ABSTRACT
Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together, our data indicate that ablation of tissue-resident macrophages represents an important strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.
Subject(s)
Cisplatin , Macrophages , Ototoxicity , Cisplatin/adverse effects , Cisplatin/toxicity , Animals , Macrophages/drug effects , Macrophages/metabolism , Ototoxicity/etiology , Ototoxicity/prevention & control , Mice , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Hearing Loss/chemically induced , Hearing Loss/prevention & control , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , Kidney Diseases/chemically induced , Kidney Diseases/prevention & control , Kidney Diseases/pathology , Cochlea/drug effects , Cochlea/metabolism , Cochlea/pathology , Mice, Inbred C57BL , Aminopyridines , PyrrolesABSTRACT
In vertebrates, the glucocorticoid response through the hypothalamic-pituitary-adrenal (HPA) axis controls many essential functions, including behavior, metabolism, and ontogenetic transitions. However, there are tradeoffs associated with high levels of glucocorticoids, including reduced growth rate and lowered immunity. These tradeoffs drive variation in the timing of the development of the HPA axis across taxa. In anurans (frogs and toads), corticosterone has critical roles in development and behavior, and concentrations can fluctuate in response to environmental stressors. Given the role of corticosterone in ontogenetic changes and behaviors, we hypothesized that species with immediate habitat transitions and challenges would develop an HPA axis early in development. To test this hypothesis, we studied tadpoles of the dyeing poison frog ( Dendrobates tinctorius ), a species in which tadpoles hatch terrestrially and are transported to pools of water by their parent. We measured the excretion rate and whole-body concentration of corticosterone and the corticosterone response to adrenocorticotropic hormone (ACTH). We found no significant differences in excretion rates and whole-body concentration of corticosterone, nor physiological response to ACTH injection across tadpole development. These findings indicate that the glucocorticoid response is developed early in ontogeny. These findings generally differ from those found in other species of tadpoles, which may suggest the unique ecological pressures of D. tinctorius has shaped the development of its HPA axis. More broadly, this study illustrates how life history strategies and tradeoffs of glucocorticoids impact the timing of the development of the HPA axis. Highlights: The timing of HPA axis development differs across species. We studied the HPA axis across tadpole development in Dendrobates tinctorius . No difference in corticosterone concentration across development.No difference in corticosterone response to ACTH across development.Results suggest an early developed HPA axis is essential for their life history.
ABSTRACT
BACKGROUND: Health care providers play a crucial role in increasing overall awareness, screening, and treatment of cancer, leading to reduced cancer mortality. We sought to characterize the impact of provider density on colorectal cancer population-level mortality. METHODS: County-level provider data, obtained from the Area Health Resource File between 2016 and 2018, were used to calculate provider density per county. These data were merged with county-level colorectal cancer mortality 2016-2020 data from the Centers for Disease Control and Prevention. Multivariable regression was performed to define the association between provider density and colorectal cancer mortality. RESULTS: Among 2,863 counties included in the analytic cohort, 1,132 (39.5%) and 1,731 (60.5%) counties were categorized as urban and rural, respectively. The colorectal cancer-related crude mortality rate was higher in counties with low provider density versus counties with moderate or high provider density (low = 22.9, moderate = 21.6, high = 19.3 per 100,000 individuals; P < .001). On multivariable analysis, the odds of colorectal cancer mortality were lower in counties with moderate and high provider density versus counties with low provider density (moderate odds ratio 0.97, 95% confidence interval 0.94-0.99; high odds ratio 0.88, 95% confidence interval 0.86-0.91). High provider density remained associated with a lower likelihood of colorectal cancer mortality independent of social vulnerability index (low social vulnerability index and high provider density: odds ratio 0.85, 95% confidence interval 0.81-0.89; high social vulnerability index and high provider density: odds ratio 0.93, 95% confidence interval 0.89-0.98). CONCLUSION: Regardless of social vulnerability index, high county-level provider density was associated with lower colorectal cancer-related mortality. Efforts to increase access to health care providers may improve health care equity, as well as long-term cancer outcomes.
Subject(s)
Colorectal Neoplasms , Social Vulnerability , Humans , Colorectal Neoplasms/mortality , Male , Female , Aged , Middle Aged , United States/epidemiology , Rural Population/statistics & numerical data , Health Personnel/statistics & numerical dataABSTRACT
BACKGROUND: Inflammatory bowel disease may affect the pathogenesis and clinicopathologic course of colorectal cancer. We sought to characterize the impact of inflammatory bowel disease on outcomes after colectomy and/or proctectomy for a malignant indication. METHODS: Patients diagnosed with colorectal cancer as well as a pre-existing comorbid diagnosis of Crohn's disease or ulcerative colitis between 2018 and 2021 were identified from Medicare claims data. The postoperative textbook outcome was defined as the absence of complications, as well as no extended hospital stay, 90-day readmission, or mortality. Postdischarge disposition and expenditures were also examined. RESULTS: Among 191,684 patients with colorectal cancer, 4,770 (2.5%) had a pre-existing diagnosis of inflammatory bowel disease. Patients with inflammatory bowel disease-associated colorectal cancer were less likely to undergo surgical resection (no inflammatory bowel disease: 47.6% vs inflammatory bowel disease: 42.1%; P < .001). Among patients who did undergo colorectal surgery, individuals with inflammatory bowel disease were less likely to achieve a textbook outcome (odds ratio 0.64 [95% confidence interval 0.58-0.70]). In particular, patients with inflammatory bowel disease had higher odds of postoperative complications (odds ratio 1.24 [1.12-1.38]), extended hospital stay (odds ratio 1.41 [1.27-1.58]), and readmission within 90 days (odds ratio 1.56 [1.42-1.72]) (all P < .05). Patients with inflammatory bowel disease-associated colorectal cancer were less likely to be discharged to their home under independent care (odds ratio 0.77 [0.68-0.87]) and had 12.2% higher expenditures, which correlated with whether the patient had a postoperative textbook outcome. CONCLUSION: One in 40 patients with colorectal cancer had concomitant inflammatory bowel disease. Inflammatory bowel disease was associated with a lower probability of achieving ideal postoperative outcomes, higher postdischarge expenditure, as well as worse long-term survival after colorectal cancer resection.
Subject(s)
Colectomy , Colorectal Neoplasms , Health Care Costs , Postoperative Complications , Humans , Male , Female , Aged , Colorectal Neoplasms/surgery , Colorectal Neoplasms/economics , Colorectal Neoplasms/complications , Colorectal Neoplasms/mortality , Colectomy/economics , United States/epidemiology , Postoperative Complications/economics , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Health Care Costs/statistics & numerical data , Proctectomy/economics , Aged, 80 and over , Medicare/economics , Medicare/statistics & numerical data , Retrospective Studies , Inflammatory Bowel Diseases/surgery , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/economics , Patient Readmission/statistics & numerical data , Patient Readmission/economics , Length of Stay/statistics & numerical data , Length of Stay/economics , Treatment Outcome , Colitis, Ulcerative/surgery , Colitis, Ulcerative/complications , Colitis, Ulcerative/economicsABSTRACT
Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.
Subject(s)
Cochlea , Animals , Mice , Guinea Pigs , Humans , Rats , Swine , Hair Cells, Auditory , Microscopy, Fluorescence , Machine LearningABSTRACT
BACKGROUND: Left-sided colorectal surgery demonstrates high anastomotic leak rates, with tissue ischemia thought to influence outcomes. Indocyanine green is commonly used for perfusion assessment, but evidence remains mixed for whether it reduces colorectal anastomotic leaks. Laser speckle contrast imaging provides dye-free perfusion assessment in real-time through perfusion heat maps and quantification. OBJECTIVE: This study investigates the efficacy of advanced visualization (indocyanine green versus laser speckle contrast imaging), perfusion assessment, and utility of laser speckle perfusion quantification in determining ischemic margins. DESIGN: Prospective intervention group using advanced visualization with case-matched, retrospective control group. SETTINGS: Single academic medical center. PATIENTS: Forty adult patients undergoing elective, minimally invasive, left-sided colorectal surgery. INTERVENTIONS: Intraoperative perfusion assessment using white light imaging and advanced visualization at 3 time points: T1-proximal colon after devascularization, before transection, T2-proximal/distal colon before anastomosis, and T3-completed anastomosis. MAIN OUTCOME MEASURES: Intraoperative indication of ischemic line of demarcation before resection under each visualization method, surgical decision change using advanced visualization, post hoc laser speckle perfusion quantification of colorectal tissue, and 30-day postoperative outcomes. RESULTS: Advanced visualization changed surgical decision-making in 17.5% of cases. For cases in which surgeons changed a decision, the average discordance between the line of demarcation in white light imaging and advanced visualization was 3.7 cm, compared to 0.41 cm ( p = 0.01) for cases without decision changes. There was no statistical difference between the line of ischemic demarcation using laser speckle versus indocyanine green ( p = 0.16). Laser speckle quantified lower perfusion values for tissues beyond the line of ischemic demarcation while suggesting an additional 1 cm of perfused tissue beyond this line. One (2.5%) anastomotic leak occurred in the intervention group. LIMITATIONS: This study was not powered to detect differences in anastomotic leak rates. CONCLUSIONS: Advanced visualization using laser speckle and indocyanine green provides valuable perfusion information that impacts surgical decision-making in minimally invasive left-sided colorectal surgeries. See Video Abstract . UTILIDAD CLNICA DE LAS IMGENES DE CONTRASTE MOTEADO CON LSER Y LA CUANTIFICACIN EN TIEMPO REAL DE LA PERFUSIN INTESTINAL EN RESECCIONES COLORRECTALES DEL LADO IZQUIERDO MNIMAMENTE INVASIVAS: ANTECEDENTES:La cirugía colorrectal del lado izquierdo demuestra altas tasas de fuga anastomótica, y se cree que la isquemia tisular influye en los resultados. El verde de indocianina se utiliza habitualmente para evaluar la perfusión, pero la evidencia sobre si reduce las fugas anastomóticas colorrectales sigue siendo contradictoria. Las imágenes de contraste moteado con láser proporcionan una evaluación de la perfusión sin colorantes en tiempo real a través de mapas de calor de perfusión y cuantificación.OBJETIVO:Este estudio investiga la eficacia de la evaluación de la perfusión mediante visualización avanzada (verde de indocianina versus imágenes de contraste moteado con láser) y la utilidad de la cuantificación de la perfusión con moteado láser para determinar los márgenes isquémicos.DISEÑO:Grupo de intervención prospectivo que utiliza visualización avanzada con un grupo de control retrospectivo de casos emparejados.LUGARES:Centro médico académico único.PACIENTES:Cuarenta pacientes adultos sometidos a cirugía colorrectal electiva, mínimamente invasiva, del lado izquierdo.INTERVENCIONES:Evaluación de la perfusión intraoperatoria mediante imágenes con luz blanca y visualización avanzada en tres puntos temporales: T1-colon proximal después de la devascularización, antes de la transección; T2-colon proximal/distal antes de la anastomosis; y T3-anastomosis completa.PRINCIPALES MEDIDAS DE VALORACIÓN:Indicación intraoperatoria de la línea de demarcación isquémica antes de la resección bajo cada método de visualización, cambio de decisión quirúrgica mediante visualización avanzada, cuantificación post-hoc de la perfusión con láser moteado del tejido colorrectal y resultados posoperatorios a los 30 días.RESULTADOS:La visualización avanzada cambió la toma de decisiones quirúrgicas en el 17,5% de los casos. Para los casos en los que los cirujanos cambiaron una decisión, la discordancia promedio entre la línea de demarcación en las imágenes con luz blanca y la visualización avanzada fue de 3,7 cm, en comparación con 0,41 cm (p = 0,01) para los casos sin cambios de decisión. No hubo diferencias estadísticas entre la línea de demarcación isquémica utilizando láser moteado versus verde de indocianina (p = 0,16). El moteado con láser cuantificó valores de perfusión más bajos para los tejidos más allá de la línea de demarcación isquémica y al mismo tiempo sugirió 1 cm adicional de tejido perfundido más allá de esta línea. Se produjo una fuga anastomótica (2,5%) en el grupo de intervención.LIMITACIONES:Este estudio no tuvo el poder estadístico suficiente para detectar diferencias en las tasas de fuga anastomótica.CONCLUSIONES:La visualización avanzada utilizando moteado láser y verde de indocianina proporciona información valiosa sobre la perfusión que impacta la toma de decisiones quirúrgicas en cirugías colorrectales mínimamente invasivas del lado izquierdo. (Traducción-Dr. Ingrid Melo).
Subject(s)
Anastomotic Leak , Indocyanine Green , Laser Speckle Contrast Imaging , Humans , Female , Male , Indocyanine Green/administration & dosage , Middle Aged , Anastomotic Leak/prevention & control , Anastomotic Leak/diagnosis , Aged , Laser Speckle Contrast Imaging/methods , Minimally Invasive Surgical Procedures/methods , Coloring Agents/administration & dosage , Colon/blood supply , Colon/surgery , Colon/diagnostic imaging , Retrospective Studies , Colectomy/methods , Prospective Studies , Anastomosis, Surgical/methods , Ischemia/prevention & control , Ischemia/diagnosis , Case-Control StudiesABSTRACT
This scoping review aimed to determine whether the COVID-19 pandemic influenced any modifications to patient selection methods or prioritisation and services provided by proton therapy (PT) centres. This review was conducted based on the PRISMA methodology and Joanna Briggs Institute scoping review guidelines. A literature search was performed in Medline, Embase, Web of Science and Scopus, as well as grey literature. Keywords such as "COVID-19" and "Proton Therapy" were used. Articles published from 1 January 2020 in English were included. In total, 138 studies were identified of which 11 articles met the inclusion criteria. A scoping review design was chosen to capture the full extent of information published relating to the aim. Six of 11 articles included statements regarding treatment of COVID-19 patients. Three publications recommended deferred or alternative treatment, two indicated to treat urgent/emergency patients and one reported continuous treatment for infectious patients. Recurring impacts on PT provision included more frequent use of unconventional therapies, reduced referrals, delayed treatment starts and CT simulation, change in treatment target volumes and staffing limitations due to pandemic restrictions. Consequently, telehealth consults, remote work, reduction in patient visitors, screening procedures and rigorous cleaning protocols were recommended. Few publications detailed changes to patient selection or workflow methods during the pandemic. Further research is needed to obtain more detailed information regarding current global patient selection methods in PT, collecting this data could aid in future planning for PT in Australia.
Subject(s)
COVID-19 , Proton Therapy , Humans , Proton Therapy/adverse effects , Protons , Pandemics , Patient SelectionABSTRACT
Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results.
Subject(s)
Hearing Loss , Humans , Hearing Loss/chemically induced , Hearing Loss/prevention & control , Clinical Trials as TopicABSTRACT
Cisplatin is a widely used and highly effective anti-cancer drug with significant side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced ototoxicity and nephrotoxicity, we used PLX3397, an FDA-approved inhibitor of the colony-stimulating factor 1 receptor (CSF1R), to eliminate tissue-resident macrophages during the course of cisplatin administration. Mice treated with cisplatin alone (cisplatin/vehicle) had significant hearing loss (ototoxicity) as well as kidney injury (nephrotoxicity). Macrophage ablation using PLX3397 resulted in significantly reduced hearing loss measured by auditory brainstem responses (ABR) and distortion-product otoacoustic emissions (DPOAE). Sensory hair cells in the cochlea were protected against cisplatin-induced death in mice treated with PLX3397. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis as well as reduced plasma blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together our data indicate that ablation of tissue-resident macrophages represents a novel strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.
ABSTRACT
Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90'000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.
ABSTRACT
Approximately 5% of all colorectal cancers develop within a hereditary colorectal cancer syndrome. Patients and families with these syndromes have an increased risk of colorectal and extracolonic cancers that develop at an early age. Recognition and diagnosis of these conditions are crucial to management and risk reduction. Surgeons must be aware of the unique aspects of the timing and extent of surgery (both therapeutic and prophylactic) within these syndromes, particularly for the most common syndromes, Lynch syndrome and familial adenomatous polyposis.
Subject(s)
Adenomatous Polyposis Coli , Colorectal Neoplasms, Hereditary Nonpolyposis , Colorectal Neoplasms , Neoplastic Syndromes, Hereditary , Adenomatous Polyposis Coli/complications , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/surgery , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms/therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Humans , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/geneticsABSTRACT
The mouse utricle model system is the best-characterized ex vivo preparation for studies of mature mammalian hair cells (HCs). Despite the many advantages of this model system, efficient and reliable quantification of HCs from cultured utricles has been a persistent challenge with this model system. Utricular HCs are commonly quantified by counting immunolabeled HCs in regions of interest (ROIs) placed over an image of the utricle. Our data indicate that the accuracy of HC counts obtained using this method can be impacted by variability in HC density across different regions of the utricle. In addition, the commonly used HC marker myosin 7a results in a diffuse cytoplasmic stain that is not conducive to automated quantification and must be quantified manually, a labor-intensive task. Furthermore, myosin 7a immunoreactivity is retained in dead HCs, resulting in inaccurate quantification of live HCs using this marker. Here we have developed a method for semi-automated quantification of surviving HCs that combines immunoreactivity for the HC-specific transcription factor Pou4f3 with labeling of activated caspase 3/7 (AC3/7) to detect apoptotic HCs. The discrete nuclear Pou4f3 signal allowed us to utilize the binary or threshold function within ImageJ to automate HC quantification. To further streamline this process, we created an ImageJ macro that automates the process from raw image loading to a final quantified image that can be immediately evaluated for accuracy. Within this quantified image, the user can manually correct the quantification via an image overlay indicating the counted HC nuclei. Pou4f3-positive HCs that also express AC3/7 are subtracted to yield accurate counts of surviving HCs. Overall, we present a semi-automated method that is faster than manual HC quantification and identifies surviving HCs with high accuracy.
Subject(s)
Hair Cells, Auditory , Saccule and Utricle , Animals , Gene Expression Regulation , Hair , Mice , Transcription FactorsABSTRACT
The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell mechanotransduction in the mammalian cochlea. We sought to create a model of EP dysfunction for the purposes of transcriptional analysis and treatment testing. By administering a single dose of cisplatin, a commonly prescribed cancer treatment drug with ototoxic side effects, to the adult mouse, we acutely disrupt EP generation. By combining these data with single cell RNA-sequencing findings, we identify transcriptional changes induced by cisplatin exposure, and by extension transcriptional changes accompanying EP reduction, in the major cell types of the SV. We use these data to identify gene regulatory networks unique to cisplatin treated SV, as well as the differentially expressed and druggable gene targets within those networks. Our results reconstruct transcriptional responses that occur in gene expression on the cellular level while identifying possible targets for interventions not only in cisplatin ototoxicity but also in EP dysfunction.
ABSTRACT
Deep inspiration breath hold (DIBH) radiotherapy is a technique used to manage early stage left-sided breast cancer. This study compared dosimetric indices of patient-specific X-ray versus proton therapy DIBH plans to explore differences in target coverage, radiation doses to organs at risk, and the impact of breast size. Radiotherapy plans of sixteen breast cancer patients previously treated with DIBH radiotherapy were re-planned with hybrid inverse-planned intensity modulated X-ray radiotherapy (h-IMRT) and intensity modulated proton therapy (IMPT). The total prescribed dose was 40.05 Gy in 15 fractions for all cases. Comparisons between the clinical, h-IMRT, and IMPT evaluated doses to target volumes, organs at risk, and correlations between doses and breast size. Although no differences were observed in target volume coverage between techniques, the h-IMRT and IMPT were able to produce more even dose distributions and IMPT delivered significantly less dose to all organs at risk than both X-ray techniques. A moderate negative correlation was observed between breast size and dose to the target in X-ray techniques, but not IMPT. Both h-IMRT and IMPT produced plans with more homogeneous dose distribution than forward-planned IMRT and IMPT achieved significantly lower doses to organs at risk compared to X-ray techniques.
ABSTRACT
BACKGROUNDCisplatin is widely used to treat adult and pediatric cancers. It is the most ototoxic drug in clinical use, resulting in permanent hearing loss in approximately 50% of treated patients. There is a major need for therapies that prevent cisplatin-induced hearing loss. Studies in mice suggest that concurrent use of statins reduces cisplatin-induced hearing loss.METHODSWe examined hearing thresholds from 277 adults treated with cisplatin for head and neck cancer. Pretreatment and posttreatment audiograms were collected within 90 days of initiation and completion of cisplatin therapy. The primary outcome measure was a change in hearing as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).RESULTSAmong patients on concurrent atorvastatin, 9.7% experienced a CTCAE grade 2 or higher cisplatin-induced hearing loss compared with 29.4% in nonstatin users (P < 0.0001). A mixed-effect model analysis showed that atorvastatin use was significantly associated with reduced cisplatin-induced hearing loss (P ≤ 0.01). An adjusted odds ratio (OR) analysis indicated that an atorvastatin user is 53% less likely to acquire a cisplatin-induced hearing loss than a nonstatin user (OR = 0.47; 95% CI, 0.30-0.78). Three-year survival rates were not different between atorvastatin users and nonstatin users (P > 0.05).CONCLUSIONSOur data indicate that atorvastatin use is associated with reduced incidence and severity of cisplatin-induced hearing loss in adults being treated for head and neck cancer.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT03225157.FUNDINGFunding was provided by the Division of Intramural Research at the National Institute on Deafness and Other Communication Disorders (1 ZIA DC000079, ZIA DC000090).
Subject(s)
Cisplatin/adverse effects , Head and Neck Neoplasms , Hearing Loss , Ototoxicity/epidemiology , Aged , Atorvastatin/administration & dosage , Cisplatin/administration & dosage , Female , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/epidemiology , Hearing Loss/chemically induced , Hearing Loss/epidemiology , Humans , Incidence , Male , Middle Aged , Prospective Studies , Retrospective StudiesABSTRACT
INTRODUCTION: The significantly greater cost of proton therapy compared with X-ray therapy is frequently justified by the expected reduction in normal tissue toxicity. This is often true for indications such as paediatric and skull base cancers. However, the benefit is less clear for other more common indications such as breast cancer, and it is possible that the degree of benefit may vary widely between these patients. The aim of this work was to demonstrate a method of individualised selection of left-sided breast cancer patients for proton therapy based on cost-effectiveness of treatment. METHODS: 16 left-sided breast cancer patients had a treatment plan generated for the delivery of intensity-modulated proton therapy (IMPT) and of intensity-modulated photon therapy (IMRT) with the deep inspiration breath-hold (DIBH) technique. The resulting dosimetric data was used to predict probabilities of tumour control and toxicities for each patient. These probabilities were used in a Markov model to predict costs and the number of quality-adjusted life years expected as a result of each of the two treatments. RESULTS: IMPT was not cost-effective for the majority of patients but was cost-effective where there was a greater risk reduction of second malignancies with IMPT. CONCLUSION: The Markov model predicted that IMPT with DIBH was only cost-effective for selected left-sided breast cancer patients where IMRT resulted in a significantly greater dose to normal tissue. The presented model may serve as a means of evaluating the cost-effectiveness of IMPT on an individual patient basis.
Subject(s)
Cost-Benefit Analysis , Patient Selection , Proton Therapy/economics , Unilateral Breast Neoplasms/radiotherapy , Female , Humans , Radiotherapy Planning, Computer-AssistedABSTRACT
BACKGROUND AND PURPOSE: Proton therapy has been proposed as a technique to improve the long-term quality of life of breast cancer patients. This is due to its ability to reduce the dose to healthy tissue compared to conventional X-ray therapy. The aim of this study was to investigate the risk of secondary carcinogenesis due to proton therapy compared to hybrid IMRT for breast treatments. MATERIAL AND METHODS: In this study, the Pinnacle treatment planning system was used to simulate treatment plans for 15 female left-sided whole breast cancer patients with deep inspiration breath hold scans. Two treatment plans were generated for each patient: hybrid intensity modulated radiotherapy (h-IMRT) and intensity modulated proton therapy (IMPT). Using the dose-volume histograms (DVHs) from these plans, the mean lifetime attributed risk (LAR) for both lungs and the contralateral breast were evaluated using the BEIR VII and Schneider full risk models. RESULTS: The results from both risk models show lower LAR estimates for the IMPT treatment plan compared to the h-IMRT treatment plan. This result was observed for all organs of interest and was consistent amongst the two separate risk models. For both treatment plans, the organs from most to least at risk were: ipsilateral lung, contralateral breast, and contralateral lung. In all cases, the risk estimated via the BEIR VII model was higher that the Schneider full risk model. CONCLUSION: The use of proton therapy for breast treatments leads to reduced risk estimates for secondary carcinogenesis. Therefore, proton therapy shows promise in improving the long term treatment outcome of breast patients.
Subject(s)
Breast Neoplasms , Neoplasms, Second Primary , Proton Therapy , Radiotherapy, Intensity-Modulated , Unilateral Breast Neoplasms , Breast Neoplasms/radiotherapy , Female , Humans , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/etiology , Organs at Risk , Proton Therapy/adverse effects , Quality of Life , Radiotherapy Dosage , Radiotherapy Planning, Computer-Assisted , Radiotherapy, Intensity-Modulated/adverse effects , Unilateral Breast Neoplasms/radiotherapyABSTRACT
Sound localization requires extremely precise development of auditory brainstem circuits, the molecular mechanisms of which are largely unknown. We previously demonstrated a novel requirement for non-apoptotic activity of the protease caspase-3 in chick auditory brainstem development. Here, we used mass spectrometry to identify proteolytic substrates of caspase-3 during chick auditory brainstem development. These auditory brainstem caspase-3 substrates were enriched for proteins previously shown to be cleaved by caspase-3, especially in non-apoptotic contexts. Functional annotation analysis revealed that our caspase-3 substrates were also enriched for proteins associated with several protein categories, including proteins found in extracellular vesicles (EVs), membrane-bound nanoparticles that function in intercellular communication. The proteome of EVs isolated from the auditory brainstem was highly enriched for our caspase-3 substrates. Additionally, we identified two caspase-3 substrates with known functions in axon guidance, namely Neural Cell Adhesion Molecule (NCAM) and Neuronal-glial Cell Adhesion Molecule (Ng-CAM), that were found in auditory brainstem EVs and expressed in the auditory pathway alongside cleaved caspase-3. Taken together, these data suggest a novel developmental mechanism whereby caspase-3 influences auditory brainstem circuit formation through the proteolytic cleavage of extracellular vesicle (EV) proteins.
ABSTRACT
Cisplatin is a widely used anti-cancer drug used to treat a variety of cancer types. One of the side effects of this life-saving drug is irreversible ototoxicity, resulting in permanent hearing loss in many patients. In order to understand why cisplatin is particularly toxic to the inner ear, we compared the hearing loss and cochlear uptake of cisplatin to that of two related drugs, carboplatin and oxaliplatin. These three drugs are similar in that each contains a core platinum atom; however, carboplatin and oxaliplatin are considered less ototoxic than cisplatin. We delivered these three drugs to mice using a 6-week cyclic drug administration protocol. We performed the experiment twice, once using equimolar concentrations of the drugs and once using concentrations of the drugs more proportional to those used in the clinic. For both concentrations, we detected a significant hearing loss caused by cisplatin and no hearing loss caused by carboplatin or oxaliplatin. Cochlear uptake of each drug was measured using inductively coupled plasma mass spectrometry (ICP-MS) to detect platinum. Cochlear platinum levels were highest in mice treated with cisplatin followed by oxaliplatin, while carboplatin was largely excluded from the cochlea. Even when the drug doses were increased, cochlear platinum remained low in mice treated with oxaliplatin or carboplatin. We also examined drug clearance from the inner ear by measuring platinum levels at 1 h and 24 h after drug administration. Our findings suggest that the reduced cochlear platinum we observed with oxaliplatin and carboplatin were not due to increased clearance of these drugs relative to cisplatin. Taken together, our data indicate that the differential ototoxicity among cisplatin, carboplatin, and oxaliplatin is attributable to differences in cochlear uptake of these three drugs.