50% of all cervical cancers and the majority of head and neck malignancies. Inactivation of the HPV E6 protein represents the opportunity for a novel molecular targeted approach for medical treatment of HPV-16 expressing cancers of the cervix and oropharynx.
Adjuvant donafenib for patients with hepatocellular carcinoma at high risk of recurrence following radical resection: A multi-center, retrospective study in China.
Authors: Zhang ShenYu , Yang Guibing , Song Ruipeng , Wang Wei , Meng Fanzheng , Yin Dalong , Wang Jiabei , Zhang Shugeng , Cai Wei , Liu Yao , Wang Jizhou , Luo Dayong , Liu Lianxin
Published: June 2024

e15129

Background: The implementation of adjuvant therapy in reducing tumor recurrence of hepatocellular carcinoma (HCC) is an essential approach for extending the prognosis of patients. The exploration of treatment strategies that are both efficacious and secure remains a prominent area of research in recent years. Donafenib is a novel, oral, small-molecule, multikinase inhibitor, and has demonstrated promising efficacy and safety profiles in preclinical and clinical studies. However, there is currently a lack of reported data on the adjuvant donafenib for HCC following radical resection (R0). The present study aimed to explore the efficacy and safety of adjuvant donafenib for HCC patients at high risk of recurrence following R0. Methods: This retrospective study analyzed 196 patients who underwent R0 for HCC between April 2021 and October 2022. All patients exhibited at least one of the following high risk recurrence factors:① single lesion > 5 cm or multiple lesions of any size; ② microvascular invasion (MVI); and ③ satellite nodules. Among these patients, 49 received donafenib, while 147 (control group) did not. In the donafenib group, donafenib was administered at a dose of 100 or 200 mg bid until tumor recurrence and serious adverse events (AEs). The 1-year and 2-year recurrence-free survival (RFS) rates and overall survival (OS) rates were compared between the two groups, as well as the incidence of adverse events (AEs) in the donafenib group. Inverse probability of treatment weighting (IPTW) was used. Results: The patient population consisted of 167 males and 29 females, with a median age of 59 (range 30-83). All patients exhibited a high risk of recurrence (number of tumors single/multiple, 167/29; tumor size within 5.0/above 5.0 cm, 78/118; MVI yes/no, 140/56; satellite nodules yes/no, 39/157). The median follow-up was 21.8 (range 3.8-32.0) months. Before IPTW, the donafenib group exhibited significantly higher 1-year and 2-year RFS rates compared to the control group (83.7%, 68.0% vs 66.7%, 47,6%, p = 0.023), while no significant difference in 1-year and 2-year OS rates (97.8%, 93.9% vs 91.8%, 80.6%, p = 0.120). After IPTW, the 1-year, 2-year RFS rates and OS rates were more favorable for the donafenib group compared to the control group (86.6%, 72.5% vs 64.8%, 45.0%, P = 0.004; 97.9%, 95.6% vs 89.5%, 77.9%, P = 0.043, respectively). In the donafenib group, AEs occurred in 44 patients, including 39 with grade 1 or 2 AEs and 5 with grade 3 AEs. The most common AEs included hand-foot skin reaction, decreased platelet count, and diarrhea. Conclusions: Adjuvant donafenib may improve RFS of HCC patients at high risk of recurrence following R0, while exhibiting favorable safety. This finding deserves further exploration.
Multicenter study evaluating the utility of AI-aided HER2 scoring in the clinically relevant categories.
Authors: Krishnamurthy Savitri , Canas Marques Rita , Borkowski Piotr , Cates Justin , Shearon Elisabeth , MacGrogan Gaetan , Ding Qingqing , Chandra Pranil , Morphew Emilie , Yassin Rawia , Sweeney Keith , Sun Hongxia , Riben Michael , Wheeler Darren , Globerson Yuval , Ziv Raz , Etoz Sevde , Grinwald Maya , Vecsler Manuela
Published: June 2024

e15150

Background: The availability of multiple therapeutic options for breast cancer patients with varying levels of protein expression necessitates precise and standardized HER2 scoring. This study explored the clinical utility of AI-aided HER2 scoring of whole-slide digital images by pathologists in breast core needle biopsies and excisions. Methods: The study included patients (n=764) with multiple subtypes of invasive breast cancer from 3 US reference laboratories and 1 academic medical center. The non-interventional two-arm multi-reader study retrospectively compared manual digital vs. AI-aided HER2 scoring of 8 pathologists. The fully automated HER2 AI solution detects the invasive tumor area and then classifies the tumor cells based on staining pattern based and the 2023 ASCO/CAP guidelines to output slide-level HER2 score. Both study arms were compared to reference ground truth (GT) established by the consensus of two breast subspecialists, ground truthers (GTer), who reviewed the slides digitally. One site recorded the time taken for HER2 scoring of both arms to determine the efficacy of the HER2 AI solution. Results: The initial interobserver agreement among expert GT pathologists for each HER2 score, 0, 1+, 2+, 3+, were 83%, 63.8%, 46%, and 92.6, respectively. At the clinically meaningful cut-offs, the reader pathologists’ performance improved with the AI support. At the 0 vs. 1+/2+/3+ and 0/1+ vs 2+/3+ clinical cutoffs, the readers' accuracy was 86.3% vs 88.6% and 93.7%, 93.8% with and without AI support, respectively. The AI use contributed to approximately 12%-time savings for the readers at the medical center. The AI solution demonstrated high accuracy for HER2 scoring, with 89.2% agreement with GT for 0 vs 1+/2+/3+ scores and 93.1% for 0/1+ vs 2+/3+ cutoff. The results will be updated in the final submission with the additional site data. The reader feedback survey regarding the solution’s usability will also be presented. Conclusions: The pathologists demonstrated improvements in consistency, evidenced by inter-reader agreement and accuracy with the aid of the AI. The AI solution can improve efficiency toward accurate HER2 scoring. [Table: see text]
The clinical utility of the 90-gene expression assay on diagnosis and management in patients with cancer of unknown or unclear primary.
Authors: Qi Peng , Sun Yifeng , Xu Qinghua , Wang Qifeng , Zhou Xiaoyan
Published: June 2024

e15172

Background: The diagnosis and management of patients with cancer of unknown or unclear primary present significant clinical hurdles, often culminating in unfavorable outcomes. A randomized phase III trial (CUP001) has demonstrated that site-specific treatment guided by the 90-gene-expression assay (Canhelp-Origin Assay) resulted in more therapy options, and significantly improved progression-free survival compared with empirical chemotherapy in patients with cancer of unknown primary. This study evaluated the clinical utility of the 90-gene expression assay in the diagnosis and management of patients with cancer of unknown or unclear primary. Methods: Patients who underwent the 90-gene expression assay at Fudan University Shanghai Cancer Center (FUSCC) between February 2023 and December 2023 were enrolled in the study. Data collection encompassed patient demographics, clinical characteristics, and pathological features. Results: Patient enrollment began in February 2023 and closed in December 2023 after enrolling 303 patients with 51 inpatient cases and 244 pathological consultation cases (from 144 sites). Among them, 295 patients met all inclusion criteria, yielding an overall success rate of 97.4% (295/303). Tumor cells were enriched by either macrodissection (N = 257) or microdissection (N = 38), with median highest similarity scores of 57.5 and 67.1, respectively. Using a positive cutoff value of the highest similarity score ≥45.3, the positivity rates for macrodissection and microdissection were 66.5% (171/257) and 81.6% (31/38), respectively. Of the enrolled patients, 177 (60%) were male, and 118 (40%) were female, with a median age of 63 years (range: 25 to 85 years). Predictive results encompassed 21 tumor types, with the most common being gastroesophageal cancer (N = 40, 13.6%), lung cancer (N = 37, 12.5%), breast cancer (N = 36, 12.2%), head and neck squamous cell carcinoma (N = 29, 9.8%), and ovarian cancer (N = 28, 9.5%). Of 166 samples with an assigned grade, 89.8% were poorly differentiated or undifferentiated, 6.0% were moderately differentiated, and 4.2% were well differentiated. The consistency of prediction results and clinicopathological results will be further evaluated after follow-up. Conclusions: This study demonstrates that the 90-gene expression assay has diagnostic implications for patients with cancer of unknown or unclear primary. This affirms its clinical utility as a standard diagnostic approach in the diagnosis and management of these patients, facilitating the formulation of more precise treatment strategies and ultimately enhancing prognosis.
Evaluation of biomarkers of response in patients with breast cancer with BRCA 1/2 pathogenic variants treated with PARP inhibitors.
Authors: Akkoc Mustafayev Fatma Nihan , Gutierrez Angelica M. , Munsell Mark F. , Chen Junjie , Schlacher Katharina , Tainer John A. , Albarracin Constance T. , Arun Banu
Published: June 2024

e15188

Background: Several prospective studies highlight the pivotal role of PARP inhibitors (PARPi) in treating BRCA-associated breast cancers (BC), demonstrating a significant overall response rate (ORR) of up to 60% in advanced BC patients with BRCA 1/2 germline pathogenic variants (PV). Despite their clinical efficacy, the factors predicting PARPi response, the mechanisms of resistance to PARPi, and the clinical strategies to overcome these challenges are still unknown. The aim of this study is to establish tissue microarrays (TMA) from primary breast tumor tissue from BC patients with BRCA1/2 PVs who were treated with PARPi and identify biomarkers of PARPi resistance. Methods: Stage 4 BC patients with BRCA 1/2 PVs who presented to the University of Texas MD Anderson Cancer Center Breast Medical Oncology clinics and were treated with PARPi between 2008-2023 were identified using our database. Available patient tissue samples were obtained from institutional tumor banks. TMA from breast tumor tissue created and evaluated by our collabrating pathologists for expression of biomarkers:Wee-1, MRE, BP1,and c-Myc. Clinical and tumor characteristics analyzed included:Age at diagnosis, treatment details, tumor characteristics including histological type, hormonal receptor status, Her-2/Neu status, grade, Ki-67 and clinical outcome. Descriptive statistics, the Fisher exact test, and the log rank test were used to report patient characteristics and outcomes. Here we report on initial TMA construct and biomarker analysis. Results: So far TMA from 12 patients treated with PARPi were succesfully constructed. Patient characteristics include: Median age of 36.5 years (29-57). Nine (75%) and 3 (25%) patients had BRCA1 and BRCA2 mutations, respectively. All patients had invasive ductal carcinoma and 9 (75%) had triple negative BC. Most patient (75%) had high nuclear grade BC and median Ki-67 was 75 (15-90). In 11 evaluable patients, the ORR was 72.7%. The median OS was 383.6 months (95% CI 62.5-383.6) and median PFS was 31.5 months (95% CI 10.8-NE). No significant difference in biomarker expression was observed between PARPi-responders and non-responders (Table1). Conclusions: This report presents unique data on novel predictive biomarkers of response and evaluates the evidence for potential biomarkers. Further analysis on a larger TMA cohort is ongoing. [Table: see text]
Synergistic cytotoxicity of histone deacetylase, poly-ADP ribose polymerase inhibitors and decitabine in breast and ovarian cancer cells: Therapeutic implications.
Authors: Tsimberidou Apostolia Maria , Valdez Benigno C. , Yuan Bin , Baysal Mehmet A. , Chakraborty Abhijit , Andersson Borje S.
Published: June 2024

e15193

Background: Innovative strategies are needed for breast and ovarian cancer. We explored the synergistic cytotoxicity of histone deacetylase inhibitors (HDACi), poly(ADP-ribose) polymerase inhibitors (PARPi), and decitabine (DAC, D) in breast and ovarian cancer cells. The drugs affect epigenetic regulation and DNA repair, making them promising anticancer therapies. Methods: Breast (MDAMB231 and MCF-7) and ovarian (HEY-T30 and SKOV-3) cells were exposed to HDACi (panobinostat, Pano, P; vorinostat; Vori, V), PARPi (talazoparib, TLZ, T; olaparib, Ola, O) and DAC. Synergism was assessed by MTT and clonogenic assays. Changes in DNA damage response/repair markers were assessed with Western blotting. Results: The combinations of HDACi, PARPi, and DAC had synergistic effects in all cell lines, evidenced by combination index <1. Clonogenic assay confirmed sensitivity of all cell lines to the 3-drug combinations (Pano, TLZ, DAC; Pano, Ola, DAC; Vori, TLZ, DAC; Vori, Ola, DAC). Cell proliferation was inhibited by 50% - 70%, and Annexin V positivity was 51% - 58% in all cells exposed to the combinations. Western blots showed inhibited protein PARylation, cleaved caspase 3 and PARP1 (suggestive of apoptosis), and down-regulated c-MYC. The 3-drug combinations induced more DNA damage (increased phosphorylation of ƔH2AX) than the individual drugs, impaired DNA repair (decreased ATM, BRCA1, ATRX proteins; Artemis), and altered gene expression (reduced NuRD complex subunits). DNA damage caused by HDACis and DAC may confer increased cellular dependence on protein PARylation, increasing sensitivity to combined HDACi, PARPi, and DAC. The P values comparing the inhibitory effects of each drug combination with that of individual drugs (MTT assay) are shown in Table ( P ≤ .05, statistically significant). Conclusions: The results support exploring HDACi, PARPi, and DAC combinations to overcome drug resistance and improve patient outcomes, and carefully designed clinical trials are warranted in breast and ovarian cancer. [Table: see text]
Development of HLB3-002 (recombinant human PH20 stand-alone) and its applicability as an anticancer diffusion agent.
Authors: Kim Heeyoun , Byun Juyoung
Published: June 2024

e15195

Background: HLB3-002 is a standalone of Halozyme's rHuPH20 (Original) and has the same amino acid sequence. HLB3-002 is being developed as a drug diffusion agent that decomposes subcutaneous hyaluronan, allowing substances such as anticancer drugs to be administered subcutaneously. This study was conducted to compare the in vivo efficacy and PK of original and HLB3-002 to confirm equivalence and thereby prove its applicability as a drug diffusion agent. Methods: In the in vivo efficacy test, Trypan blue was mixed with each original and HLB3-002 and administered subcutaneously to confirm diffusion and reconstruction equivalence in the nude mouse. The PK test was conducted using Rituximab, prepared in the same formulation as Rituximab SC by adding HLB3-002. A single dose was administered subcutaneously to the nape of the rat, and 12 points were collected for 28 days. The PK samples were measured by ELISA. When the Cmax and AUClast ratios of Rituximab between 2 groups were within 80.00 to 125.00%, they were evaluated as biologically equivalent. Results: As a result of efficacy test, the diffusion area of HLB3-002 was 104.7% compared to the original, which was confirmed to have an equivalent diffusion efficacy. In the skin reconstruction test, it was confirmed that both original and HLB3-002 rebuilt the skin layer to a similar to the negative control after 48 hours. As a result of the PK, Compared to Rituximab SC, the Cmax of Rituximab+HLB3-002 was similar at 98.53% and AUClast at 95.50%. Conclusions: Through an in vivo efficacy and PK test, we confirmed an equivalent drug diffusion effect, confirming that HLB3-002 applicability as an anticancer drug diffusion agent.[Table: see text]
A rapid assessment tool for systemic treatment outcomes in colorectal cancer with deep bidirectional transformers.
Authors: Kim Hyunwook , Yuh Taeho , Choi Jeong Eun , Baek Eunsil , Kim Han Sang , Beom Seung-Hoon , Ahn Joong Bae , Shin Sang Joon
Published: June 2024

e15567

Background: Retrospective investigations involving cancer treatment encounter the challenge of manually reviewing voluminous imaging reports to identify the best responses and the timing of disease progression. Here, we employed natural language processing, specifically deep bidirectional transformers, to automate the extraction of treatment response data. Methods: Data were sourced from the Yonsei Cancer Data Library database, focusing on patients with stage II-IV colorectal cancer at the Yonsei Cancer Center from Jan 1, 2010, to Dec 31, 2020. Imaging reports from 6,574 patients were gathered, amounting to 97,119 CT readings. Among these, 9,000 CT reports corresponding to 2,859 patients were randomly subjected to multilabel manual labeling by four radiology experts, based on the RECIST version 1.1 classification (CR/NED, PR, SD, PD). The pretrained BERT-base-uncased model was employed and fine-tuned for the downstream tasks of multilabel classification. 6,765 reports were used for training, while the remaining 1,000 reports were divided equally between the validation and test sets. Additionally, an algorithm for integrating and extracting treatment response data was also implemented. Clinical data were meticulously collected for 47 patients with stage IV early-onset colorectal cancer (EOCRC) receiving palliative first-line chemotherapy. The primary objective was to evaluate the model’s accuracy in predicting the timing of disease progression events within a ±30-day window. Secondary objectives focused on the model’s ability to identify the best response and its timing within a ±45-day window. Results: The evaluation of the classification accuracy across 1,000 individual CT reports, categorized as CR/NED (319), PR (86), SD (272), and PD (298), revealed accuracy with an AUROC of 0.956 and an F1 score of 0.823. All EOCRC patients were initially diagnosed with stage IV disease, and 45 out of 47 (95.7%) underwent metastasectomy either before initiating chemotherapy or during the first-line chemotherapy treatment. In clinical evaluation, the model demonstrated 72.3% (95% Confidence Interval [CI], 59.5-85.1) accuracy in predicting the day of disease progression within a ±30-day window. It achieved 55.3% (95% CI, 41.1-69.5) accuracy in predicting the best response category and its timing within ±45-days. Notably, the model was more accurate in predicting CR/NED at 72% compared to SD and PR, which had accuracy of 27.3% and 15.4%, respectively. Conclusions: Our model demonstrated high performance in classifying CT reports, which is expected to provide rapid insights into patient progress and improve clinical decision-making. However, the complexity involved in integrating and extracting data result in slight constraints in performance. This emphasizes the need for further research into multimodal large language models that can integrate a wider variety of clinical data.
Rethinking rectal cancer management through COVID: Real word evidence in a public hospital in the south of Brazil.
Authors: Fabra Lucas Fernando , Nassif Pereira Lima Marta , Pereira Rodrigo Perez , Azevedo Sergio Jobim , Tarta Claudio , Stanham Valentina De Souza , Ley Laura Lessa Gaudie , Hütten Debora Oliveira
Published: June 2024

e15620

Background: Treatment of locally advanced rectal cancer is based on a combination of radiotherapy and chemotherapy, either as adjuvant, neoadjuvant or total strategies. Short course radiotherapy followed by neoadjuvant chemotherapy, as described in the RAPIDO trial, was chosen by our Oncology, Radiotherapy and Coloproctological tumor board at Hospital de Clínicas de Porto Alegre during the COVID19 pandemic as a measure to reduce hospital visits and thus the possibility of transmission and infection by the SARS-COV-2 virus. Methods: We performed an observational analysis, including all patients treated with short course radiotherapy for locally advanced rectal cancer, at the Hospital de Clínicas de Porto Alegre in the period between January 2020 and March 2023. Metastatic patients were included, either treated with curative or palliative intent. Demographic characteristics, clinical staging, timing of chemotherapy, radiotherapy and surgery were analyzed. Clinical response was evaluated through sigmoidoscopy and clinical rectal exam. Patients with complete clinical response were offered the watch and wait strategy or surgery, after careful discussion of the possible benefits and risks. Results: Ninety-six patients were submitted to short course radiotherapy in the period described. Seven (7) patients were excluded; 89 patients were included in the final analysis. Fifty-five percent were male; mean age was 62 ±12.5 years; 52.8% were ECOG 1 at the diagnosis. Median CEA value at diagnosis was 7 ng/mL (CI 95%:4.4 - 9.8). Sixty-four percent were stage III, 31.4% stage IV, 3.3% stage II. Ninety-eight percent completed the programmed radiotherapy treatment. Only two patients received less than 25Gy. Forty-nine percent of patients completed the whole planned chemotherapy treatment; 15.7% were treated with palliative intent chemotherapy and 5.6% couldn’t receive chemotherapy for other reasons. Clinical response data were available in 62 patients: the main reason for unavailable clinical response was metastatic disease. Disease control was achieved in 98.4% of the cases, with only 1 patient having progressive disease during treatment (1.6%). The overall clinical response rate was 72.6%, 25.8% had stable disease and 24.2% complete clinical response. Fifteen of the 16 patients that presented with complete clinical response opted into a watch and wait strategy, achieving a 1-year disease free survival of 86.6%. Conclusions: Adopting the RAPIDO approach had a positive outcome in our advanced rectal cancer population. Short course radiotherapy followed by chemotherapy achieved excellent rates of disease control. Almost 25% of the non-metastatic patients undergoing RAPIDO treatment achieved complete clinical response opting into a watch and wait program.
An economic analysis of low-energy contact x-ray brachytherapy for treatment of rectal cancer.
Authors: Sun Myint Arthur , Bennett Hayley , Rao Christopher , Batten Leona , Hasler Elise , Jarrom David , Prettyjohns Matthew , Barrington Craig
Published: June 2024

e15622

Background: Health Technology Wales sought to evaluate the clinical and cost-effectiveness of contact x-ray brachytherapy (CXB) in conjunction with external-beam radiotherapy (EBRT), compared to EBRT alone for early-stage (T2–3b, N0–1, M0) rectal cancer in a surgically fit population. Methods: An economic analysis was performed using a decision analytical, state transition model. Analysis was performed from a third-party payer perspective over a life-time horizon. The model was populated using data from the Organ Preservation in Early Rectal Adenocarcinoma (OPERA) trial. Results: . CXB was estimated to provide 0.2 quality-adjusted life years (QALYs) per patient at an additional cost of $1118 per person. CXB was cost-effective compared with external beam boost at a cost of $5623 per QALY gained. These findings did not change in deterministic sensitivity analysis and CXB was cost-effective in over 90% of probabilistic sensitivity analyses. Conclusions: CXB is likely to be cost-effective with a high degree of certainty in this patient population.
Unveiling the influence of hyponatremia on morbidity, mortality, and resource utilization in colorectal carcinoma: Insights from a 5-year nationwide study.
Authors: Hotwani Priya , Kumar Vikash , Vachhani Bhavyakumar , Gaddam Mrunanjali , Jayakumar Jayalekshmi , Ginjupalli Manasa , Sanghvi Ankushi , Nanavaty Dhairya , Clement Jincy
Published: June 2024

e15657

Background: Historically, Hyponatremia has been associated with higher mortality rates and longer hospital stays in patients with solid tumors. The existing literature contains limited information on the connection between hyponatremia and Colorectal cancer (CRC). Thus, our study aimed to assess the impact of hyponatremia on mortality, morbidity, and resource usage in patients with CRC. Methods: A retrospective analysis using the National Inpatient Sample database and International Classification of Diseases, Tenth Revision codes was conducted to examine the impact of hyponatremia on mortality, morbidity, and resource utilization in patients with CRC. Categorical variables were compared using chi-square tests, while continuous variables were compared using t-tests. Multivariable regression analyses were performed, adjusting for demographics, hospital-level characteristics, and relevant comorbidities. Confounding variables were adjusted using multivariate logistic and linear regression analyses. These included gender, race, Charlson Comorbidity Index, chronic kidney disease, congestive heart failure, cirrhosis, nephrotic syndrome, hypothyroidism, adrenal insufficiency, alcohol use disorder, and admission for hypovolemia or psychogenic polydipsia and various patient and hospital characteristics. Results: A total of 337,190 patients with a primary diagnosis of colon cancer were included in the study, of which 12.6% (3,369) presented with hyponatremia (Table 1). The in-hospital mortality rate was 7.8% for patients with hyponatremia, compared to 4.1% for patients without hyponatremia. After adjusting for confounding factors, hyponatremia was found to significantly increase the odds of mortality (adjusted odds ratio [aOR] for mortality 1.85, 95% confidence interval [CI]: 1.68–2.03, P < 0.01). Patients with colon cancer and hyponatremia also had higher odds of developing sepsis (OR = 2.60), acute kidney injury (OR = 2.63), peritonitis (OR = 2.25), and ICU admission (OR = 2.12) (Table 1). Additionally, hyponatremia was associated with increased resource utilization, as evidenced by a longer mean length of stay and higher mean total hospital charges. Conclusions: This retrospective analysis demonstrated that hyponatremia significantly increases mortality, morbidity, and resource utilization in individuals with CRC. Patients with colorectal cancer and hyponatremia have substantially higher mortality rates, underscoring the importance of monitoring sodium levels and implementing appropriate interventions to prevent and manage this electrolyte imbalance. The high incidence rates of sepsis, acute kidney injury, and peritonitis, along with frequent ICU admissions, provide further evidence of the negative impact of hyponatremia on patient outcomes.
Unveiling the influence of SGLT2 inhibitors on clinical outcomes in patients with cancer with therapy-related cardiac dysfunction: A meta-analysis and systemic review.
Authors: Shafique Nouman , Shaikh Safia , Irshad Khurram , Muhibullah - , Qadeer Abdul , Pulipati Yochitha , Tariq Sheraz Ahmad , Bajwa Shammas , Kaur Navneet , Memon Roha Saeed , Ahmed Shahroze , Naqvi Syed Mujtaba Ali , Umer Ahmed Muaaz , Akbar Usman Ali , Khan Sana , Javeed Zainab , Ghaffar Ali , Gillani Muhammad Usama , Raza Munis , Kirchoff Robert W.
Published: June 2024

e24003

Background: Cancer patients undergoing chemotherapy suffer from a variable degree of cancer therapy–related cardiac dysfunction and heart failure (HF). It is known that sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF independent of diabetes mellitus and left ventricular ejection fraction; our study aims to investigate the potential benefits of SGLT2 inhibitory therapy specifically in cancer patients undergoing chemotherapy. Methods: We performed an electronic search on PubMed, Embase, and Cochrane, from the inception of databases till January 29, 2024, to identify all the articles that compared the use of SGLT2 inhibitors in adult (≥18 years) with type 2 diabetes mellitus and exposure to cardiotoxic antineoplastic therapy, subsequently diagnosed with cardiomyopathy, heart failure, or LVEF < 40%. The data was extracted and pooled using a random effects model to calculate the odds ratio (OR) with a respective 95% confidence interval (CI). R software (v.4.3) was used for all statistical analyses. Results: Our search identified three observational studies with a total of 3,164 patients (SGLT2- inhibitor group: 1,550; Control group: 1,614). We found that the use of SGLT2 inhibitors was associated with a lower risk of all-cause mortality (OR: 0.25 [0.20, 0.31]; I2 = 16%; p < 0.001), hospitalizations from heart failure (OR: 0.25 [0.10, 0.62]; I2 = 0%; p = 0.003), and acute exacerbation of heart failure (OR: 0.35 [0.27, 0.47]; I2 = 0%; p < 0.001). Conclusions: Our findings suggest a favorable association between the use of SGLT2 inhibitors and reduced mortality, as well as improved cardiac clinical outcomes in cancer patients undergoing chemotherapy. However, further validation through large-scale studies and randomized controlled trials across diverse malignancies is warranted to establish the efficacy of these drugs. [Table: see text]
Incidence of cardiotoxicity after high cumulative dose of anthracyclines in adult patients with advanced soft tissue sarcomas: A systematic review and meta-analysis.
Authors: Maravilla Rachelle Diane Bautista , Franco Paula Isabel Gimena , Alcala Gale Rizzae Mercado , Pilapil John Christopher Agsalud , Gorospe Agnes Evangelista , Pascual-Panganiban Anna Marie Mangune
Published: June 2024

e24004

Background: The risk of anthracycline-related cardiotoxicity increases with cumulative dose, with most available literature based from studies on breast cancer patients. Although soft tissue sarcomas are heterogenous entities, anthracycline-based chemotherapy is considered the most active regimen. This study aims to clarify the incidence of cardiotoxicity among patients with advanced soft tissue sarcomas who receive a high cumulative dose of anthracyclines. Methods: We performed a systematic search across PubMed, Cochrane, Google Scholar, and ASCO and ESMO references. Studies were eligible if they (1) investigated soft tissue sarcoma patients, (2) receiving high cumulative doses of doxorubicin ( > 450mg/m2), lipodox ( > 550mg/m2) or epirubicin ( > 900mg/m2), and (3) reported the incidence of cardiotoxicity (clinical and subclinical). Three authors independently assessed validity of the articles using the Cochrane Tool for randomized trials and the Newcastle-Ottawa scale for cohorts. Pooled analysis was performed using MetaXL with the random effects model. Pooled incidence with 95% CI and heterogeneity (Cochran's Q) were determined. Results: For doxorubicin, 4 studies with 168 patients without pre-existing cardiomyopathy, and a mean age of 47 years were included. At a mean cumulative dose of 651.1mg/m2, clinical cardiotoxicity was seen in 2.6% (0.62–5.62%,Q3) while subclinical cardiotoxicity was seen in 23.8%(17.67%-30.53%,Q86). For epirubicin, we included 3 studies with 109 patients, without pre-existing cardiomyopathy, and mean age of 39 years. At a cumulative dose of 1128.33mg/m2, clinical cardiotoxicity was seen in 5.3% (1.74–10.38%,Q25), and subclinical cardiotoxicity was seen in 13.4% (7.62%-20.50%,Q37). Conclusions: The incidence of cardiotoxicity in patients with advanced soft tissue sarcomas receiving high cumulative dose of anthracyclines is comparable with existing data on breast, lymphoma and leukemia patients. Subclinical cardiotoxicity is more prominent. Majority of the patients received cardioprotective strategies during their treatment (dexrazoxane or continuous infusions of doxorubicin). Evidence with regard to lipodox is lacking.
Arterial stiffness and aortic hemodynamics as predictors for new or worsening cardiovascular events in childhood cancer survivors: A report from the St. Jude lifetime cohort.
Authors: Maharaj Arun , Dhaduk Rikeenkumar , Mulrooney Daniel A. , Armstrong Gregory T. , Wogksch Matthew , Hudson Melissa M. , Ehrhardt Matthew J. , Duprez Daniel , Dixon Stephanie B. , Krull Kevin R. , Ness Kirsten K.
Published: June 2024

e24006

Background: Survival following childhood cancer has improved due to advances in treatment and supportive care. However, survivors are at high risk of cardiovascular diseases (CVDs) later in life. Aortic artery stiffening, captured by measuring the speed and magnitude of forward and reflected pulse waves, is an independent predictor of CVD and mortality in the general population. Methods: We evaluated associations between vascular function and new or worsening CVDs [coronary artery disease (CAD), cardiomyopathy, and hypertension (HTN)] among a subset (n = 249) of St. Jude Lifetime Cohort (SJLIFE) participants who had baseline vascular function assessment and returned for a standard follow up study visit (mean age at baseline (years) ± standard deviation: 34 ± 9 years, follow-up: 39 ± 9 years). CVD conditions were graded (dichotomized as grades 0-1 and 2-4) using the Common Terminology Criteria for Adverse Events (CTCAE). Aortic stiffness, brachial and aortic blood pressure (BP), and aortic wave reflection (augmented pressure, augmentation index (AIx), AIx adjusted to a heart rate of 75 beats/min (AIx75), time and magnitude of the forward and reflected waves) were assessed using wave separation analyses. T-tests were used to test mean values between the groups with higher (2-5) and lower (0-1) grades. These tests informed the selection of identified variables for multivariate logistic models, which were adjusted for age, sex, race, body mass index, physical activity, smoking status, drinking behavior and vasoactive medications. Results: Most participants had a history of Hodgkin lymphoma (53.8%) or leukemia (20.5%) and 25.7% other diagnoses. There were 169 (67.9%) participants who had cranial/neck radiation, 167 (67.9%) received anthracyclines, and 150 (60.2%) alkylating agents. At baseline 38.2% had ≥grade 2 HTN, 9.2% cardiomyopathy, and 4% CAD. Having ≥ grade 2 CVDs was significantly associated with augmented markers of brachial and aortic BP, arterial stiffness, and wave reflection. Regression analyses revealed that AIx75 ≥ 17% was associated with an increased risk of new or worsening HTN (odds ratio (OR) 3.29, 95% confidence interval (CI) 1.03-10.48) and new or worsening cardiomyopathy (OR 4.06, 95% CI 1.02-16.16) an average of 5 years after baseline vascular testing. Conclusions: Childhood cancer survivors diagnosed with grades 2-4 CVDs at a baseline visit had elevated aortic stiffness and augmented indices of wave reflection compared to those with < grade 2 CVDs. Elevated AIx75 was associated with new or worsening HTN and cardiomyopathy five years later. Early detection and treatment of vascular dysfunction may ameliorate CVD late effects in childhood cancer survivors.
The metabolic profiles of patients with autologous hematopoietic stem cell transplantation with graft versus host disease.
Authors: Dunham Alden J. , Benyahia Steven , Kansara Bhargav , Ellis Lauren , Eichelberger Gerry Samantha , Ekram Jahanzaib , Alomar Mohammed
Published: June 2024

e24010

Background: Graft versus host disease (GvHD) is a serious inflammatory complication of hematopoietic stem cell transplant (HSCT) and a leading contributor to morbidity and mortality in HSCT patients. Previous studies have identified increased risk of cardiovascular death in HSCT patients who develop GvHD and characterized echocardiographic changes associated with chronic GvHD. However, details of the metabolic derangements in HSCT patients who develop GvHD remain poorly studied. Methods: This is a retrospective study of patients who underwent HSCT at H. Lee Moffitt Cancer Center and later developed severe chronic GVHD at 1 year. Metabolic data including weight, blood pressure, and lipid profile were recorded at baseline and at 1 year after HSCT. Results: Between January 1, 2010, and December 31, 2020, 1805 patients who received allogeneic HSCT were reviewed. At 1 year, 371 patients (20.5%) had severe GVHD. Compared to baseline, patients had higher total cholesterol (209 vs 183 mg/dL, P < 0.001), high-density lipoprotein (61 vs 47 mg/dL, P < 0.001), and triglycerides (211 vs 163 mg/dL, P < 0.001) at 1 year of follow up. Low-density lipoprotein values were not significantly different (107 vs 102 mg/dL, p = 0.15). Patient weight was significantly less at 1 year (163 vs 183 lbs, p < 0.001). Although blood pressure was not significantly different between baseline and 1 year, more patients were placed on antihypertensive medications at 1 year (50% vs 31%). Conclusions: This study finds that patients who undergo allogeneic HSCT and subsequently develop severe GVHD are at risk for metabolic derangements that may worsen cardiovascular health. We specifically demonstrate an increased need for antihypertensive therapy and elevations in total cholesterol and serum triglycerides. Further research is needed on the impact of these derangements on major adverse cardiac events and the role of cardiovascular risk factor management in these patients.
Comparison of infective endocarditis in patients with and without malignancy: A propensity score matched analysis.
Authors: Winn Soe , Kansakar Sajog , Shikhrakar Shreeja , Guragain Ashish , Chudy-Onwugaje Dilichukwu
Published: June 2024

e24030

Background: Cancer patients are at a higher risk of infective endocarditis (IE) due to immunosuppressed state, indwelling catheters and recurrent infections. Due to the clinical scenario being relatively uncommon, there is lack of real-world data on prevalence, trends and outcomes of IE in cancer patients. Methods: We extracted data from the National Inpatient Sample (NIS) Database from 2016 to 2020. We included all admissions ≥18 years old with a principal diagnosis of IE with and without a cancer diagnosis using International Classification of Diseases Tenth Revision (ICD-10) codes. Propensity score matching was performed to balance hospital characteristics, patient demographics and comorbidities between the two groups. Univariate logistic regression was performed in the balanced cohorts. The primary outcome was inpatient mortality. Analysis was performed using STATA-MP, version 14.2. Results: A total of 70,225 admissions for IE were identified between 2016-2020, of which 2,294 (3.27%) had a history or active cancer. The annual number of admissions for IE did not show a significant change (p trend = 0.56); however, the proportion of IE patients with cancer doubled from 2.33% to 4.61% (p trend < 0.01) over the study period. After propensity score matching, there was no significant difference in in-hospital mortality (odds ratio [OR] 1.30, 95% CI 0.79-2.16, p = 0.31) between IE patients with and without cancer. Cohort with cancer had lower odds of experiencing respiratory failure (OR 0.52, 95% CI 0.33-0.83, p < 0.01) and stroke (OR 0.35, 95% CI 0.25-0.49, p < 0.01), although venous thromboembolism was more common in cohort with cancer (OR 3.03, 95% CI 1.76-5.21, p < 0.01). There was no difference in acute kidney injury or shock between the two groups. Cohort with cancer was less likely to undergo valve replacement surgery (OR 0.42, 95% CI 0.31-1.24, p < 0.01). The median length of stay (11 days vs 14 days, p < 0.01) and hospital charges ($70,698 vs $86,763, p < 0.01) were higher in the cohort without cancer. Conclusions: Underlying cancer was seen in growing proportion of admissions for IE over the study period. The pattern of complications was different between patients with and without cancer, which underscores the importance of cancer history in management of IE. Although there was no difference in mortality between patients with and without cancer, patients with cancer were less likely to undergo valve replacement surgery during the admission. Further research is needed to explore the specific factors influencing treatment decisions and long-term outcomes in cancer patients with IE.