Tract Toxicity Research Articles

Abstract 3148: ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers

Abstract Lung cancer has the highest rates of incidence (2.1 million cases/year) and mortality (1.8 million deaths/year) among all cancers worldwide. Approximately 15% of lung cancers are small cell lung cancer (SCLC). SCLC is typically diagnosed at late stages, with approximately 70% of patients having extensive stage disease at time of diagnosis. Unfortunately, these patients have a dismal 5-year survival rate of approximately 3%. In contrast to non-small cell lung cancer (NSCLC), there has been little advancement in the treatment of SCLC, with no biomarker directed therapies available for patients. SEZ6 is overexpressed in most SCLC’s and other neuroendocrine tumor types. This overexpression and limited normal tissue expression suggest SEZ6 would be a good target for the development of an antibody drug conjugate (ADC). Validation of SEZ6 as an ADC target was supported by signs of clinical activity for ABBV-011, a SEZ6-targeting calicheamicin ADC. Preclinical and clinical data suggest an increased therapeutic index for Top1i ADCs relative to calicheamicin ADCs. Furthermore, Top1i inhibition is an effective mechanism of action in SCLC with topotecan approved in 2L, although significant toxicity limits broad utility. As such, we hypothesized that a SEZ6-Top1i ADC would enable effective Top1 inhibition in tumor cells and reduce toxicity relative to ABBV-011 or systemic chemotherapy, driving increased therapeutic benefit. ABBV-706 is an ADC comprised of the same SEZ6 targeting antibody as ABBV-011 conjugated to AbbVie’s topoisomerase-1 (Top1) inhibitor. ABBV-706 is a potent anti-proliferative agent in SEZ6 positive SCLC cell lines, with sub- to low-nanomolar activity. SEZ6 dependence was demonstrated by the correlation of SEZ6 mRNA expression to ABBV-706 growth inhibition. On-target Top1i activity was confirmed in cells treated with ABBV-706 as measured by dose-dependent induction of γ-H2AX, a marker of DNA damage, and G2/M arrest. ABBV-706 possessed superior anti-tumor activity compared to ABBV-011 in a panel of SCLC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models with a range of SEZ6 expression levels. In addition, ABBV-706 had activity in the setting of resistance to cisplatin/etoposide (1L SoC in SCLC), in combination with cisplatin, and in SEZ6-expressing neuroendocrine liver and cervical PDX models. ABBV-706 has favorable pharmacokinetics and is well-tolerated in cynomolgus monkeys with bone marrow and gastrointestinal tract toxicities common to other Top1 inhibitors. ABBV-706 shows promise as an agent for the treatment of SCLC and other difficult to treat SEZ6 expressing neuroendocrine tumors. ABBV-706 has completed dose escalation, and dose expansion is currently ongoing in a Phase 1 FIH clinical study (NCT05599984). Citation Format: Emily J. Faivre, Marybeth A. Pysz, Eoghainín Ó hAinmhire, Laura Kreckler, Kelly Doyle, Aloma D'Souza, Zhiyong Ding, Trusha Sondkar, Dolonchampa Maji, Fan Zhao, Andrew Phillips. ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3148.

In-silico approach: predictive ADME/T properties and ACE inhibitory action of isolated compounds of Aspidopterys sps

The current research study aimed to study Isolated phytocompounds of Aspidopterys sps (A. indica and A.cordata) by invitro antihypertensive activity, in-silico molecular docking, and ADME/T analysis. The preceding reports had revealed a fact of polyphenols and triterpenoids have an ability to control blood pressure by inhibition of Angiotensin converting enzyme (ACE). The isolated ligands Catechin, Isoorientin, Fisetin, and Ursolic acid (A , B, C and D) tested for ACE inhibition, docked with target Human Angiotensin-converting enzyme employing Autodock 4.2, drug-likeliness, physicochemical nature, toxicity prediction by Swiss ADME, ProTox tools available online. All phytoconstituents showed optimistic dose-responsive inhibition, Compounds exhibited magnificent IC50 (15.38 ± 0.53) μg/ml, B (20.21± 0.34 μg/ml), C (17.62 ± 0.78 μg/ml), D (23.98 ± 0.65 μg/ml), Captopril (15.86±0.32 μg/ml). Molecule A showed utmost binding energy (-7.3 K.cal/mol) significant alignment with target protein and good interactions compared to Captopril (-6.7) and Lisinopril (-7.38 K.cal/mol). Prediction of ADME/T and ligands showed good pharmacokinetic properties characterized by high absorption in the gastrointestinal tract, oral bioavailability, and minimal toxicity and high binding energies, so these bioactive compounds could be further explored as possible antihypertensive drugs.

Evaluation of the toxicity of prophylactic extended-field radiation therapy with volumetric modulated arc therapy in combination with concomitant chemoradiotherapy in patients with locally advanced stage IIIC1r cervical cancer according to the 2018 FIGO classification.

To evaluate the toxicity of prophylactic extended-field radiation therapy (EFRT) combined with volumetric modulated arc therapy (VMAT) in combination with cisplatin chemotherapy for locally advanced stage IIIC1r cervical cancer [2018 International Federation of Gynecology and Obstetrics (FIGO)]. Thirty patients with stage IIIC1r cervical cancer were treated with EFRT combined with concurrent cisplatin. Acute toxicities were evaluated according to the common terminology criteria for adverse events (CTCAE v.5). Delayed toxicities were evaluated according to the classification criteria of radiation damage toxicity of the Radiation Therapy Oncology Group (RTOG). The efficacy of the regimens was evaluated using response evaluation criteria in solid tumors (RECIST v1.1). Spearman correlation was used to analyze the correlation between acute gastrointestinal toxicity (nausea) and the small bowel V45. Predictive value analysis was performed using a receiver operating characteristic (ROC) curve. There were no grade ≥ 3 acute toxicities. The most common acute toxicity observed was nausea (grade 2 in 40%), which was positively correlated with the volume of the small intestine receiving 45 Gy. When the V45 of the small intestine was > 83.2 cc, the risk of grade 2 acute upper digestive tract toxicity (nausea) increased. The major late toxicities had the following distributions: Grade 1 diarrhea, 36.7%; Grade 1 abdominal pain, 13.3%; and Grade 1 radiation cystitis. No grade ≥ 2 late toxicities were observed. Treatment of locally advanced stage IIIC1r cervical cancer with EFRT combined with VMAT and concurrent cisplatin chemotherapy was well tolerated, and the acute toxicity profile was acceptable. Significant grade 3 acute/delayed toxicities were not observed.

Hyaluronan nanoplatelets exhibit extended residence time compared to spherical and ellipsoidal nanomaterials with equivalent surface potentials and volumes after oral delivery in rats.

The physicochemical properties of colloidal particles-such as size, surface properties, and morphology-play a crucial role in determining their behaviors and transit through the gastrointestinal (GI) tract. While some data exist for nonspherical nanomaterials (NMs) composed of silica or polystyrene, there is limited understanding of NMs composed of polysaccharides and polymers. This study explores the fate and GI tract residence time of hyaluronan-based NMs with distinctive hexagonal morphology and flat surfaces (nanoplatelets) following administration to rats. The behavior of these nanoplatelets was compared to NMs with spherical and ellipsoidal morphologies. The three types of NMs were labeled with a near-infrared dye (Cy5.5) and administered in single doses to healthy rats, followed by real-time in vivo imaging over 24 hours. The results revealed that altering NM morphology from spherical to ellipsoidal did not significantly affect GI tract residence time or toxicity profiles in vitro and in vivo. However, nanoplatelets exhibited a stronger Cy5.5 fluorescence signal in the abdominal region and demonstrated slower gastric emptying than spherical and ellipsoidal NMs. Ex vivo analysis of excised GI tracts rinsed with saline indicated that nanoplatelets adhered more effectively to the tightly bound mucus layer. Furthermore, histological examination of colon sections showed that nanoplatelets induced a minimal global inflammation score comparable to that of healthy rats. This study underscores the potential of hyaluronan-based nanoplatelets for oral administration, offering promising directions for both fundamental research and practical applications in nanomedicine.

A disproportionality analysis of adverse events caused by GnRHas from the FAERS and JADER databases.

Gonadotrophin-releasing hormone analogs (GnRHas) play a significant role in addressing gynecological diseases, central precocious puberty, and cancer. However, ensuring the safety of GnRHas in real-world applications requires continuous vigilance. In light of this, we undertook a disproportionality analysis focused on adverse events (AEs) associated with GnRHas using data from both the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER). We evaluated GnRHas-associated AEs and characterized the clinical priority of unlisted AEs caused by each GnRHa from the different databases. In the disproportionality analysis, we applied two adjusted algorithms to identify signals related to GnRHas in the FAERS and JADER databases from 2004 to 2023. Additionally, we utilized the Statistical Analysis System (SAS, 9.4) to examine potential and high-aROR (adjusted reporting odds ratio) signals associated with GnRHas. We performed clinical priority assessment for suspicious PTs and an analysis of serious/non-serious outcomes. We also gathered information on the onset times of AEs linked with GnRHas from both databases. From January 2004 to September 2023, FAERS and JADER recorded a total of 50,360,413 and 1,440,200 AEs, respectively. Employing two algorithms, the suspicious preferred terms (PTs) related to leuprolide (Leu) were 562 potential PTs (44 unlisted in specifications), followed by goserelin (Gos) with 189PTs (28 unlisted), triptorelin (Tri) with 172PTs (28 unlisted), and Leu-JADER with 85PTs (10 unlisted). At the same PT level, the differences in GnRHas between the two databases were observed, such as cardiac failure, diabetes mellitus, liver disorder, dementia, suicidal ideation, interstitial lung disease, urinary disorders, and hypertensive crisis. In an analysis of serious vs. non-serious outcomes, a total of 43 AEs of Leu were more likely to be reported as serious AEs with p < 0.05 (such as asthenia, urinary retention, diabetes mellitus, interstitial lung disease, gait disturbance, and so on), following by Tri (6 AEs), and Gos (4 AEs). Based on the clinical priority score, 41PTs of Leu, 26PTs of Tri, 24PTs of Gos, and 8PTs of Leu-JADER were graded as weak. There were 3PTs of Leu, 2PTs of Tri, 4PTs of Gos, and 2PTs of Leu-JADER that were graded as moderate. Notably, in the assessment of the relevant evidence, 2PTs (loss of libido and urinary tract toxicity caused by Leu), 1PT (electrolyte imbalance caused by Tri), and 2PTs (anorexia and suicidal ideation caused by Gos) showed a strong level of evidence with "++." The differences in the signal strength of the same PTs from two databases were also worth noting. Moreover, the median onset time for GnRHas (Leu, Tri, and Gos) was 23days (0, 298), 22days (0, 181), and 217days (29, 706), respectively, as median (Q1, Q3). An examination of two databases revealed suspicious AEs associated with GnRHas. Our study found potential new AE signals of GnRHas and supported continuous clinical monitoring, pharmacovigilance, regional differences, and further studies of GnRHas.

Dose-Volume Parameters to the Urinary Tract Sub-Volumes and Predictors of Genitourinary Acute Toxicity in a Phase 2 Clinical Trial Assessing MRI-Guided Prostate Boost for Localized Prostate Cancer - The Miami BlastM Trial.

The relationship between radiotherapy dose to the sub-volumes of the genitourinary (GU) tract and GU toxicity is poorly understood, particularly in prostate cancer patients treated with an intraprostatic dominant lesion (IDL) boost. While the use of IDL boost improves outcomes, it results in higher doses to GU structures and potentially increased toxicity. We investigated the association between dose-volume histogram (DVH) parameters for urinary tract sub-volumes and GU toxicity in the context of IDL boost in patients enrolled in the Miami BlastM Trial. DVH data were assessed for patients enrolled in the Miami BlastM, a randomized phase 2 trial (NCT20140627) evaluating upfront versus integrated IDL boost. IDL GTV boost consisted of either 12-14 Gy administered on day 1 or integrated boost of 2.4 Gy per fraction (91.2 Gy total, 98.5 Gy 2.0 Equiv), with the prostate receiving 76 Gy in 38 fractions. Bladder trigone (BTg) and urethra sub-volumes were contoured retrospectively on planning CT scans. GU toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE) version 4 and International Prostate Symptom Score (IPSS). DVHs of the bladder, BTg, bladder minus BTg, prostatic urethra, and bulbomembranous urethra were examined. The primary composite endpoint was CTCAE GU acute toxicity grade (G) ≥2 and/or IPSS increase of ≥10 from baseline. Secondary endpoints were GU acute toxicity G≥2, GU late toxicity G≥2, and IPSS increase of ≥10 from baseline. Univariable and multivariable logistic regression analyses were performed. A total of 129 patients treated between February 2015 and January 2022 were eligible for analysis. One hundred and one (78%) patients developed either GU acute toxicity G≥2 (68%) and/or an IPSS increase of ≥10 from baseline (30%). Less than 2% of patients developed GU toxicity G≥3. BTg V30 Gy was significantly associated with IPSS increase ≥10 (p = 0.046). The bulbomembranous urethral maximum dose was significantly associated with GU acute toxicity G≥2 and GU late toxicity G≥2 (p <0.05 for both). Average maximum and mean urethral doses were 88.9 and 81.5 Gy, respectively. The BTg maximum dose, V20 Gy, V30 Gy, and V40 Gy were not significantly associated with the primary composite endpoint (p = 0.56, 0.75, 0.89, 0.82, respectively). On multivariable analysis, a higher bulbomembranous urethral maximum dose was significantly associated with GU acute toxicity G≥2 and/or IPSS increase of ≥10 from baseline (p = 0.019). Our data suggest a dose-effect relationship between maximum doses to the bulbomembranous urethra and GU toxicity. A better understanding of RT-related changes to specific sub-volumes of the urethra and strategies to mitigate urethral dose could enhance the therapeutic ratio in prostate cancer patients treated with MRI-guided IDL boost.

Biomodified Extracellular Vesicles Remodel the Intestinal Microenvironment to Overcome Radiation Enteritis.

Ionizing radiation (IR) is associated with the occurrence of enteritis, and protecting the whole intestine from radiation-induced gut injury remains an unmet clinical need. Circulating extracellular vesicles (EVs) are proven to be vital factors in the establishment of tissue and cell microenvironments. In this study, we aimed to investigate a radioprotective strategy mediated by small EVs (exosomes) in the context of irradiation-induced intestinal injury. We found that exosomes derived from donor mice exposed to total body irradiation (TBI) could protect recipient mice against TBI-induced lethality and alleviate radiation-induced gastrointestinal (GI) tract toxicity. To enhance the protective effect of EVs, profilings of mouse and human exosomal microRNAs (miRNAs) were performed to identify the functional molecule in exosomes. We found that miRNA-142-5p was highly expressed in exosomes from both donor mice exposed to TBI and patients after radiotherapy (RT). Moreover, miR-142 protected intestinal epithelial cells from irradiation-induced apoptosis and death and mediated EV protection against radiation enteritis by ameliorating the intestinal microenvironment. Then, biomodification of EVs was accomplished via enhancing miR-142 expression and intestinal specificity of exosomes, and thus improved EV-mediated protection from radiation enteritis. Our findings provide an effective approach for protecting against GI syndrome in people exposed to irradiation.

Clinical influence of neoadjuvant chemoradiotherapy on immunonutritional status in locally advanced rectal cancer.

Cancer patients receiving various anti-cancer treatments commonly experience malnutrition, and many studies have reported that nutritional status is associated with survival and prognosis. Although standard neoadjuvant chemoradiotherapy (CRT) is commonly used in patients with locally advanced rectal cancer owing to its tumor-downsizing and downstaging effects, there is a lack of research on the impact of patients' nutritional status on the efficacy of neoadjuvant CRT. We investigated the immunonutritional markers before and after long-course neoadjuvant CRT in 131 patients diagnosed with locally advanced rectal cancer from March 2013 to March 2022. We divided the patients into two groups: a low prognostic nutritional index (PNI) with a cutoff value of 50.92, and a high PNI. In both groups, significant decreases in lymphocyte count and PNI and an increase in neutrophil-to-lymphocyte ratio (NLR) were observed before and after CRT (P<0.001). Furthermore, a higher proportion of patients experienced adverse effects in the low PNI group than in the high PNI group (76.6% in low PNI vs. 54.8% in high PNI, P=0.013). The most commonly reported CRT-induced adverse effect was lower gastrointestinal tract toxicity. By measuring the PNI and NLR without additional tests prior to starting neoadjuvant CRT in patients with locally advanced rectal cancer, it is possible to predict the risk of acute adverse effects caused by CRT. Additionally, providing external nutritional support to reduce the immunonutritional changes that occur during CRT can decrease side effects and potentially increase treatment compliance.

Abstract 34: Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania

Abstract Purpose: Global advancement in pediatric cancer treatment has significantly increased survival rates for children with cancer. Childhood cancer survivors (CCS) now represent a growing population at risk of potentially debilitating late effects of their treatment. This study evaluates the potential risk for long-term complications related to cancer therapy among childhood cancer survivors who completed treatment in Tanzania at Bugando Medical Centre (BMC), and compares the relative risk assessment of childhood cancer survivors at BMC as compared to the published British Childhood Cancer Survivor Study (BCCSS) cohort. Methods: Files of all patients age &amp;lt;18 yo with an oncologic diagnosis who received and completed their treatment at BMC from 2016 to 2020 were retrospectively reviewed. Extracted data included patient demographics, primary disease diagnosis and site, treatment received, and cumulative treatment doses. BCCSS risk assessment was assigned and predicted long-term follow-up surveillance needs were extrapolated from published Children’s Oncology Group Long-Term Follow-Up Guidelines. Results: 190 patients were initially identified, with 17 excluded due to missing treatment information. Among the remaining 173 patients, the mean age was 7yo, 47% were female (n=82), and the most common diagnoses were Wilms tumour (30%, n=52) and Burkitt’s Lymphoma (26%, n=45). 98% received chemotherapy (n=170), 42% (n=73) underwent tumour resection, and 8% (n=18) received radiation. Distribution of BCCSS late effect risk assessment included 6% low risk (n=10), 80% moderate risk (n=139) and 14% (n=24) high risk. This was a higher rate of moderate/severe risk (94%) compared to the published UK BCCSS cohort (84%). Based on treatment received, the late effects with highest potential risk were cardiomyopathy (57% of patients, n=98), bladder and urinary tract toxicity (50%, n=87), and ototoxicity (22%, n=38). Conclusion: Childhood cancer survivors at BMC have a higher risk of late effects as compared to published survivor cohorts in high-income countries. There is a need to develop and improve long-term follow-up care for survivors by enhancing patient and provider education to promote early detection of late effects. Based on risk assessment, survivorship programs in Tanzania should at a minimum include the capacity to perform echocardiograms, urinalysis, renal ultrasound, audiological evaluation, fundoscopic and neurological exams, and renal function test. Citation Format: Goodluck Nchasi, Gaudence Ajuaye, David Noyd, Hannah Spiegl, Erica Sanga, Heronima Joas, Kristin Schroeder. Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 34.

CsPbBr3 Perovskite Nanoparticles causes Colitis-Like Symptom via Promoting Intestinal Barrier Damage and Gut Microbiota Dysbiosis.

Lead-based perovskite nanoparticles (Pb-PNPs) with superior optoelectronic properties are promising alternatives for the next generation of photovoltaics materials. This raises a great concern about their potential exposure toxicity in biological systems. However, little is known about their adverse effects on the gastrointestinal tract system so far. Here, the aim is to investigate the biodistribution, biotransformation, potential gastrointestinal tract toxicity, and effect on the gut microbiota after oral exposure to the CsPbBr3 perovskite nanoparticles (CPB PNPs). The advanced synchrotron radiation based microscopic X-ray fluorescence scanning and X-ray absorption near-edge spectroscopy demonstrate that high doses of CPB (CPB-H) PNPs can gradually transform into different lead-based compounds, subsequently accumulating in the gastrointestinal tract, especially the colon. Meanwhile, the pathological changes of stomach, small intestine, and colon reveal that CPB-H PNPs have higher gastrointestinal tract toxicity than Pb(Ac)2 , consequently leading to colitis-like symptoms. More importantly, 16S rRNA gene sequencing analysis discloses that CPB-H PNPs cause more significant alterations in the richness and diversity of the gut microbiota related to inflammation, intestinal barrier, and immune function than Pb(Ac)2 . The findings may contribute to shedding light on understanding the adverse effects on gastrointestinal tract and gut microbiota of Pb-PNPs.

Abstract 6311: ABBV-400: An ADC delivering a novel topoisomerase 1 inhibitor to c-Met-positive solid tumors

Abstract Antibody-drug conjugate (ADC) technology is founded on the premise that antigen-mediated payload delivery selectively targets tumor cells and spares normal tissue. While approval of several ADCs has proven this to be a successful therapeutic approach, there remain opportunities to generate optimized ADCs with tailored selection of antigen matched with payload highly active in the target indication. To this end, ABBV-400 has been developed as an ADC that targets c-Met and topoisomerase-1 (Top1), both of which are overexpressed in solid tumors. The antibody is directed to the cell surface tyrosine kinase receptor, c-Met, a key driver of tumor cell growth and development of resistance to EGFR-targeted and other targeted therapeutics. Supporting this, Teliso-V, a c-Met-targeted ADC with MMAE payload, has been granted Breakthrough Therapy Designation in non-small cell lung cancer (NSCLC). To extend activity of a c-Met-targeted ADC to patients with tumors expressing lower c-Met levels and to indications, such as colorectal cancer (CRC), where MMAE-based ADCs have not been effective, a novel topoisomerase-1 inhibitor linker-drug was developed. Screening over 400 linker-drugs identified a unique, potent Top1 inhibitor with a cleavable valine-alanine linker and stable bromoacetamide attachment designed to minimize systemic payload release. Preclinically ABBV-400 exhibits favorable pharmacokinetics, anti-proliferative activity in vitro, and compelling efficacy in NSCLC, gastroesophageal, and CRC xenograft models. Furthermore, ABBV-400 is well tolerated by cynomolgus monkeys with bone marrow and gastrointestinal tract toxicities common to other Top1 inhibitors. This pairing of a novel linker-drug and an antibody with demonstrated clinical activity provides an exciting opportunity to treat patients with c-Met expression in indications sensitive to Top1 inhibition. ABBV-400 has progressed through dose escalation, and dose expansion is currently ongoing in a Phase 1 FIH clinical study (NCT05029882). All authors were employees of AbbVie during this research. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication Citation Format: Regina M. Reilly, Cheng Ji, Ryan P. Matuszak, Mark G. Anderson, Lora Tucker, Nadezda Klunder, Adelyn L. Lazo, Erwin R. Boghaert, Marybeth A. Pysz, Aloma D’Souza, Laura Kreckler, Milan Bruncko, Brittney J. Mills, Matthew Ravn, George Doherty, Kevin J. Freise, Andrew C. Phillips. ABBV-400: An ADC delivering a novel topoisomerase 1 inhibitor to c-Met-positive solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6311.

The Safety and Efficacy of Salvage Stereotactic Radiation Therapy in Patients with Intraprostatic Tumor Recurrence After Previous External Radiation Therapy: Phase 1 Results from the GETUG-AFU 31 Study

BackgroundThere is no consensus on the best local salvage treatment for prostate cancer recurrence after primary external beam radiotherapy. Prospective data on stereotactic body radiation therapy (SBRT) are very scarce. ObjectiveTo determine the optimal dose regimen for salvage SBRT. Design, setting, and participantsThe present report concerns the phase 1 part of the GETUG-AFU 31 multicenter open-label study. The main inclusion criteria were histologically proven biochemical recurrence, clinical stage T1-T2 upon relapse, multiparametric magnetic resonance imaging data, prostate-specific antigen (PSA) level ≤10 ng/ml prior to salvage SBRT, PSA doubling time >10 mo, and an International Prostate Symptom Score of ≤12. InterventionFive or six fractions of 6 Gy were delivered using focal SBRT. Outcome measurements and statistical analysisDose-limiting toxicity (DLT) was defined as grade ≥3 gastrointestinal or genitourinary tract toxicity, or any grade 4 toxicity (according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03) occurring in the first 18 wk following treatment initiation. A time-to-event continual reassessment method was used to select the dose regimen. Results and limitationsTwenty-one patients were treated (median [interquartile range] age: 76.8 yr [72.2–80.8]), including 12 at 6 × 6 dose level. No DLT was observed. The acute grade 2 genitourinary tract toxicity rate was 19%. With a median follow-up of 12.3 mo, the estimated cumulative incidence of late grade 2 genitourinary toxicity was 41.2% (95% confidence interval: 18.1–63.1%). No grade >2 genitourinary toxicity and no grade ≥2 gastrointestinal toxicity were reported. All treated patients were alive and relapse free at the last follow-up. ConclusionsA 6 × 6 Gy dose regimen was selected for our phase 2 study of salvage SBRT. With a short follow-up period, the level of toxicity appears to be acceptable. Patient summaryThere is no consensus on the best local treatment for patients with local relapse after radiotherapy for prostate cancer. Prospective data are very scarce. Our early phase trial allowed us to recommend six fractions of 6 Gy using high-precision radiotherapy for further studies.

Venetoclax-Targeted Therapy in t(11;14) AL Amyloidosis Patients after Frontline Daratumumab and Cybord: A Retrospective Analysis from the French Amyloidosis Network

Background: Systemic AL amyloidosis is caused by the deposition of misfolded monoclonal immunoglobulin serum free light chains (sFLC) in various organs. Treatment of AL amyloidosis relies mainly on chemotherapy aimed at suppressing the underlying secreting plasma cell clone. Organ responses and survival are greatly influenced by the degree of hematological response evaluated by the decrease in sFLC. Over the last 2 years, anti CD38 monoclonal antibodies (mAb), such as daratumumab (DARA), have emerged as breakthrough targeted therapies for patients (pts) with AL amyloidosis and DARA received approval in combination with CyBorD in frontline pts. Unfortunately, some pts will still not achieve complete response (CR) or ultimately relapse. BCL-2 inhibition represents a promising therapeutic approach in plasma cells dyscrasia and venetoclax (VEN) is an oral BCL-2-selective BH3 mimetic. VEN has shown activity in multiple myeloma (MM) cell lines with t(11;14), partly because of greater BCL-2 co-dependence of such clones. VEN is safe in MM pts with encouraging clinical efficacy. VEN should provide a novel targeted therapy in AL amyloidosis as 50-60% of the pts have a t(11;14). Various retrospective cohorts are now reported with VEN alone or in combination with bortezomib (BOR) and/or DARA, with rapid and deep hematological and organ responses. Objective: To report efficacy of VEN based regimen in AL amyloidosis pts as consolidation or relapsed therapy in frontline AL pts treated with DARA-CyBorD or equivalent. Material & Methods: In this retrospective study, we reviewed charts of 9 pts with AL amyloidosis, from the French Amyloidosis Network, who received VEN as part of their regimen as consolidation (n=3) or for biological progressive disease (n=6) after DARA-CyBorD frontline therapy. Individual data were prospectively and retrospectively collected in the French Amyloidosis database. Pts should have received at least 1 cycle of VEN-containing regimen to be analyzed. Responses were reviewed using current criteria for CR (serum and urine negative immunofixation and normal involved FLC) and for very good partial response (VGPR;differential FLC<40 mg/l). Results: Regarding baseline characteristics (Table 1), pts had a median age of 67 years (IQR:61-71) and all except one had more than 10% bone marrow plasma cells (but no overt MM). Six pts had ≥2 organs involved with heart in 67 % and kidney in 56 %; 6 had MAYO stage 3/4 and median NT-proBNP/troponin levels were 3333 ng/l (IQR:185-9685) and 44 pg/ml (IQR:18-96), respectively. Six pts had FLC only AL amyloidosis. Median dFLC for the whole cohort was 255 mg/l (IQR:140-1060), and 6 pts had baseline dFLC>180 mg/l. All pts had t(11;14) with an additional 11q gain in 3, and 1q gain in 1. Median time from diagnosis to VEN therapy was 6.0 months (IQR: 2.5-7.5). Regarding frontline therapy, 7 pts received DARA-CyborD (median 3 cycles), 1 DARA-CyBorD plus CAEL and 1 pt received DARA-RVD. All pts were DARA exposed, 8 pts had a suboptimal response to DARA and 2 were DARA "refractory". Five pts never reached VGPR or better with DARA-based regimen. VEN (400 mg/day) was given alone in 1 pt or in association with dexamethasone/DEXA (n=1), BOR (n=2), or DARA+BOR (n=5); Median time on therapy was 7.0 months (IQR:3.0-9.5). At data cut-off (06/2022), 6 pts had discontinued therapy because of CR (n=5) and/or GI tract toxicity (n=4). The hematologic response rate was 89%; 78% of pts achieved CR, and 11% partial response (PR) (Figure 1). Among CR pts, all pts achieved dFLC<10 mg/l, and 2 had an iFLC<10 mg/l. Responses were fast and median time to CR was 1 month (IQR:1-3). Regarding VEN monotherapy +/_ DEXA, 50% of pts reached CR; with the addition of BOR, or DARA+BOR, CR was 100, and 80%, respectively. In consolidation pts, all pts achieved CR in 1 month (1-3) with the addition of VEN to DARA-CyBorD. In progressive/relapsed pts, 4/6 (67%) achieved CR and 1 was in stable disease. One pt reached PR and progressed to end-stage renal disease. Finally, both DARA R/R pts reached CR with VEN alone or in association with BOR. Summary & Conclusion: Venetoclax is a promising targeted therapy in AL amyloidosis. Venetoclax can be used in combination with daratumumab and/or bortezomib as consolidation or relapsed therapy after frontline DARA-CyBorD, even in refractory patients, with expected good safety profile. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Optimisation of Radiation Therapy in Bladder Preservation Therapy for Patients With Clinical Stage T2N0M0 Bladder Cancer

AimsA novel bladder preservation therapy, the OMC (Osaka Medical College) regimen, which combines radiation therapy with balloon-occluded arterial infusion of anticancer agents, is a treatment option for patients with muscle-invasive bladder cancer (MIBC). We retrospectively analysed the effects of changes in radiation dose and irradiation field on treatment efficacy and adverse events.The purpose of this study is to use the results of this study to help determine a course of radiation therapy for bladder preservation therapy of cT2N0M0 MIBC. Materials and methodsWe examined 352 patients with clinical stage T2N0M0 (cT2N0M0) MIBC classified into the following groups based on the irradiation method: group A, the whole pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group B, the small pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group C, the whole pelvis (40 Gy/20 fractions) + local bladder (10 Gy/5 fractions). ResultsThe complete response rate, 3-year overall survival and progression-free survival rates in group A were 92.9%, 94.9% and 82.1%, respectively; in group B were 87.2%, 86.7% and 76.7%, respectively; and in group C were 95.2%, 92.6% and 71.1%, respectively. No significant differences between the groups were noted. The incidence of ≥grade 3 urinary tract and gastrointestinal toxicities were not significantly different among the groups (group A: 7.8%, 1.7%; B, 11.1%, 0%; C, 7.1%, 1.8%, respectively). The 3-year progression-free rates of the common iliac lymph node (CILN) region in patients who received whole-pelvis and small-pelvis irradiation were 99.0 and 89.0% (P < 0.01), respectively, with the latter group having significantly high lymph node recurrence in the CILN region. ConclusionsOur findings showed that the optimal radiation therapy for patients with cT2N0M0 MIBC undergoing the OMC regimen is whole-pelvis irradiation including the CILN region, with a total dose of 50 Gy/25 fractions.

Sexual dimorphism in gut microbiota dictates therapeutic efficacy of intravenous immunoglobulin on radiotherapy complications

IntroductionWith the mounting number of cancer survivors, the complications following cancer treatment become novel conundrums and starve for countermeasures. Intravenous immunoglobulin (IVIg) is a purified preparation for immune-deficient and autoimmune conditions. ObjectivesHere, we investigated whether IVIg could be employed to fight against radiation injuries and explored the underlying mechanism. MethodsHematopoietic or gastrointestinal (GI) tract toxicity was induced by total body or abdominal local irradiation. High-throughput sequencing was performed to analyze the gut microbiota configurations and gene expression profile of small intestine. The untargeted metabolomics of gut microbiome was assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analyses. Hydrodynamic-based gene delivery was used to knockdown the target genes in vivo. ResultsIntravenous injection of IVIg protected against radiation-induced hematopoietic and GI tract toxicity in female mice but not in males. IVIg structured sex-characteristic gut microbiota configurations in abdominal irradiated mice. The irradiation enriched gut Lachnospiraceae in female mice but reduced those in males. IVIg injection combined with oral gavage of Lachnospiraceae or its metabolite hypoxanthine, alleviated radiation toxicity in male mice however, Lachnospiraceae or hypoxanthine alone failed to ameliorate the injuries. Abdominal local irradiation drove sex-distinct gene expression signatures in small intestine. Mechanistic investigation showed that replenishment of Lachnospiraceae or hypoxanthine offset abdominal radiation-reduced PLD1 expression in male mice. In females, irradiation elevated PLD1 expression. Deletion of PLD1 in GI tract of female mice erased the radioprotective effects of IVIg. ConclusionIVIg battles against radiation injuries in a sex-specific, gut microbiome-dependent way through Lachnospiraceae/hypoxanthine/PLD1 axis. Our findings provide a sex-precise therapeutic avenue to improve the prognosis of cancer patients with radiotherapy in pre-clinical settings.

The respiratory cytotoxicity of typical organophosphorus flame retardants on five different respiratory tract cells: Which are the most sensitive one?

Triphenyl phosphate (TPHP) is a frequently used flame retardant and indoor semi-volatile pollutant exposing humans with endocrinal disrupting effects. However, its respiratory tract toxicity remains unclear. Herein, we mainly focused on exploring the cytotoxicity of TPHP to the cells from five different parts of the human respiratory tract (from top to bottom): human nasal epithelial (HNEpC) cells, human bronchial epithelial (16HBE) cells, normal nasopharyngeal epithelial (NP69) cells, human lung epithelial cells (Beas-2B) cells, and human lung fibrocells (HFL1 cells) cells. The cell viability, micronucleus induction, endoplasmic reticulum stress gene, intracellular Ca2+ concentration, mitochondrial membrane potential (MMP) were investigated in short-term as well as extended exposure of TPHP. HFL1 and HNEpC cells were found to be irreversible damage, while other three type cells achieved homeostasis through self-rescue. Moreover, expression of downstream genes of Nrf2 signaling pathway were upregulated for 1.3–7.0 times and glutathione detoxification enzyme activity changed for 2–10 (U/mg protein) in HNEpC cells. Furthermore, the vascular endothelial growth factor (VEGF), a disease-related factor, increased 1.0–3.5-fold in HNEpC cells. RNA-sequencing results suggested that protein linkage recombination, molecular function regulation and metabolic processes signal pathway were all affected by TPHP exposure in HNEpC. This is a first report to compare respiratory cytotoxicity in whole human respiratory tract under OPFR exposure and found HNEpC cells were the most sensitive target of TPHP. Molecular biological mechanisms uncovered that TPHP exposure in HNEpC can induce the activation of MAPK signal pathway and demonstrate potential respiratory growth differentiation and stress disorder in human nasal cells upon TPHP exposure.

Identification of Escherichia coli β-glucuronidase inhibitors from Polygonum cuspidatum Siebold &amp; Zucc.

Gut bacterial β-glucuronidase (GUS) can reactivate xenobiotics that exert enterohepatic circulation- triggered gastrointestinal tract toxicity. GUS inhibitors can alleviate drug-induced enteropathy and improve treatment outcomes. We evaluated the inhibitory effect of Polygonum cuspidatum Siebold & Zucc. and its major constituents against Escherichia coli GUS (EcGUS), and characterized the inhibitory mechanism of each of the components. Trans-resveratrol 4’-O-β-D-glucopyranoside (HZ-1) and (-)-epicatechin gallate (HZ-2) isolated from P. cuspidatum were identified as the key components and potent inhibitors. These two components displayed strong to moderate inhibitory effects on EcGUS, with Ki values of 9.95 and 1.95 μM, respectively. Results from molecular docking indicated that HZ-1 and HZ-2 could interact with the key residues Asp163, Ser360, Ile 363, Glu413, Glu504, and Lys 568 of EcGUS via hydrogen bonding. Our findings demonstrate the inhibitory effect of P. cuspidatum and its two components on EcGUS, which supported the further evaluation and development of P. cuspidatum and its two active components as novel candidates for alleviating drug-induced damage in the mammalian gut.

Digestive tract toxicity associated with exposure to 2,4-dichlorophenoxyacetic acid in rats.

2,4-Dichlorophenoxyacetic acid (2,4-D) is a herbicide of the chlorophenoxy class and the second most widely used herbicide applied to several different crops worldwide. Environmental factors, especially those related to diet, strongly affect the risk of developing cancer of the gastrointestinal tract. There is currently no evidence to determine whether there is an association between 2,4-D exposure and gastrointestinal disorders. We evaluated the histological effect of chronic oral and inhalation exposure to 2,4-D on the digestive tract of rats. Eighty male adult albino Wistar rats were divided into 8 groups (n=10): two control groups, one for inhalation and one for oral exposure, and 6 groups exposed orally or by inhalation at three different concentrations of 2,4-D [3.71×10-3 grams of active ingredient per hectare (gai/ha), 6.19×10-3 gai/ha, and 9.28×10-3 gai/ha]. The animals were exposed for 6 months. The esophagus, stomach, and intestine were collected for histopathological analysis. Animals exposed to 2,4-D had hyperkeratosis of the esophagus, regardless of the exposure route. All animals exposed to a higher concentration of 2,4-D orally presented mild dysplasia of the large intestine. In the small intestine, most animals exposed to moderate and high concentrations of 2,4-D had mild dysplasia. No gastric changes were observed in any of the groups studied. Chronic exposure to 2,4-D, especially at moderate and high concentrations, regardless of the exposure route, caused reactive damage to the esophagus (hyperkeratosis) and dysplastic changes to the intestine.

Inhibition of gut bacterial β-glucuronidase by chemical components from black tea: Inhibition interactions and molecular mechanism

Gut bacterial β -glucuronidase is regarded as an important molecular target for several therapeutic applications. Inhibitors of β -glucuronidase can effectively alleviate the drug-induced gastrointestinal tract toxicity. In this study, the ethanol extracts of black tea was found to display significant inhibitory activities against Escherichia coli β -glucuronidase (EcGUS), and seven polyphenols including catechins and theaflavins were identified as the key components responsible for the strong inhibitory potency of black tea towards EcGUS. Among these seven identified naturally occurring inhibitors, (−)-catechin gallate (CG), theaflavin-3-monogallate (TF-3-G), theaflavin-3′-monogallate (TF-3′-G) and theaflavin-3,3′-digallate (TFDG) were more potent inhibitors of EcGUS compared with (−)-epicatechin gallate (ECG), (−)-gallocatechin gallate (GCG), and (−)-epigallocatechin gallate (EGCG). Furthermore, molecular docking and molecular dynamics simulation results further indicated that TFDG could bind in the cavity of EcGUS and interacted with key residues Ser360, Glu413 and Ile560 of EcGUS through hydrogen bonds. Taken together, these data offer important information for efficient development of black tea and its catechins and theaflavins constituents for treating drug-induced enteropathy.

Testing potential mechanisms of conspecific sperm precedence in Drosophila pseudoobscura.

Drosophila pseudoobscura females that co-occur with sister species D. persimilis show elevated fertilization by conspecific sperm when they mate with both a heterospecific and a conspecific male. This phenomenon, known as conspecific sperm precedence (CSP), has evolved as a mechanism to avoid maladaptive hybridization with D. persimilis. In this study, we assessed pericopulatory (during mating) and postcopulatory (after mating) traits in crosses with sympatric or allopatric D. pseudoobscura females and conspecific or heterospecific males to evaluate potential mechanisms of CSP in this system. We observed shorter copulation duration in crosses with sympatric females, but found no difference in quantity of sperm transferred or female reproductive tract toxicity between sympatry and allopatry. Our data show some support for the hypothesis that parasperm, a short, sterile sperm morph, can protect fertile eusperm from the D. pseudoobscura female reproductive tract, though it is unclear how this might affect patterns of sperm use in sympatry vs. allopatry. Overall, these results suggest that copulation duration could potentially contribute to the elevated CSP observed in sympatry.