G2 G3 Research Articles

Optimizing Water Productivity through the Conjunctive Use of Borewell and Canal Water for Enhancing Sheep Productivity in Arid Climate of Western Rajasthan, India

In the arid regions of Rajasthan, water scarcity poses a significant challenge to both agriculture and livestock productivity. Sustainable practices in such climates require effective management of limited water resources. This study focuses on optimizing water productivity through the conjunctive use of canal water and borewell water to address the problem of water scarcity while maximizing output per unit of water. The experiment involved eighteen healthy lambs of aged 2-3 months which were managed intensively and divided into three groups of six lambs each based on a randomized block design. All groups were fed Pennisetum glaucum (pearl millet) and Medicago sativa (lucerne) ad-libitum along with concentrates adjusted according to their body weights. The groups were offered three types of drinking water: canal water (G1), a combination of canal and borewell water (G2) and borewell water (G3) in a clean bucket twice a day. No significant effect on total feed intake and body weight of the lambs was found based on the drinking water source. However, G1 and G2 lambs, which were offered canal water, consumed significantly (p<0.05) less water (74.4 ± 1.84 liters) compared to the lambs in G3 (81.6 ± 1.91 liters). The virtual water requirement per kilogram of weight gain, calculated from both direct water intake and indirect intake through feed was lowest in G1 lambs (5771.34 liters) followed by G2 lambs (6129.00 liters) and G3 lambs (6312.00 liters) per kilogram of weight gain, respectively. These results indicate that water productivity was highest with canal water (G1) and lowest with borewell water (G3) per kilogram of weight gain. This study underscores the importance of efficient water management in maximizing productivity and resource use efficiency in water-limited arid regions.

Upper, middle, and lower CALYX accesses for prone percutaneous nephrolithotomy: a comparative study.

To compare upper, middle and lower calyceal accesses for prone percutaneous nephrolithotomy regarding stone-free rates, residual stones, haemoglobin drop and fluoroscopic time. The prospective comparative clinical study was conducted from September 2018 to March 2021 at Al- Yarmouk Teaching Hospital, Baghdad, Iraq, and comprised patients of either gender aged 18-78 years with renal stones treated with percutaneous nephrolithotomy. They were divided into three groups on the basis of calyx access: upper calyx G1, mid-calyx G2, and lower calyx G3. Procedure-related parameters, such as fluoroscopic time, stone-free rates and haemoglobin drop, were analysed in detail. Patients were followed up within 1-week postsurgery through complete blood count, ultrasound and computerised tomography. Data was analysed using SPSS 27. Of the 151 patients with a mean age of 46.01±14.7 years, 89(58.9%) were males and 62(41.1%) were females. There were 63(41.7%) patients in G1, 38(25.2%) in G3 and 50(33.1%) in G3. The diameter of renal stones ranged from 20-60mm. There were 45(71.4%) patients with stone-free outcome in G1, 22(57.9%) in G2 and 37(74%) in G3 (p>0.05). There was no significant difference in the mean haemoglobin drop among the groups (p>0.05). No significant intergroup difference was observed in terms of access in the sequelae regarding residual stone and haemoglobin drop.

Abstract PO5-01-14: Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event

Abstract Background: Over the past decade, there have been notable changes in the definition of risk estimation in patients with early-stage breast cancer (EBC). Specifically, within the timeframe of 2000 to 2017, following Estrogen Receptor (ER) positive and HER2-negative EBC cases were classified as low risk according to the University Hospitals of Leuven (UHL) criteria of that time: if ER H-score was >200: all patients with tumors N0 and Grade (G) 1, ≤pT2; or G2-3 pT1a-b; in patients ≥40 years with tumors N0 and G2 pT1c-2 or G3 pT1c; in patients ≥ 55 years with tumors N0 G3 pT2 or N1 any Grade, pT≤2. For lower H-scores, other criteria applied. However, despite undergoing endocrine therapy, a subset of these patients with clinically low-risk tumors unexpectedly experienced metastasis within five years of initial diagnosis. This unforeseen outcome may indicate potential undertreatment, as these patients did not receive adjuvant chemotherapy. We have conducted a case-cohort study of those patients with early relapse and performed the current clinical risk assessment methods and genomic risk analyses. Methods: In this study, we included patients with ER-pos, HER2-neg early-stage breast cancer diagnosed between 1-1-2000 and 31-12-2017, who were classified as low-risk tumors by UHL guidelines at that time, who were older than 35 but younger than 71 years, had an unilateral, unifocal breast tumor with tumor size up to 5 cm. These patients did not receive adjuvant chemotherapy. We selected the patients that experienced early distant recurrence, defined as distant recurrence (DR) within 5 years after the initial diagnosis. To ensure comparability for the analyses they were matched to controls for grade, menopausal status, tumor size, lymphovascular invasion, progesterone receptor status, and the year of diagnosis. For each patient, we have calculated the clinical risk score according to the criteria outlined by Mymammaprint.com, based on the modified Adjuvant Online tool used in the MINDACT trial. For the analysis, formalin-fixed paraffin-embedded (FFPE) breast tumor tissue samples were subjected to in-house validated targeted RNA-based Mammaprint(MP) analysis by NGS (MP Agendia). Results: Of the 3190 patients with EBC at UHL during the study period, 2476 patients were considered for this analysis and fitted the clinical low-risk criteria defined low-risk at UHL. Among those, only 42 or 1.7% of the eligible cohort had developed metastasis within 5 years. Tissue for MP analysis was available for 35 of these cases and for their matched control. Due to technical failure, the 1:1 matching was lost and MP results were known for 28 cases and 27 controls. The patient and tumor characteristics of both groups were comparable. In this UHL clinical low-risk group, 21/28 (75%) cases would be identified as clinical high-risk by MyMammaprint.com and 18/27 (67%) controls. We identified 13 patients (46.43%) with high genomic risk within the group with DR and 9 (33.33%) within the control group. There was no statistically significant difference (p=0.412) in the proportion of genomically high-risk patients within the group with DR compared to the control group. Conclusions: In a database of patients with EBC of whom 98% did not develop metastasis within 5 years, we observed in a small series of chemotherapy naïve patients with early DR and UHL-defined clinical low-risk tumors, that nearly half had a genomically high risk of distant metastasis. Albeit numerically higher than the matched-control group, this observation was not significant and would warrant a larger sample size and power to confirm these results. Table. Genomic versus Clinical Risk by MyMammaprint.com Citation Format: Josephine Van Cauwenberge, Hava Izci, Hans Wildiers, Sileny Han, Christine Desmedt, Giuseppe Floris, Sara Vander Borght, Ann Smeets, Ines Nevelsteen, Isabelle Vanden Bempt, Patrick Neven. Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-14.

Stereotactic Body Radiation Therapy for Oligoprogressive Pleural Mesothelioma: Fine-Tuning the Optimal Doses

There is growing evidence of a role of stereotactic body radiation therapy (SBRT) in the treatment of patients with oligoprogressive pleural mesothelioma (PM). The objective of this study was to investigate the optimal radiation therapy doses and schedules in this setting. The records of patients treated with SBRT (>5 Gy per fraction) for oligoprogression of PM at 2 institutions from June 2014 to September 2022 were reviewed. Patients were divided into 2 groups: “intermediate-dose” SBRT (i-SBRT; total dose, 30-36 Gy in 5-6 fractions) and “high-dose” SBRT (h-SBRT; total dose, 45-50 Gy in 4-8 fractions). The comparison between the 2 groups in terms of local control (LC) and toxicity was the primary endpoint of the study. Overall, 23 patients were treated for 25 pleural lesions. All had received upfront chemotherapy with platinum/pemetrexed. Fifteen patients were treated with i-SBRT and 8 patients with h-SBRT. The median equivalent dose was 40 Gy (range, 40-49.6) in the i-SBRT group and 74.46 Gy (range, 64-88) in the h-SBRT group. Six-month, 1-year, and 2-year LC were 100%, 100%, and 80% in the i-SBRT group and 100%, 100%, and 67% in the h-SBRT group, respectively (p =.94). Only 2 patients (1 for each dose group) had a recurrence in the radiation therapy field, both after experiencing a distant relapse. No severe acute and late toxicities were observed in the i-SBRT group, whereas in the h-SBRT group, 2 patients experienced G2 acute and late thoracic pain and 1 patient experienced G2 acute and G3 chronic thoracic pain. In our experience, SBRT is a safe and effective option for selected patients with oligoprogressive PM. Use of intermediate total doses keeping the dose per fraction high seems to offer an excellent LC, avoiding the risk of severe toxicity.

BladderGATE: Atezolizumab + intravesical BCG (bacillus Calmette-Guerin) upfront combination in patients with high risk non-muscle invasive bladder cancer (NMIBC)—Phase I-II ONCOSUR study.

595 Background: Intravesical Bacillus Calmette-Guerin (BCG) induction + BCG maintenance after transurethral resection is the current standard of care for patients (pts) with high-risk non-muscle invasive bladder cancer (NMIBC). Recurrence rate at 2 years and 5 years are around 30-40% and 70-80% respectively. Atezolizumab is a IgG1 monoclonal antibody targeting PD-L1 and is associated with long-term durable remissions in pts with metastatic urothelial cancer (MS. van der Heijden . Eur Urol 2021) and for pts with unresponsive NMIBC (PC. Black . Eur Urol 2023) with excellent results. Atezolizumab in combination with standard BCG could provide synergistic benefit for pts with NMIBC. BladderGATE (NCT04134000) is a phase Ib-II study which evaluates the safety and efficacy of upfront atezolizumab + intravesical BCG in pts with high-risk NMIBC. Methods: Pt had confirmed histopathology of high-risk NMIBC, BCG naïve or stopped >2 years ago, WHO PS 0-2 and adequate hematologic and organ function. Dose-escalation design to identify DLT and MTD (9 pts) and to evaluate safety and efficacy in an expansion cohort (30 pts) were programed. Pt received six weekly induction instillations, and maintenance instillations at 3, 6 and 12 months + intravenously atezolizumab 1200 mg every 3 weeks, up to 1 year. Urine/blood and tissue samples were collected for translational and biomarker correlative study. Primary objective is disease free survival. Secondary objectives include safety profile and quality of life. Results: Finally 36 pt were included, median age 70 years, 86% men, 61% of pt were former smokers, 22% smokers and 17% had never smoked, and tumor size was ≥3 cm in 44% of pt. With a 22 months median follow-up, 56% of pt had completed BCG treatment and 89% had received adequate BCG treatment (5 induction plus at least 2 maintenance instillations). Thirteen pts discontinued atezolizumab due to immune-related AEs (7 pts) (g2 dermatitis, g3 hepatitis, encephalitis, pneumonitis, myocarditis, adrenal insufficiency and psoriasis), due to early-relapse disease (3 pts) and progressive-disease (3 pts). All irAEs were solved and no toxic death were reported. Of the 36 pts analyzed, 6 pts showed local recurrence (17%), 5 pts with high-risk NMIBC (14%) and 1 pt with low-risk NMIBC, 1 pt with UTUC, and 3 pts with local muscle invasive bladder cancer progressive-disease (8 %). Preliminary 2-year disease free survival is 72.8% (95% CI: 56.1% - 89.5%). Conclusions: The combination strategy of atezolizumab + intravesical BCG upfront in high-risk NMIBC pts appears feasible and safe. A 14% of 2-years local recurrence-rate and 8% of local progressive-disease are promising results, pending to randomized Ph3 ALBAN study data (GETUG). Supported by Roche-Spain. Clinical trial information: NCT03425201 .

Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score

BackgroundPartial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes.MethodsA retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW).ResultsA total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046–0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021–0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011–0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016–0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified.ConclusionsOur findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan.Trial registrationThis study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).

A Molecular Dynamics Simulation of Complexes of Fullerenes and Lysine-Based Peptide Dendrimers with and without Glycine Spacers.

The development of new nanocontainers for hydrophobic drugs is one of the most important tasks of drug delivery. Dendrimers with hydrophobic interiors and soluble terminal groups have already been used as drug carriers. However, the most convenient candidates for this purpose are peptide dendrimers since their interiors could be modified by hydrophobic amino acid residues with a greater affinity for the transported molecules. The goal of this work is to perform the first molecular dynamics study of the complex formation of fullerenes C60 and C70 with Lys-2Gly, Lys G2, and Lys G3 peptide dendrimers in water. We carried out such simulations for six different systems and demonstrated that both fullerenes penetrate all these dendrimers and form stable complexes with them. The density and hydrophobicity inside the complex are greater than in dendrimers without fullerene, especially for complexes with Lys-2Gly dendrimers. It makes the internal regions of complexes less accessible to water and counterions and increases electrostatic and zeta potential compared to single dendrimers. The results for complexes based on Lys G2 and Lys G3 dendrimers are similar but less pronounced. Thus, all considered peptide dendrimers and especially the Lys-2Gly dendrimer could be used as nanocontainers for the delivery of fullerenes.

FEATURES OF THE RB1 GENE EXPRESSION IN BRAIN TUMORS

Summary. Aim: to determine the features of the RB1 gene expression at mRNA and protein levels in malignant cells of brain neoplasms, as well as to reveal the relationship between the RB1 expression levels and the degree of tumor malignancy. Object and methods: Samples of surgical material of 27 patients with brain tumors G2–G4. RB1 gene expression levels were assessed by q-PCR, and the RB protein by immunohistochemistry. The RB1 gene expression pattern in brain tumors was also performed using bioinformatic analysis of the Oncomine and Protein Atlas databases. Statistical analysis was performed using the GraphPadPrism9 program. Results: we have found that the expression patterns of the RB1 gene at the mRNA and protein levels in brain tumors are mainly unidirectional. The RB1 expression pattern showed high heterogeneity in samples of astrocytoma NOS (Not Otherwise Specified): pilocytic G2, diffuse astrocytoma G2–G3, glioblastoma G4, and atypical meningioma (mixed variant) G2, where from 20 to 60% of tumors were positive, while in all embryonic tumors of CNS NOS — pineoblastoma G4 and medulloblastoma G4, RB1 gene expression was detected at the mRNA and protein levels. Conclusions: the molecular mechanisms underlying the inactivation of the RB-E2F pathway require further fundamental research to find the causes of brain tumors and markers for improved personalized diagnosis and prognosis of the course of disease.

Incidence and Management of Appendiceal Neuroendocrine Tumors in Pediatric Population: A Bicentric Experience with 6285 Appendectomies.

Neuroendocrine tumors (NETs) are rare tumors that arise from neuroendocrine cells and are the most common tumors of the appendix. NETs of the appendix usually cause no symptoms and often go unnoticed until they cause acute appendicitis or are discovered during an accidental appendectomy. As the trend towards the conservative treatment of acute appendicitis increases in the pediatric population, the question arises as to whether the majority of NETs go undetected and are only discovered at an advanced stage. The purpose of the proposed study is to review the incidence and outcomes of treatment for NETs of the appendix in children and include the data presented in the data pool for further review. From 1 January 2009 to 1 November 2023, a total of 6285 appendectomies were performed in two large pediatric centers in Croatia. After a retrospective review of the case records and histopathologic findings, a total of 31 children (0.49%) were diagnosed with NET of the appendix and included in the further analysis. The primary outcome of this study was the incidence and treatment outcome of pediatric patients diagnosed with NET of the appendix. Secondary outcomes included the patients' demographic, clinical, and laboratory data and the histopathologic characteristics of tumor species. The overall incidence of NETs of the appendix was stable over the study years, with minor fluctuations. The median age of patients was 14 (interquartile range-IQR: 12, 16) years, with a female predominance (64.5%). The majority of patients (96.8%) presented with acute abdominal pain and underwent appendectomy because acute appendicitis was suspected. Acute appendicitis was confirmed by histopathology in 18 (58%) cases. NETs of the appendix were not detected preoperatively in any of the patients. Among patients with confirmed acute appendicitis, most (n = 14; 77.8%) were found to have non-perforated acute appendicitis. In most children, the tumor was located at the tip of the appendix (n = 18; 58.1%), and the majority of tumors had a diameter of less than 1 cm (n = 21, 67.7%). The mitotic count (n = 25, 80.6%) and Ki-67 proliferation index (n = 23, 74.2%) were low in most patients, so most tumors were classified as NET G1 (n = 25, 80.6%), while NET G2 and NET G3 were found in four (12.9%) and two (6.5%) patients, respectively. All children were treated with appendectomy only. The median follow-up time was 54 (IQR: 24, 95) months. The incidence of appendiceal NET among pediatric patients is very low. NET occurs most frequently in adolescents, with a female predominance. Most tumors are less than 1 cm in diameter, located at the tip, and associated with non-perforated appendicitis. Appendectomy is the treatment of choice, and major surgery was not necessary in our cohort.

Safety of Elranatamab in Patients with Triple-Class Refractory Relapsed/Refractory Multiple Myeloma (RRMM) in Magnetismm-17, a North American Expanded Access Protocol

BACKGROUND In the phase 2, registrational MagnetisMM-3 (NCT04649359) trial, patients with RRMM who had not previously received a B cell maturation antigen (BCMA)-directed therapy (n=123) achieved an objective response rate of 61% with single-agent elranatamab (ELRA), a BCMA-CD3 bispecific antibody. Common treatment-emergent adverse events (TEAEs) included infections (70%; 40% grade [G] 3/4) and CRS (58%; all G1/2). Here we report on the safety of ELRA in the MagnetisMM-17 (MM-17; NCT05462639) trial, a North American Expanded Access Protocol (EAP). METHODS MM-17 is an ongoing, single-arm, open-label study for patients with triple-class refractory RRMM (refractory to ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody), and who had no prior BCMA-directed therapy. Patients must be ≥18 years of age and have a confirmed diagnosis of MM, measurable disease by IMWG criteria, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, adequate organ function, and no active, uncontrolled infection. The study is being conducted in the US and Canada. The primary objective is to provide access to ELRA for patients with RRMM and no access to comparable/alternative therapy. The secondary objective is to evaluate the safety and tolerability of ELRA. Patients received subcutaneous ELRA 76 mg once every week on a 28-day cycle after step-up doses of 12 and 32 mg during week 1. Dose frequency was reduced to once every 2 weeks (Q2W) after ≥6 cycles in patients with persistent response (≥partial response), and then from Q2W to Q4W after ≥6 Q2W cycles. Patients received ELRA until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or ELRA becomes commercially available. TEAEs were graded by NCI CTCAE v5.0, except cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which were graded according to the American Society for Transplantation and Cellular Therapy criteria (ASTCT). RESULTS As of April 28, 2023, 20 patients had enrolled in the trial. Median patient age was 72.5 years (range 53-82); 50% male, 85% white, and 15% Black/African American. At baseline, most patients had an ECOG PS of 1 (95%), and 40% had R-ISS disease stage III. Patients had a median of 4 prior lines of therapy (range 2-8); 95% and 35% of patients had triple-class and penta-drug refractory disease, respectively. At the time of data cut-off, 2 patients had discontinued due to progressive disease. Median treatment duration was 0.95 months (range 0.26-2.83); median relative dose intensity was 98.3% (range 48-105). TEAEs were reported in all 20 patients, with G3 or G4 events reported in 13 (65%). There were no G5 events. Thirteen (65%) patients developed CRS, all events were G1 (50%) or G2 (15%); no events G ≥3 were reported. After the first step-up dose, 11 (55%) patients had a CRS event. CRS events occurred in 3 patients (15%) and 1 patient (5%) after the second step-up dose and first treatment dose, respectively. The median time to onset was 2 days (range 1-4), and the median time to resolution was 3 days (range 1-5). ICANS occurred in 2 of the 20 patients (10%), both events were G1, with 1 occurring after the first step-up dose and the other after the second step-up dose. The median time to onset was 3 days (range 3-3) and the median time to resolution was 2.5 days (range 2-3). Four (20%) patients had infections, including 1 event each of G1 sinusitis, G2 acute sinusitis, G2 folliculitis, G2 upper respiratory tract infection and G3 bacterial conjunctivitis. Cytopenias were reported in 11 (55%) patients. The most common (occurring in ≥3 [15%] patients) cytopenias were neutropenia (30%; G3/4 25%), lymphopenia (20%; G3/4 15%), and thrombocytopenia (15%; G3/4 10%). CONCLUSIONS Early safety data (median treatment duration &amp;lt;1 month) from this ongoing expanded access protocol of elranatamab in patients with RRMM are consistent with results from the phase 2, registrational MagnetisMM-3 trial, with no new safety signal identified.

Laparoscopic extraperitoneal radical cystoprostatectomy: for whom and how?

Background. Laparoscopic radical cystectomy is an established reliable minimally invasive method for the treatment of muscle-invasive bladder cancer. However, in the elderly and patients with serious comorbidities, laparoscopic radical cystectomy is still associated with high risk of complications. There are only a few reports on the use of extraperitoneal access for laparoscopic radical cystectomy in the literature. At the same time, extensive experience has been accumulated in laparoscopic extraperitoneal radical prostatectomy and retroperitoneoscopic operations on the kidney showing significant advantages of extraperitoneal access. Aim. To present initial results of laparoscopic radical cystectomy through extraperitoneal access in medically ill patients.Materials and methods. Between 2017 and 2021, extraperitoneal laparoscopic radical cystectomy was performed at the Volgograd Regional Uronephrology Center in four male patients with tumors affecting the bladder, stages T2–T4. All patients had serious comorbidities. In 3 patients, grade G2–G3 muscle-invasive bladder cancer was histologically verified prior to cystectomy. Two of them had invasion in the posterior urethra. One patient was diagnosed with prostate adenocarcinoma (Gleason score 8 (5 + 3)) with invasion into the bladder wall, ureterohydronephrosis and stage IV chronic kidney disease. None of the patients received neoadjuvant therapy: in 2 cases surgeries were emergency due to recurrent hemorrhages, and 3 patients had significantly decreased kidney function.Results. All operations were performed completely laparoscopically through extraperitoneal access. In 1 case, urine diversion was performed transperitoneally into a colon conduit. Simultaneous retroperitoneoscopic ureterocutaneostomy was performed in two patients: on one side (in a patient with a single functioning kidney) and on both sides, respectively. In a patient with stage V chronic kidney disease and permanent dialysis, bilateral simultaneous retroperitoneal nephrectomies were performed.In 2 patients, salvage cystectomy was done for recurrent bleeding that couldn’t be managed by conservative methods. The maximum intraoperative blood loss did not exceed 500 mL. Bowel function in all patients was recovered within 24–36 hours after the intervention.Conclusion. Laparoscopic extraperitoneal radical cystectomy is a reproducible minimally invasive surgical procedure for bladder cancer treatment that has advantages in terms of postoperative recovery in patients with severe comorbidities. The use of extraperitoneal access may be a rational alternative for salvage cystectomy in male patients. More observations are needed to determine the place of the method in the surgical treatment of muscle invasive bladder cancer.

Nivolumab in Lymphomatoid Granulomatosis (LYG) and Other Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders (LPDs) and Non-Hodgkin Lymphomas (NHLs) with Systemic and/or CNS Involvement: Preliminary Analysis of Efficacy and Safety from an Ongoing Phase II Study

Background: Programmed cell death protein-1 (PD-1) is a signaling molecule on the surface of T-cells that suppresses the cytotoxic effects of T-cells on tumor cells. We previously demonstrated increased PD-1 expression on CD8+ T-cells compared to healthy controls in pts with LYG, which could be reversed with immunotherapy using interferon alpha-2b (Melani et al. Lancet Haematol. 2023). Additionally, elevated expression of programmed death-ligand 1 (PD-L1) has been observed in other EBV-LPDs and NHLs as well as in chronic viral infections, such as EBV. Given this likely shared disease pathobiology, we hypothesized that treatment with the anti-PD-1 antibody, nivolumab, may reverse T-cell exhaustion and result in anti-tumor responses in pts with LYG and other EBV-LPDs and NHLs, including those with systemic and/or CNS involvement. Methods: Relapsed/refractory (R/R) EBV-LPD and NHL pts age ≥ 12y with adequate organ function were eligible. Untreated pts were eligible if EBV-LPD. Exclusions included prior use of PD-1/PD-L1/PD-L2/CD137/CTLA-4 antibodies, solid organ transplant, and HIV infection. Pts with a known immunodeficiency or autoimmune illness were eligible if not requiring steroids or immunosuppression within 14d of study. CNS involvement was permitted if no seizure activity within 4w of study. Nivolumab 480 mg IV was given q4w for up to 2y. Pts who achieved CR discontinued nivolumab after 1y of treatment. Responding patients with relapse or progression within 1y of discontinuing treatment were eligible for retreatment. Baseline evaluation included CT, PET, MRI brain, flow cytometry of peripheral blood and CSF, BM biopsy, and optional tumor biopsy. Restaging CT scans were performed after cycles 3, 6, 13, and 19, and end of treatment (EoT). PET was performed after cycles 1, 3, and EoT. Surveillance CT was performed q3m for 1y, q6m for yrs 2-5, and annually thereafter. Results: 11 pts were enrolled and treated; 6 (55%) with EBV-LPD and 5 (45%) with EBV-NHL (all DLBCL). EBV-LPD subtypes included 4 pts with G1-2 LYG and 1 pt each with EBV B-LPD of the CNS and CAEBV. Median age was 48y (range 20-67), and all pts had stage III/IV disease with extranodal involvement of the lung most common in 64% (7/11) and CNS disease in 18% (2/11). Median baseline absolute CD8 count (cells/mcL) was 86 (range 9-1237; normal: 178-853), CD4 count (cells/mcL) was 255 (range 99-1304; normal: 359-1565), and EBV VL in plasma (Log10 IU/mL) was undetected (range undetected-6.78; normal: &amp;lt;2.3). Median prior therapies were 1 (range 0-6) with 3 previously untreated LPD pts and 50% of previously tx pts were refractory to last tx. In 10 pts evaluable for response(1 came off tx prior to restaging), ORR and CR rate were both 60% (6/10). CR rate was 67% (4/6) in EBV-LPD, including 75% (3/4) with LYG, and 50% (2/4) in EBV-NHL (Fig 1A). One (50%) of 2 EBV-LPD pts with CNS involvement achieved CR after 3C of therapy and remains in ongoing response. Median TTR was 3.0m with 50% (3/6) responses ongoing from 3-56m after first response (Fig 1B). With a median follow up of 32m, 2y PFS and OS was 33% and 72% overall. By cohort, median PFS was 36m in EBV-LPD and 1m in EBV-NHL (p=0.003), with a 2y OS of 100% in EBV-LPD and 40% in EBV-NHL (p=0.04). Three EBV-NHL pts died, all of disease progression. One EBV-NHL pt stopped therapy after 2C due to radiographic disease progression in the kidney, but later developed CR without further therapy and remains in remission 56m after stopping therapy consistent with initial pseudoprogression. Adverse events (AEs) were as expected for nivolumab therapy with the most common AEs (% pts) including maculopapular rash (27%), diarrhea (18%), hypothyroidism (18%), and fatigue (18%). One pt developed an immune-mediated G2 myositis and G3 hepatitis following 3C of therapy which resolved after drug discontinuation and corticosteroids. Conclusion: Nivolumab is well tolerated in pts with LYG and other EBV-LPDs and NHLs without unexpected toxicities. Preliminary activity, including durable CRs, is noted across all pt cohorts, including 1 EBV-LPD pt with CNS involvement. With small numbers, statistically longer PFS and OS was observed with nivolumab in LYG and EBV-LPD compared to EBV-NHL, indicating that monotherapy may be sufficient for LYG and other EBV-LPDs, but combination therapy is likely needed for pts with EBV-NHL. Study enrollment continues to better assess the activity and durability of nivolumab in LYG and other EBV-LPDs and NHLs.

P425 TEAMWORK IS SUCCESSFUL (3): IMMUNOTHERAPY WITH IMMUNE CHECKPOINT INHIBITORS (ICIS) FAVOURABLE RESPONSE AND CARDIOVASCULAR COMPLICATION. A CASE REPORT

Abstract Immunotherapy in recent years has revolutionized the oncology practice. ICIs targeting T lymphocyte antigen–4 (CTLA–4) and programmed death–1/ligand–1 (PD–1/PD–L1) transformed treatment landscape of many different cancers. The answers occur in a substantial fraction of patients and are often durable. ICI‘s combined block (CB) (CTLA–4 + PD–1/PD–L1) seems to improve even further clinical outcomes compared to monotherapies. However, this treatment exposes patients to the risk of immune adverse events (iAE) including cardiovascular (CV) iAE, which can be potentially fatal and, in any case, compromise the continuation of oncological treatment. Here we present the case of a young woman with advanced renal cancer (Stage IV, T3b, N0, M1) in ICI combined block therapy (Nivolumab + Ipilumab) complicated early by a pericardial effusion (PE) Clinical case Oct 2021: a 48 yrs old woman with sarcomatoid and rhabdoid renal cell cancer with liver metastases underwent left radical nephrectomy and splenectomy + cavotomy for neoplastic thrombus removal. Dec 21, she started ICIs CB (Nivolumab + Ipilumab) X 4 and sequential Nivolumab. March 2022: on CT assessment for disease restaging at the end of induction therapy with nivolumab + Ipilumab a favorable response of metastases was detected but incidental finding of G2–G3 PE was identified (figure 1). Therapy with prednisone (1 mg/kg/day) and Colchicine 0.5 mg/day was promptly started with progressive reduction of the effusion in the serial cardiological checks without recurrence although maintenance immunotherapy with Nivolumab was rechallenged. ICIs was permanently discontinued in June 2022 due to gastrointestinal G4 toxicity. At MRI evaluation after 6 months ICIs discontinuation (December 2022), liver metastases were further reduced compared to previous assessments. Conclusion This case confirms that the association between iAE side effects and efficacy of ICIs is a real possibility. Vigilant surveillance and close collaboration between oncologists and cardiologists facilitate timely capture of CV iAE and appropriate management to allow effective management.

An miRNA Signature Predicts Grading of Pancreatic Neuroendocrine Neoplasms.

Grading pancreatic neuroendocrine neoplasms (PNENs) via mitotic rate and Ki-67 index score is complicated by interobserver variability. Differentially expressed miRNAs (DEMs) are useful for predicting tumour progression and may be useful for grading. Twelve PNENs were selected. Four patients had grade (G) 1 pancreatic neuroendocrine tumours (PNETs); 4 had G2 PNETs; and 4 had G3 PNENs (2 PNETs and 2 pancreatic neuroendocrine carcinomas). Samples were profiled using the miRNA NanoString Assay. There were 6 statistically significant DEMs between different grades of PNENs. MiR1285-5p was the sole miRNA differentially expressed (p=0.03) between G1 and G2 PNETs. Six statistically significant DEMs (miR135a-5p, miR200a-3p, miR3151-5p, miR-345-5p, miR548d-5p and miR9-5p) (p<0.05) were identified between G1 PNETs and G3 PNENs. Finally, 5 DEMs (miR155-5p, miR15b-5p, miR222-3p, miR548d-5p and miR9-5p) (p<0.05) were identified between G2 PNETs and G3 PNENs. The identified miRNA candidates are concordant with their patterns of dysregulation in other tumour types. The reliability of these DEMs as discriminators of PNEN grades support further investigations using larger patient populations.

An improved generative adversarial network for remote sensing image super‐resolution

AbstractSpatial resolution is an important indicator that measures the quality of remote sensing images. Image texture has been successfully recovered by generative adversarial networks in deep learning super‐resolution (SR) methods. However, the existing methods are prone to image texture distortion. To solve the above problems, this paper proposes an improved generative adversarial network to enhance the super‐resolution reconstruction effect of medium‐ and low‐resolution (LR) remote sensing images. This network is based on the Super Resolution Generative Adversarial Network (SRGAN), which makes great improvements in the structure of the connection between the inside and outside of the residual block and the design of the model loss function. At the same time, the G1–G2–G3 structure between residuals effectively combines the image information of the three scales of small, medium and large. The model loss function can be designed based on the Charbonnier loss function to narrow the pixel distance between the reconstructed remote sensing image and the original image. Furthermore, targeted perceptual loss can direct the network to restore the texture details of the image according to the semantic category. The subjective and objective evaluation of the generated images and the ablation experiments prove that compared with SRGAN and other networks, our method can generate more realistic and reliable textures. Additionally, the indicators [peak signal‐to‐noise ratio (PSNR), structural similarity (SSIM), multiscale structural similarity (MS‐SSIM)] used to measure the quality of the reconstructed image obtain improved objective quantitative evaluation.

Parent-child separation and intergenerational transmission of substance use and disorder: Testing across three generations.

There is evidence for intergenerational transmission of substance use and disorder. However, it is unclear whether separation from a parent with substance use disorder (SUD) moderates intergenerational transmission, and no studies have tested this question across three generations. In a three-generation study of families oversampled for familial SUD, we tested whether separation between father (G1; first generation) and child (G2; second generation) moderated the effect of G1 father SUDs on G2 child SUDs. We also tested whether separation between father (G2) and child (G3; third generation) moderated the effect of G2 SUDs on G3 drinking. Finally, we tested whether G1-G2 or G2-G3 separation moderated the mediated effect of G1 SUDs on G3 drinking through G2 SUDs. G1 father-G2 child separation moderated intergenerational transmission. In families with G1-G2 separation, there were no significant effects of father SUD on G2 SUD or G3 drinking. However, in nonseparated families, greater G1 father SUDs predicted heightened G2 SUDs and G3 grandchild drinking. In nonseparated families, G1 father SUDs significantly predicted G2 SUDs, which predicted G3 drinking. However, G2-G3 separation predicted heightened G3 drinking regardless of G2 and G1 SUDs. Parental separation may introduce risk for SUDs and drinking among youth with lower familial risk.

Radiomic Features Applied to Contrast Enhancement Spectral Mammography: Possibility to Predict Breast Cancer Molecular Subtypes in a Non-Invasive Manner

We aimed to investigate the association between the radiomic features of contrast-enhanced spectral mammography (CESM) images and a specific receptor pattern of breast neoplasms. In this single-center retrospective study, we selected patients with neoplastic breast lesions who underwent CESM before a biopsy and surgical assessment between January 2013 and February 2022. Radiomic analysis was performed on regions of interest selected from recombined CESM images. The association between the features and each evaluated endpoint (ER, PR, Ki-67, HER2+, triple negative, G2-G3 expressions) was investigated through univariate logistic regression. Among the significant and highly correlated radiomic features, we selected only the one most associated with the endpoint. From a group of 321 patients, we enrolled 205 malignant breast lesions. The median age at the exam was 50 years (interquartile range (IQR) 45-58). NGLDM_Contrast was the only feature that was positively associated with both ER and PR expression (p-values = 0.01). NGLDM_Coarseness was negatively associated with Ki-67 expression (p-value = 0.02). Five features SHAPE Volume(mL), SHAPE_Volume(vx), GLRLM_RLNU, NGLDM_Busyness and GLZLM_GLNU were all positively and significantly associated with HER2+; however, all of them were highly correlated. Radiomic features of CESM images could be helpful to predict particular molecular subtypes before a biopsy.

Chronic Kidney Disease Classification Predicts Short-Term Outcomes of Patients Undergoing Pancreaticoduodenectomy

BackgroundThe impact of chronic kidney disease (CKD) on pancreaticoduodenectomy has not been well established. In this study, we investigated the effects of preoperative CKD in patients undergoing pancreaticoduodenectomy. MethodsA retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database identified patients who underwent pancreaticoduodenectomy between 2015 and 2019. The estimated glomerular filtration rate (eGFR) for each patient was calculated using the CKD-Epidemiology Collaborative (CKD-EPI) 2021 equation. Kidney function was stratified according to the Kidney Disease: Improving Global Outcomes (KDIGO) Classification: G1, normal/high function (estimated glomerular filtration rate ≥ 90 ml/min/1.73 m2); G2–G3, mild/moderate CKD (89–30 ml/min/1.73 m2); and G4–G5, severe CKD (≤ 29 ml/min/1.73 m2). The 30-day overall complications and outcomes were compared using regression models accounting for demographics and comorbidities. ResultsA total of 20,656 (55.7% men) patients were identified. Univariate analysis showed that compared to G1 patients, G2–G3 and G4–G5 had higher rates of overall complications (p < 0.001), need for readmission (p = 0.004), need for reoperation (p < 0.001), discharge to the care facility (p < 0.001), death (p < 0.001), and average length of stay (p < 0.001). On multivariable regression, G2–G3 renal function was found to be an independent risk factor for overall (1.10 [1.04–1.17], p = 0.002), pulmonary (1.23 [1.10—1.37], p < 0.001), hematologic (1.08 [1.02–1.16], p = 0.015), and renal (1.29 [1.11–1.49], p < 0.001) complications; discharge to care facility (1.10 [1.02–1.19], p = 0.045); and 30-day mortality (1.25 [1.01–1.56], p = 0.045). G4–G5 renal function was a predictor of worse outcomes for the prior variables and an independent risk factor for cardiovascular complications (2.70 [1.44–4.96], p = 0.001) and length of stay (1.32 [1.13–1.56], p < 0.001). ConclusionsThe degree of CKD was related to the overall complications and outcomes after pancreaticoduodenectomy. Therefore, the CKD classification should be strongly considered in the preoperative risk stratification of these patients.

The role of elective neck dissection in T1 and T2 nasal cavity squamous cell carcinomas

PurposeTo evaluate the role of elective neck dissection (END) on oncological outcome in early-stage nasal cavity squamous cell carcinomas (SCCs).MethodsIn total, 87 patients with T1 (n = 59; 67.8%) and T2 (n = 28; 32.2%) SCCs were evaluated regarding performance of END, regional recurrences (RR) and its impact on cancer-specific survival (CSS). We further created a risk score based on T-classification, tumor subsite and grading to identify patients whom may benefit from END and calculated the corresponding numbers needed to treat (NNT) to prevent RR.ResultsNine (10.3%) patients experienced RR of whom 3 (5.1%) were T1 and 6 (21.4%) T2 tumors (p = 0.042). All RR originated from moderately or poorly differentiated (G2–G3) SCCs of the nasal septum or vestibule. END was done in 15 (17.2%) patients and none of those experienced RR (p = 0.121). Onset of RR represented the worst prognostic factor for CSS (HR 23.3; p = 0.007) with a 5y-CSS of 44.4% vs. 97.3% (p < 0.001). RR occurred in none of the patients with no or low risk scores compared to 31.6% (6/19) in patients with high-risk scores (p = 0.006). Accordingly, three high-risk patients would need to undergo END (NNT 2.63) to prevent RR compared to a NNT of 8 for the whole cohort.ConclusionsAlthough rare, occurrence of RR significantly deteriorates outcome in early stage nasal cavity SCCs, which could be effectively reduced by performance of END. The importance of END is currently underestimated and our proposed risk score helps identifying those patients who will benefit from END.

Effect of cut-out rescan procedures on the accuracy of an intraoral scanner used for digitizing an ear model: An in vitro study.

The purpose of this study was to evaluate the impact of the rescanning of mesh holes of different diameters on the accuracy of an intraoral scanner (IOS) used to digitize an ear model. An ear model was digitized using an intraoral scanner (Medit i500) to obtain a reference mesh. A baseline experimental scan was created by editing a duplicate of the reference mesh using the cut-out tool of the IOS software. Three equal groups were created based on the diameter of the cut-out areas: 2 mm (G1), 5 mm (G2), and 8 mm (G3) (n=15). The cut-out areas were rescanned and a total of 45 digital files were exported. The discrepancy between the reference and the experimental digital scans was measured using the root mean square calculation (RMS). The data were analyzed by a Kruskal-Wallis test followed by a post hoc Dunn's test with Bonferroni correction. The trueness values ranged from 19.53 to 27.13 µm. There were significant differences in the RMS error values among the groups tested (p < 0.001) and post hoc multiple comparisons showed significant differences between the G1 and G2 groups (p=0.04), G1 and G3 groups (p < 0.001), and G2 and G3 groups (p=0.004). Overall, the precision values ranged from 4.93 to 7.73 µm and significant differences in the RMS values were only found between the G1 and G2 groups (p=0.014). Mesh hole rescanning affected the scanning accuracy (trueness and precision) of the IOS tested. The larger the diameter of the mesh holes, the less the trueness of the IOS tested. The precision values seemed to be less affected compared with the trueness by the cut-out and rescanning procedures.