Normal Organ Research Articles

Stereotactic body radiotherapy using helical tomotherapy for hepatocellular carcinoma: clinical outcome and dosimetric comparison of Hi-ART vs. Radixact.

Helical tomotherapy (HT), a unique rotational dose delivery machine, has been updated from Hi-ART to Radixact. We retrospectively evaluated the treatment outcomes of stereotactic body radiotherapy (SBRT) using HT for hepatocellular carcinoma (HCC) and compared the dosimetric details of Hi-ART and Radixact. Between April 2014 and November 2020, 28 patients with HCC were treated with SBRT using HT for a cure at Soonchunhyang University College of Medicine, Bucheon. According to the Barcelona Clinic Liver Cancer classification, 9 patients had stage 0 disease, 12 had stage A, 4 had stage B, and 3 had stage C. The tumor size ranged from 1 cm to 8 cm (median, 2 cm). The SBRT dose ranged from 40 to 60 Gy (median, 48 Gy) with 4 fractions. Twenty-three patients were treated with Hi-ART and 5 patients were treated with Radixact. To compare the dosimetric parameters between Hi-ART and Radixact, we created treatment plans with the same constraints, pitch, modulation factor, and field width for the same patient in pairs. The median follow-up time from the date of SBRT administration was 24 months (range, 3-67 months). The local failure-free survival and intrahepatic failure-free survival rates were 96% and 58% at 1 year, 84% and 36% at 2 years, and 76% and 18% at 3 years, respectively. The overall survival rate was 93% at 1 year, 93% at 2 years, and 53% at 3 years, respectively. When the paired treatment plans were reviewed, the beam-on time and intermediate dose-spillage were found to be significantly reduced in Radixact than Hi-ART (P<0.001). With regard to normal organ sparing, the irradiated dose to the total liver, normal liver, heart, and kidney was significantly lower with Radixact (P<0.001). SBRT using HT for HCC showed favorable treatment outcomes. Radixact, the latest version, physically improved treatment efficiency by reducing treatment time and provided better organ sparing than Hi-ART.

Polypharmacy in Older Adults.

Polypharmacy, associated with adverse health outcomes, is common in older adults owing to increasing chronic conditions. In addition to normal organ system changes that affect pharmacokinetic, and pharmacodynamics of medications, drug-drug interaction and drug-disease interactions should be reviewed. Tools to minimize polypharmacy should be considered when treating older adults.

90Y-Labeled Gold Nanoparticle Depot (NPD) Combined with Anti-PD-L1 Antibodies Strongly Inhibits the Growth of 4T1 Tumors in Immunocompetent Mice and Induces an Abscopal Effect on a Distant Non-Irradiated Tumor.

The effectiveness and normal tissue toxicity of a novel nanoparticle depot (NPD) brachytherapy seed incorporating gold nanoparticles (AuNPs) labeled with β-particle emitting, 90Y (termed a "radiation nanomedicine"), were studied for the treatment of 4T1 triple-negative murine mammary carcinoma tumors in Balb/c mice and for inducing an abscopal effect on a distant non-irradiated tumor alone or combined with anti-PD-L1 immune checkpoint antibodies. Balb/c mice with two subcutaneous 4T1 tumors─a primary tumor and a distant secondary tumor were implanted intratumorally (i.t.) in the primary tumor with NPD incorporating 3.5 MBq of 90Y-AuNPs (1 × 1014 AuNPs) or unlabeled AuNPs, alone or combined with systemically administered anti-PD-L1 antibodies (200 μg i.p. three times/week for 2 weeks) or received anti-PD-L1 antibodies alone or no treatment. The primary tumor was strongly growth-inhibited over 14 d by NPD incorporating 90Y-AuNPs but only very modestly inhibited by NPD incorporating unlabeled AuNPs. Anti-PD-L1 antibodies alone were ineffective, and combining anti-PD-L1 antibodies with NPD incorporating 90Y-AuNPs did not further inhibit the growth of the primary tumor. Secondary tumor growth was inhibited by treatment of the primary tumor with NPD incorporating 90Y-AuNPs, and growth inhibition was enhanced by anti-PD-L1 antibodies. Treatment of the primary tumor with NPD incorporating unlabeled AuNPs or anti-PD-L1 antibodies alone had no effect on secondary tumor growth. Biodistribution studies showed high uptake of 90Y in the primary tumor [516-810% implanted dose/g (%ID/g)] but very low uptake in the secondary tumor (0.033-0.16% ID/g) and in normal tissues (<0.5% ID/g) except for kidneys (5-8% ID/g). Very high radiation absorbed doses were estimated for the primary tumor (472 Gy) but very low doses in the secondary tumor (0.13 Gy). There was highdose-heterogeneity in the primary tumor with doses as high as 9964 Gy in close proximity to the NPD, decreasing rapidly with distance from the NPD. Normal organ doses were low (<1 Gy) except for kidneys (4 Gy). No normal tissue toxicity was observed, but white blood cell counts (WBC) decreased in tumor-bearing mice treated with NPD incorporating 90Y-AuNPs. Decreased WBC counts were interpreted as tumor response and not toxicity since these were higher than that in healthy non-tumor-bearing mice, and there was a direct association between WBC counts and 4T1 tumor burden. We conclude that implantation of NPD incorporating 90Y-AuNPs into a primary 4T1 tumor in Balb/c mice strongly inhibited tumor growth and combined with anti-PD-L1 antibodies induced an abscopal effect on a distant secondary tumor. This radiation nanomedicine is promising for the local treatment of triple-negative breast cancer tumors in patients, and these therapeutic effects may extend to non-irradiated lesions, especially when combined with checkpoint immunotherapy.

Treatment of Choice for Resectable Cervical Esophageal Cancer: Surgery and Definitive Chemoradiotherapy with or without Dose Escalation

<h3>Purpose/Objective(s)</h3> Cervical esophageal cancer is rare subgroup which epicenter of tumor located between upper esophageal sphincter and sternum notch, for 5% to 10% of all esophageal cancers. Most of patients of cervical esophageal cancer needed hypopharyngectomy and laryngectomy for complete resection, pre-operative chemotherapy (CTx) or chemoradiotherapy (CRT) is needed, and even definitive CRT has been widely accepted treatment of choice for laryngeal preservation. We reviewed our institutional experiences to compare and tried to suggest the treatment directions for resectable cervical esophageal cancer. <h3>Materials/Methods</h3> A total of 197 patients who were diagnosed as cervical esophageal cancer without distant metastasis between January 2001 and December 2020 were identified. Of those, 47 patients were excluded in this study because of unresectable stage (e.g., initial stage T4 or extensive nodal stage), 100 patients had definitive chemoradiotherapy and 50 patients had surgery. In surgery group, 16 patients received preoperative treatment (CRT; 6 patients, CTx alone; 10 patients) and 16 patients received postoperative treatment (CRT; 6 patients, CTx alone, 6 patients, radiotherapy alone; 4 patients). Definitive CRT group patients were divided into high-dose group (≥59.4 Gy, n=71), and standard dose group (<59.4 Gy, n=29). <h3>Results</h3> The median follow-up was 30 months (5-225 months) for surviving patients. Of 50 patients with median age 63 in surgery group, 21 (42%), 9 (18%), 18 (36%), 2 (4%) patients were stage I, II, III and IV respectively. Patients in CRT group was statistically significant different in age (median 67) and stage as 19 (19%), 30 (30%), 44 (44%), 7 (7%) patients were stage I, II, III, IV. There was no statistical difference in overall survival (OS) (3-year OS: 61.2% vs 62.9%, p=0.976) and progression free survival (PFS) (3-year PFS: 47.5 % vs 53.0%, p=0.589). Treatment related toxicity (Grade≥2) were significantly higher in surgery group than CRT group (14(28%) vs 12 (12%), p=0.015), even only 6 patients received hypopharyngectomy and laryngectomy. In subgroup analysis between high-dose group and standard dose group, OS and loco-regional failure free survival (LRFS) was significantly higher in high-dose group (3-year OS: 65.4% vs 51.7%, p=0.046, 3-year LRFS 68.7% vs 42.5%). There was no significant difference between two group (High-dose group 9 (12.7%) vs Standard dose group 3 (10.3%), p=0.106). <h3>Conclusion</h3> There was no significant difference in OS and PFS between surgery and CRT group although surgery group had patient selection bias for patients with earlier stage and younger age. Also, LRFS were better with high-dose CRT than standard group which lead to better OS and consequently achieved favor OS in general CRT group. High dose RT was not associated with higher toxicity rate, mainly because recent intensity modulated RT could give higher dose while saving normal organ toxicity. Thus, high dose CRT should be considered as initial treatment for cervical esophagus than surgery.

Ultrasmall Folate Receptor Alpha Targeted Enzymatically Cleavable Silica Nanoparticle Drug Conjugates Augment Penetration and Therapeutic Efficacy in Models of Cancer.

To address the key challenges in the development of next-generation drug delivery systems (DDS) with desired physicochemical properties to overcome limitations regarding safety, in vivo efficacy, and solid tumor penetration, an ultrasmall folate receptor alpha (FRα) targeted silica nanoparticle (C'Dot) drug conjugate (CDC; or folic acid CDC) was developed. A broad array of methods was employed to screen a panel of CDCs and identify a lead folic acid CDC for clinical development. These included comparing the performance against antibody-drug conjugates (ADCs) in three-dimensional tumor spheroid penetration ability, assessing in vitro/ex vivo cytotoxic efficacy, as well as in vivo therapeutic outcome in multiple cell-line-derived and patient-derived xenograft models. An ultrasmall folic acid CDC, EC112002, was identified as the lead candidate out of >500 folic acid CDC formulations evaluated. Systematic studies demonstrated that the lead formulation, EC112002, exhibited highly specific FRα targeting, multivalent binding properties that would mediate the ability to outcompete endogenous folate in vivo, enzymatic responsive payload cleavage, stability in human plasma, rapid in vivo clearance, and minimal normal organ retention organ distribution in non-tumor-bearing mice. When compared with an anti-FRα-DM4 ADC, EC112002 demonstrated deeper penetration into 3D cell-line-derived tumor spheroids and superior specific cytotoxicity in a panel of 3D patient-derived tumor spheroids, as well as enhanced efficacy in cell-line-derived and patient-derived in vivo tumor xenograft models expressing a range of low to high levels of FRα. With the growing interest in developing clinically translatable, safe, and efficacious DDSs, EC112002 has the potential to address some of the critical limitations of the current systemic drug delivery for cancer management.

Evaluating health outcomes in the treatment of hypothyroidism.

Clinical hypothyroidism is defined by the inadequate production of thyroid hormone from the thyroid gland to maintain normal organ system functions. For nearly all patients with clinical hypothyroidism, lifelong treatment with thyroid hormone replacement is required. The primary goal of treatment is to provide the appropriate daily dose of thyroid hormone to restore normal thyroid function for each individual patient. In current clinical practice, normalization of thyrotropin (TSH) level is the primary measure of effectiveness of treatment, however the use of a single biomarker to define adequate thyroid hormone replacement is being reevaluated. The assessment of clinical health outcomes and patient-reported outcomes (PROs), often within the context of intensity of treatment as defined by thyroid function tests (i.e., undertreatment, appropriate treatment, or overtreatment), may play a role in evaluating the effectiveness of treatment. The purpose of this narrative review is to summarize the prominent health outcomes literature in patients with treated hypothyroidism. To date, overall mortality, cardiovascular morbidity and mortality, bone health and cognitive function have been evaluated as endpoints in clinical outcomes studies in patients with treated hypothyroidism. More recent investigations have sought to establish the relationships between these end results and thyroid function during the treatment course. In addition to clinical event outcomes, patient-reported quality of life (QoL) has also been considered in the assessment of adequacy of hypothyroidism treatment. From a health care quality perspective, treatment of hypothyroidism should be evaluated not just on its effectiveness for the individual patients but also to the extent to which patients of different sociodemographic groups are treated equally. Ultimately, more research is needed to explore differences in health outcomes between different sociodemographic groups with hypothyroidism. Future prospective studies of treated hypothyroidism that integrate biochemical testing, PROs, and end result clinical outcomes could provide a more complete picture into the effectiveness of treatment of hypothyroidism.

Donor neo-atrial cuff construction after accidental lower lobe vein transection

BackgroundAn inadequate donor left atrial cuff is a rare technical issue after graft procurement for lung transplantation. With regard to the shortage of suitable donor organs for lung transplantation, these organs should be surgically reconstructed to avoid the loss of an organ and a futile intervention in the critically ill recipient.Case presentationWe report a case of a 62-year old patient who underwent bilateral sequential lung transplantation for chronic obstructive pulmonary disease. During isolated lung procurement, the right inferior pulmonary vein was circumferentially transsected and separated from the right superior pulmonary and middle lobe veins. Subsequently, a reconstruction of the left atrial cuff with an acellular biological patch was performed to complete the atrium anastomosis. The patient experienced an uneventful postoperative recovery and a follow-up ventilation/perfusion scan showed normal perfusion of the right lower lobe.ConclusionsThis case demonstrates that reconstruction of an inadequate left atrial cuff with a biological patch is feasible and allows for an adequate venous drainage and therefore normal transplant organ function.

P73 is required for vessel integrity controlling endothelial junctional dynamics through Angiomotin

Preservation of blood vessel integrity, which is critical for normal physiology and organ function, is controlled at multiple levels, including endothelial junctions. However, the mechanism that controls the adequate assembly of endothelial cell junctions is not fully defined. Here, we uncover TAp73 transcription factor as a vascular architect that orchestrates transcriptional programs involved in cell junction establishment and developmental blood vessel morphogenesis and identify Angiomotin (AMOT) as a TAp73 direct transcriptional target. Knockdown of p73 in endothelial cells not only results in decreased Angiomotin expression and localization at intercellular junctions, but also affects its downstream function regarding Yes-associated protein (YAP) cytoplasmic sequestration upon cell–cell contact. Analysis of adherens junctional morphology after p73-knockdown in human endothelial cells revealed striking alterations, particularly a sharp increase in serrated junctions and actin bundles appearing as stress fibers, both features associated with enhanced barrier permeability. In turn, stabilization of Angiomotin levels rescued those junctional defects, confirming that TAp73 controls endothelial junction dynamics, at least in part, through the regulation of Angiomotin. The observed defects in monolayer integrity were linked to hyperpermeability and reduced transendothelial electric resistance. Moreover, p73-knockout retinas showed a defective sprout morphology coupled with hemorrhages, highlighting the physiological relevance of p73 regulation in the maintenance of vessel integrity in vivo. We propose a new model in which TAp73 acts as a vascular architect integrating transcriptional programs that will impinge with Angiomotin/YAP signaling to maintain junctional dynamics and integrity, while balancing endothelial cell rearrangements in angiogenic vessels.

Clinical Application of Digital 3D Reconstruction and 3D Printing Technology in Endometrial Cancer (EC) Surgery.

Aims We use CTA and magnetic resonance data to use digital three-dimensional reconstruction and 3D printing technology to reproduce the solid replication of the uterus and surrounding tissues in vitro, fully evaluate the adjacency of tumor tissues with surrounding important organs, blood vessels, and lymph nodes, and reduce the impact. The normal organ structure and function of the surgeon can shorten the operation time, reduce the bleeding during the operation, and reduce the perioperative complications of the patient to improve the prognosis of the patient. Materials and Methods Select 40 EC patients and divide them into group A (3D reconstruction data is transmitted to 3D printing equipment according to the results of CTA and MRI examination, and a 3D model is printed out according to the ratio of 1 : 1 for evaluation and judgment before surgery) and group B (according to MRI imaging examination, there were 20 cases each). Different surgical conditions, quality of life, adverse reactions, and clinical efficacy were evaluated in each group. Results The operation time, the time of the first anus exhaust, the hospitalization time after the operation, and the blood loss of the operation in group A were significantly lower than those in group B. Statistics showed that the difference was significant (P < 0.05). The quality of life scores of emotion, cognition, society, and overall health of group A were significantly higher than those of group B, while physical score, fatigue, nausea, vomiting, and pain were lower than those of group B, which were statistically significant (P < 0.05). Both groups of patients had complications after the operation, and they were asked to be followed up at the outpatient clinic 3 months after the operation. All patients recovered well. There were 19 and 18 patients in groups A and B, respectively, complaining of improvement in clinical symptoms, and the difference was not statistically significant (P < 0.05). Conclusion With the support of digital three-dimensional reconstruction and 3D printing technology, complex operations can be accurately performed, improving the efficacy and safety of patients after EC surgery, improving patient outcomes and quality of life, improving EC positioning accuracy, and reducing tumor residue.

Hyaluronidase responsive second near-infrared fluorescent nanocomplex for combined HER2 blockade and chemotherapy of HER2+ breast cancer

The human epidermal growth factor receptor-2-positive (HER2+) type is aggressive and has poor prognosis. Although anti-HER2 therapy alone or in combination with other treatment regimens showed significant improvement in survival outcomes, breast cancer patients are still suffering from tumor relapse and severe dose-limiting side effects. Thus, there is still an unmet challenge to develop effective therapeutic agents for HER2+ breast cancer treatment with minimized side effects. Herein, we produced a stimuli-responsive and tumor-targeted hyaluronic acid (HA) nanocomplex that combined HER2 blockade and chemotherapy for effective HER2+ breast cancer therapy. A hydrophobic NIR-II dye, IR1048, was covalently linked with HA to form a spherical HA-IR1048 nanoparticle (HINP), with Herceptin conjugated on the surface and paclitaxel (PTX) encapsulated inside. The fluorescent signals from the yielding Her-HINP/PTX are quenched originally, but a strong NIR-II signal is generated when HINP is degraded by the hyaluronidase that is overexpressed in breast tumors, thus allowing the tracking and visualization of Herceptin and PTX accumulation. Her-HINP/PTX peaked in HER2+ tumors at 24 h post injection as imaged by NIR-II fluorescent imaging. A significantly improved tumor growth inhibition effect was observed after five systemic treatments compared to single PTX (3.71 ± 0.41 times) or Herceptin (5.98 ± 0.51 times) treatment in a HER2-overexpressed breast cancer mouse model with prolonged survival. Collectively, the designed Her-HINP/PTX presents a new hyaluronidase-responsive and HER2 blockade nanoformulation that can visualize the accumulation of nanocomplexes and release drugs inside tumors for combined HER2+ breast cancer therapy with a great promise for translational study. Statement of significanceThe high expressions of a protein called human epidermal growth factor receptor 2 (HER2) in breast tumors make this subtype of cancer aggressive. Currently, chemotherapy combined with a HER2 antibody, Herceptin, is a preferred approach for HER2-positive breast cancer therapy. However, these breast cancer patients still suffer from tumor relapse and severe side effects because various therapeutic agents have inherent different biodistributions, resulting in insufficient treatment effects and unfavorable normal organ uptake of these therapeutic agents. Herein, we produced a nanocomplex carrying both Herceptin and chemotherapy drug to simultaneously deliver two drugs into tumors for efficient HER2+ tumor treatment with minimized side effects, providing new insights for designing a combined therapy strategy.

Lipid profile improving effect of Coriandrum sativum seed extract in rats

Background: Hyperlipidaemia is a common disease in middle-aged and elderly people. It has received attention, as it indirectly affects the normal metabolism, blood viscosity and vital organ functions. It is a risk factor for cardiovascular and cerebrovascular diseases. Therefore, the aim of the present study was to evaluate the possible antihyperlipidemic effect of Coriander sativum seed extract (CSSE) in rats fed on high-fat diet.Methods: A parallel study design was adopted on 42 albino rats, divided randomly into 7 groups with different treatments. After a 6 week-experimental course, blood samples were collected and analysed for lipid and organ function parameters. Phytochemical analysis was conducted on the used seed extract to detect the active principles underlying its effects.Results: CSSE (150 and 300 mg/kg, orally, once daily) along with a high-fat (1.5% cholesterol+1.5% coconut oil, in diet) diet resulted in a significant (p≤0.05) improvement in plasma lipid parameters, including, total cholesterol, triacyglycerols and lipoproteins, compared to the high-fat group. group. The extract significantly (p≤0.05) improved hepatic (total proteins, albumin, globulins, total conjugated and unconjugated bilirubins, AST, ALT, GGT), cardiac (CK-MB and troponin-I) and renal (urea, creatinine &amp; uric acid) biomarkers. Phytoanalysis of CSSE revealed presence of phlobatannin and flavonoids. The protection % produced by small and large doses of CSSE were dose-dependent and parallel to those of the standard antihyperlipidemic rosuvastatin (2 mg/dl orally, daily).Conclusions: These data indicate that CSSE has a marked antihyperlipidemic effect and could be a source for a promising nutraceutical antihyperlipidemic drug depending on its high phenolic and flavonoid content.

Localization of macrophage subtypes and neutrophils in the prostate tumor microenvironment and their association with prostate cancer racial disparities.

Black men are two to threetimes more likely to die from prostate cancer (PCa) than White men. This disparity is due in part to discrepancies in socioeconomic status and access to quality care. Studies also suggest that differences in the prevalence of innate immune cells and heightened function in the tumor microenvironment of Black men may promote PCa aggressiveness. We evaluated the spatial localization of and quantified CD66ce+ neutrophils by immunohistochemistry and CD68+ (pan), CD80+ (M1), and CD163+ (M2) macrophages by RNA in situ hybridization on formalin-fixed paraffin-embedded tissues from organ donor "normal" prostate (n = 9) and radical prostatectomy (n = 38) tissues from Black and White men. Neutrophils were quantified in PCa and matched benign tissues in tissue microarray (TMA) sets comprised of 560 White and 371 Black men. Likewise, macrophages were quantified in TMA sets comprised of tissues from 60 White and 120 Black men. The phosphatase and tensin homolog (PTEN) and ETS transcription factor ERG (ERG) expression status of each TMA PCa case was assessed via immunohistochemistry. Finally, neutrophils and macrophage subsets were assessed in a TMA set comprised of distant metastatic PCa tissues collected at autopsy (n = 6) sampled across multiple sites. CD66ce+ neutrophils were minimal in normal prostates, but were increased in PCa compared to benign tissues, in low grade compared to higher grade PCa, in PCa tissues from White compared to Black men, and in PCa with PTEN loss or ERG positivity. CD163+ macrophages were the predominant macrophage subset in normal organ donor prostate tissues from both Black and White men and were significantly more abundant in organ donor compared to prostatectomy PCa tissues. CD68,+ CD80,+ and CD163+ macrophages were significantly increased in cancer compared to benign tissues and in cancers with ERG positivity. CD68+ and CD163+ macrophages were increased in higher grade cancers compared to low grade cancer and CD80 expression was significantly higher in benign prostatectomy tissues from Black compared to White men. Innate immune cell infiltration is increased in the prostate tumor microenvironment of both Black and White men, however the composition of innate immune cell infiltration may vary between races.

Three-dimensional conformal radiotherapy (3D-CRT) vs. volumetric modulated arc therapy (VMAT) in deep inspiration breath-hold (DIBH) technique in left-sided breast cancer patients-comparative analysis of dose distribution and estimation of projected secondary cancer risk.

The purpose of this study was to compare two techniques of irradiation of left-sided breast cancer patients who underwent breast-conserving surgery, three-dimensional conformal radiotherapy technique (3D-CRT) and volumetric modulated arc therapy (VMAT), in terms of dose distribution in the planning target volume (PTV) and organs at risk (OARs). The second aim of the study was estimation of the projected risk of radiation-induced secondary cancer for both radiotherapy techniques. For 25patients who underwent CT simulation in deep inspiration breath-hold (DIBH), three treatment plans were generated: one using athree-dimensional conformal radiotherapy technique and two using volumetric modulated arc therapy. First VMAT-DIBH geometry consisted of three partial arcs (ARC-DIBH 3A) and second consisted of four partial arcs (ARC-DIBH 4A). Cumulative dose-volume histograms (DVHs) were used to compare dose distributions within the PTV and OARs (heart, left anterior descending coronary artery [LAD], ipsilateral and contralateral lung [IL, CL], and contralateral breast [CB]). Normal tissue complication probabilities (NTCPs) and organ equivalent doses (OEDs) were calculated using the differential DVHs. Excess absolute risks (EARs) for second cancers were estimated using Schneider's full mechanistic dose-response model. All plans fulfilled the criterium for PTV V95% ≥ 95%. The PTV coverage, homogeneity, and conformity indices were significantly better for VMAT-DIBH. VMAT showed asignificantly increased mean dose and V5Gy for all OARs, but reduced LAD Dmax by 15 Gy. For IL, CL, and CB, the 3D-CRT DIBH method achieved the lowest values of EAR: 28.38 per 10,000PYs, 2.55 per 10,000PYs, and 4.48 per 10,000PYs (p < 0.001), compared to 40.29 per 10,000PYs, 15.62 per 10,000PYs, and 23.44 per 10,000PYs for ARC-DIBH 3A plans and 41.12 per 10,000PYs, 15.59 per 10,000PYs, and 22.73 per 10,000PYs for ARC-DIBH 4A plans. Both techniques provided negligibly low NTCPs for all OARs. The study shows that VMAT-DIBH provides better OAR sparing against high doses. However, the large low-dose-bath (≤ 5 Gy) is still aconcern due to the fact that alarger volume of normal tissues exposed to lower doses may increase aradiation-induced risk of secondary cancer.

EP-368 Intraoperative identification of colorectal cancer lesions using indocyanine green labelled antibodies in preclinical murine models

Abstract Aims The ability to identify cancerous tissue intraoperatively has the potential to allow for real time identification of involved margins, lymph node involvement and extra-colonic deposits. Here we investigate whether antibodies targeting a novel receptor, anonymously referred to as LN1, a frequently over expressed protein in colorectal cancer (CRC), labelled with indocyanine green (ICG) can be used for the intraoperative detection of malignant tissue in preclinical models. Methods Representative metastatic CRC models were generated in 20 NSG mice using HCT116 human CRC cells. Mice were treated with either intravenous ICG labelled LN1 antibodies (LN1-ICG) or control treatments (untreated, free ICG or cotreatment unlabelled LN1 blocking antibody + LN1-ICG). Signal intensity of normal and malignant tissue was quantified from near infrared (NIR) endoscopy and IVIS® in-vivo imaging system. Results LN1-ICG labelled antibodies was highly effective in identifying cancerous lesions down to 500nm diameter. Quantification of NIR and IVIS images demonstrate significantly greater tumour signal in the LN1-ICG group versus controls (p=0.004 and p=0.001 respectively). Examination of normal organ tissues demonstrated signal in the liver and digestive tract in keeping with hepatobiliary clearance of ICG but nil further off-site accumulation of LN1-ICG. No difference in signal from the liver, small bowel or colon was noted between groups (p&amp;gt;0.05). Conclusion LN1-ICG labelled antibodies were highly effective at identifying even small cancerous deposits in murine models. It is highly likely that these effects could be replicated in human procedures which may allow for perioperative identification of extra-colonic deposits, involved tumour margins or lymph node involvement.

89Zr]Zr-PSMA-617 PET/CT in biochemical recurrence of prostate cancer: first clinical experience from a pilot study including biodistribution and dose estimates

PurposeProstate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived radionuclides as 89Zr (T1/2 = 78.4 h) may improve diagnostics by allowing data acquisition on later time points. In this study, we present our first clinical experience including preliminary biodistribution and dosimetry data of [89Zr]Zr-PSMA-617 PET/CT in patients with BCR of prostate cancer.MethodsSeven patients with BCR of prostate cancer who revealed no (n = 4) or undetermined (n = 3) findings on [68Ga]Ga-PSMA-11 PET/CT imaging were referred to [89Zr]Zr-PSMA-617 PET/CT. PET/CT imaging was performed 1 h, 24 h, 48 h, and 72 h post injection (p.i.) of 111 ± 11 MBq [89Zr]Zr-PSMA-617 (mean ± standard deviation). Normal organ distribution and dosimetry were determined. Lesions visually considered as suggestive of prostate cancer were quantitatively analyzed.ResultsIntense physiological uptake was observed in the salivary and lacrimal glands, liver, spleen, kidneys, intestine and urinary tract. The parotid gland received the highest absorbed dose (0.601 ± 0.185 mGy/MBq), followed by the kidneys (0.517 ± 0.125 mGy/MBq). The estimated overall effective dose for the administration of 111 MBq was 10.1 mSv (0.0913 ± 0.0118 mSv/MBq). In 6 patients, and in particular in 3 of 4 patients with negative [68Ga]Ga-PSMA-11 PET/CT, at least one prostate cancer lesion was detected in [89Zr]Zr-PSMA-617 PET/CT imaging at later time points. The majority of tumor lesions were first visible at 24 h p.i. with continuously increasing tumor-to-background ratio over time. All tumor lesions were detectable at 48 h and 72 h p.i.Conclusion[89Zr]Zr-PSMA-617 PET/CT imaging is a promising new diagnostic tool with acceptable radiation exposure for patients with prostate cancer especially when [68Ga]Ga-PSMA-11 PET/CT imaging fails detecting recurrent disease. The long half-life of 89Zr enables late time point imaging (up to 72 h in our study) with increased tracer uptake in tumor lesions and higher tumor-to-background ratios allowing identification of lesions non-visible on [68Ga]Ga-PSMA-11 PET/CT imaging.

Target Coverage and Normal Organ Sparing in Dose-Escalated Total Marrow and Lymphatic Irradiation: A Single-Institution Experience.

Purpose/ObjectivesThe aim of this study is to report historical treatment planning experience at our institution for patients receiving total marrow and lymphatic irradiation (TMLI) as part of the conditioning regimen prior to hematopoietic stem cell transplant.Materials/MethodsBased on a review of all historical clinical TMLI treatments plans, we retrieved a 12-Gy cohort of 108 patients with a prescription dose of 12 Gy to the skeletal bones, lymph nodes, spleen, and spinal canal, and retrieved a 20-Gy cohort of 120 patients with an escalated prescription dose of 20 Gy to the skeletal bones, lymph nodes, spleen, and spinal cord, and 12 Gy to the brain and liver. Representative dosimetric parameters including mean and median dose, D80, and D10 (dose covering 80% and 10% of the structure volume, respectively) for targets and normal organs were extracted and compared between the two groups of patients.ResultsFor the 12-Gy cohort, the average mean dose for normal organs ranged from 18.3% to 78.3% of 12 Gy, and the average median dose ranged from 18.3% to 77.5% of 12 Gy. For the 20-Gy cohort, the average mean dose for normal organs ranged from 13.0% to 76.0% of 20 Gy, and the average median dose ranged from 12.5% to 75.0% of 20 Gy. Compared to the mean dose to normal organs in the 12-Gy cohort, the average mean dose to normal organs increased from 0.0% to 73.1%, with only four normal organs showing a >50% increase. Normal organ dose in TMLI plans using volumetric modulated arc therapy fields fell within the dose range in historical TMLI plans.ConclusionDosimetric data in historical TMLI plans at our institution are summarized at prescription dose levels of 12 Gy and 20 Gy, respectively. Compared to the normal organ dose with a prescription dose of 12 Gy, the mean and median dose to most normal organs at an escalated prescription dose of 20 Gy had an increase less than prescription dose scaling. Dosimetric results from this study can be used as reference data to facilitate clinical implementation of TMLI at other institutions.

A Preliminary Study of Organ Weight After Histological Exclusion of Abnormality During Autopsy in the Adult Population of Uttarakhand, India.

Organomegaly can be a strong predictor of an underlying pathological condition. There are many standard tables available in various texts listing the normal organ weight range, yet there is a lack of a standard table that is accepted globally. The main reason behind this is variation in organ weight due to socioeconomic status, geographical variation, and racial and stature variation among different global populations. The Western population has different stature compared to our population, that is, residents of Uttarakhand, India.Different studies tabulated organ weights in different regions of the world and correlated with different bodily parameters such as sex, race, stature, BMI, etc, which have shown a significant variation. There are different sets of data available that cannot be accepted universally due to regional variation. Most of the studies done in various parts of the world do not specify the condition of the organ, whether it was normal at the time of study or not. The methods of dissection of organs were also not explained in different studies.In this study, a total of eight organs were weighed from 137 autopsies conducted at the mortuary of the All India Institute of Medical Sciences Rishikesh over a period of 1.5 years. It was found that the average brain weighed in males was 1313.2 gm (±127.7 gm) and among females, it was 1218.0 gm (±122.82 gm). The weight of the heart was 310.1 gm (±83.97 gm) in males and 241.2 gm (±71.42 gm) in females. Right and left lungs weighed 499.4 gm (±207.5 gm)/407.5 gm (±128.66 gm) and 459.6 gm (±179.19 gm)/369.4 gm (±144.17 gm) among males and females, respectively. The liver weight was 1477.0 gm (±370.52 gm) in males and 1309.0 gm (±274.18 gm) among females. Spleen weighed 154.0 gm (±74.63 gm) in males and 156.0 gm (±65.0 gm) in females. The right and left kidneys weighed 125.9 gm (±37.92 gm)/108.1 gm (±28.80 gm) and 126.3 gm (±31.26 gm)/106.6 gm (±22.4 gm) among males and females, respectively. In our study, we have done a histological examination to rule out any pathological condition before including the weight of the organs in the study.The present study is to derive a standard organ weight among the inhabitants of Uttarakhand, India, and to look for a variation in organ weight among different studies done in the past in different regions of the world.

Studies of ultrastructure, gene expression, and marker analysis reveal that mouse bladder PDGFRA+ interstitial cells are fibroblasts.

Fibroblasts are crucial to normal and abnormal organ and tissue biology, yet we lack basic insights into the fibroblasts that populate the bladder wall. Candidates may include bladder interstitial cells (also referred to as myofibroblasts, telocytes, and interstitial cells of Cajal-like cells), which express the fibroblast-associated marker PDGFRA along with VIM and CD34 but whose form and function remain enigmatic. By applying the latest insights in fibroblast transcriptomics, coupled with studies of gene expression, ultrastructure, and marker analysis, we observe the following: 1) that mouse bladder PDGFRA+ cells exhibit all of the ultrastructural hallmarks of fibroblasts including spindle shape, lack of basement membrane, abundant endoplasmic reticulum and Golgi, and formation of homotypic cell-cell contacts (but not heterotypic ones); 2) that they express multiple canonical fibroblast markers (including Col1a2, CD34, LY6A, and PDGFRA) along with the universal fibroblast genes Col15a1 and Pi16 but they do not express Kit; and 3) that PDGFRA+ fibroblasts include suburothelial ones (which express ACTA2, CAR3, LY6A, MYH10, TNC, VIM, Col1a2, and Col15a1), outer lamina propria ones (which express CD34, LY6A, PI16, VIM, Col1a2, Col15a1, and Pi16), intermuscular ones (which express CD34, VIM, Col1a2, Col15a1, and Pi16), and serosal ones (which express CD34, PI16, VIM, Col1a2, Col15a1, and Pi16). Collectively, our study revealed that the ultrastructure of PDFRA+ interstitial cells combined with their expression of multiple canonical and universal fibroblast-associated gene products indicates that they are fibroblasts. We further propose that there are four regionally distinct populations of fibroblasts in the bladder wall, which likely contribute to bladder function and dysfunction.NEW & NOTEWORTHY We currently lack basic insights into the fibroblasts that populate the bladder wall. By exploring the ultrastructure of mouse bladder connective tissue cells, combined with analyses of their gene and protein expression, our study revealed that PDGRA+ interstitial cells (also referred to as myofibroblasts, telocytes, and interstitial cells of Cajal-like cells) are fibroblasts and that the bladder wall contains multiple, regionally distinct populations of these cells.

Oral toxicity evaluation of genetically modified lactic acid bacteria in three generations of Sprague Dawley rats

Genetic modification has great advantages in improving performance of bacteria, but its oral safety has not been systematically evaluated. In this study, the toxicity including the reproductive toxicity of two genetically modified bacteria engineered using food-grade vectors on three generations of rats (F0, F1 and F2) were studied. Sprague Dawley rats were administrated by gavage with corresponding parent and genetically modified Lactobacillus plantarum and Lactobacillus delbrueckii at 2.5 × 10 9 CFU every other day for 8 weeks. Results showed that the transgenic Lactobacillus had no significant toxicity to the body weight, food intake or blood biochemical parameters of three generations of rats. There was no significant effect on the reproductive parameters (gestational weight and pregnancy time) and related hormones (FSH, LH, estradiol, progesterone and testosterone) of the parent rats (F0 and F1). Consistently, their offsprings had no abnormal physical conditions including body weight, body length and anogenital distances. Moreover, their pups had normal body organ weight and reasonable abnormal sperm rate. Further analyses were conducted to evaluate SOD, MDA and GPX of the ovarium in the F1 and F2 female rats, which showed no malady phenotypes. In conclusion, transgenic Lactobacillus has no toxicity to the three generations of rats.

Glucagon and Its Underutilization in Diabetes Self-Management: A Teachable Moment.

Commentaries| July 08 2023 Glucagon and Its Underutilization in Diabetes Self-Management: A Teachable Moment Katherine Wolfe; Katherine Wolfe 1Department of Pharmacy, Spartanburg Medical Center, Spartanburg, SC Search for other works by this author on: This Site PubMed Google Scholar Jennifer Nicole Clements 0000-0003-2431-6651 Jennifer Nicole Clements 2Department of Nursing Administration, Spartanburg Regional Healthcare System, Spartanburg, SC Corresponding author: Jennifer Nicole Clements, jclements1027@outlook.com Search for other works by this author on: This Site PubMed Google Scholar Corresponding author: Jennifer Nicole Clements, jclements1027@outlook.com Clin Diabetes 2023;41(2):286–288 https://doi.org/10.2337/cd22-0015 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Katherine Wolfe, Jennifer Nicole Clements; Glucagon and Its Underutilization in Diabetes Self-Management: A Teachable Moment. Clin Diabetes 1 April 2023; 41 (2): 286–288. https://doi.org/10.2337/cd22-0015 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Diabetes Search Advanced Search A woman with type 1 diabetes of 14 years’ duration is admitted to a noncritical care unit after presenting to the emergency center with hypoglycemia. According to her family member and emergency medical services personnel, the person’s blood glucose was noted to be 28 mg/dL. Pharmacy records indicate that her treatment regimen before admission included insulin glargine 40 units subcutaneously in the morning and insulin lispro 5 units subcutaneously before each meal, with a correction factor of 24 (1 unit of insulin for every 24 mg/dL above target) and that she received enough blood glucose monitoring supplies to perform four checks per day. Normal organ function is noted, and her A1C is found to have decreased from 9 to 6.2% in the past 3 months. During her 4-day hospitalization, her insulin therapy included insulin glargine 20 units subcutaneously in the morning and insulin lispro with a correction scale of 0–8... You do not currently have access to this content.