Titration of Basal and Prandial Insulin Doses With the Initiation of Glucagon-Like Peptide-1 Receptor Agonist Therapy.

Objective Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated significant efficacy in improving glycemic control in type 2 diabetes mellitus, which often results in decreased insulin dose requirements. The purpose of this study was to examine the changes in basal and prandial insulin dose requirements from baseline to three months following initiation of a GLP-1 RA. Methodology A retrospective chart review was conducted of adult insulin-treated patients at the Chertow Diabetes Center, Huntington, WV, who were started on GLP-1 RAs for 24 months. Results Mean daily basal insulin doses decreased by 8.7 units (P = 0.29; mean 8.3% change) and mean daily prandial insulin doses decreased by 9.4 units (P = 0.10; mean 18.4% change) from baseline to three months after starting a GLP-1 RA. Average hemoglobin A1c significantly decreased from 8.8% (73 mmol/mol) at baseline to 8.0% (64 mmol/mol) at three months (P < 0.001). Significant decreases from baseline to three months were also observed in mean body weight, mean low-density lipoprotein (LDL) cholesterol, and mean total cholesterol. Conclusions GLP-1 RA therapy was associated with a significant decrease in hemoglobin A1c, body weight, and LDL-cholesterol from baseline to three months after initiation. Therapy with GLP-1 RAs was also associated with an overall decrease in daily basal and prandial insulin dose requirements, although this finding did not reach statistical significance.

Association of Wilms Tumor with Crossed Fused Renal Ectopia in Children: A Case Report.

Introduction: Wilms tumor is the most common renal malignancy in children. The occurrence of Wilms tumor with various congenital genitourinary anomalies has been reported, particularly in horseshoe kidneys, hypospadias, disorder of sexual development, and double collecting system. However, Wilms tumor with crossed renal ectopia is a rare finding. Case Description: We are reporting a case report of Wilms tumor in a 3-year-old girl who presented with a huge left flank mass with cross-fused renal ectopia. After the initial workup and triphasic computed tomography scan of the chest, abdomen, and pelvis for confirmation of diagnosis and metastasis, the patient underwent image-guided tissue biopsy, followed by neoadjuvant chemotherapy, left radical nephrectomy with separation of fused right ectopic renal moiety, and adjuvant chemoradiation. Practical Implication: This report shows an association of Wilms tumor with cross-fused renal ectopia, a rare combination. Unusual findings on imaging with unilateral flank mass should be considered as part of the differential diagnosis for this rare finding. Adjuvant chemotherapy and modern imaging helped delineate the anatomy and ease the surgery for safe resection, improving the overall outcome.

Pediatric Ewing Sarcoma of Kidney: A Case Series and Review of Literature.

Introduction: Renal Ewing sarcoma is an aggressive and rare malignancy affecting children and adolescents. Limited data on its management contribute to uncertainties in treatment. Case description: We present two pediatric cases of renal Ewing sarcoma. Both cases emphasize the significance of accurate diagnosis, multimodal treatment, and long-term follow-up in achieving favorable outcomes. Accurate diagnosis of renal Ewing sarcoma is crucial for effective management. Multimodal treatment involving neoadjuvant chemotherapy, surgical resection and staging with lymph node sampling, and chemotherapy continuation has shown promising results in our cases. Long-term follow-up is essential for monitoring disease progression and ensuring optimal outcomes. Practical Implications: There is limited data published about these renal tumors, especially in the pediatric population, and most studies lack long-term follow-up, with uncertain management due to limited data. This data will add to the newer, multimodal approach and form the basis for future meta-analysis to help formulate guidelines for upcoming international meetings. Continued research efforts are necessary to optimize strategies and improve the prognosis for pediatric patients with renal Ewing sarcoma.

Emergency Angioembolization for Life-Threatening Hemorrhage in Wilms Tumor.

Introduction: Renal artery embolization has been used in a palliative fashion for symptomatic relief of hematuria or flank pain in unresectable renal cell carcinoma in adults. There is limited data on the use of embolization for actively bleeding and unresectable tumors in the oncological pediatric population. Case Description: A previously healthy 5-year-old boy with no significant past medical or surgical history presented to the clinic with gradually worsening abdominal distension associated with occasional abdominal pain, gross hematuria, and lethargy for four months. Diagnostic investigations showed an 18-cm left-sided metastatic (pulmonary) renal tumor (Wilms), which was deemed unresectable on imaging. Treatment was planned according to the SIOP-RTSG protocol. However, he became hemodynamically and vitally unstable with acute, sudden distension of the abdomen on the left side after the first cycle of chemotherapy. Imaging showed active bleeding from an inferior branch of the left renal artery. Selective angioembolization was done, and chemotherapy was reinitiated with a patent left main renal artery. Following the fourth cycle of chemotherapy, he developed hemodynamic instability and abdominal pain; imaging revealed the resolution of pulmonary nodules and bleeding from the left renal artery (main); this was again embolized, and the patient was stabilized. The patient was operated on after optimization, and a complete resection of the mass was done with negative margins. On six months follow-up, he is well. Practical Implications: To the best of our knowledge, this is the first case where angioembolization has been done in conjunction with neoadjuvant chemotherapy to downsize a Wilms tumor to achieve favorable outcomes. Continued research efforts are necessary to optimize strategies and improve the prognosis for pediatric patients, and this case is one of the prime examples.

Testicular tumours in children: a single-centre experience.

Introduction: Testicular tumours in childhood have diverse characteristics for different age ranges. This study aimed to describe the pattern, presentation and outcomes of primary testicular tumours in a paediatric population. Methods: A retrospective study was conducted from January 2010 to December 2020 on children (≤18 years) with a diagnosis of primary testicular tumour. Baseline demographics, clinical characteristics, pathology, treatment and outcomes of these patients were analysed. The data were entered into IBM SPSS Statistics version 20.0. Chi-square test and Fisher's exact test were applied to find the statistical significance, which was set at P value ≤ 0.05. Results: The study included 115 males, with 85 (73.9%) patients in the prepubertal age range with a mean age of 2.53 ± 2.06 years and 30 (26.1%) patients in the postpubertal group with a mean age of 15.73 ± 1.25 years. Yolk sac tumour was the most common (62.6%) histological subtype. Majority (46.1%) of patients had stage I disease on presentation, while 29.6% had stage IV disease. All patients underwent upfront high inguinal radical orchiectomy, which was followed by platinum-based adjuvant chemotherapy in 67% of the patients. The five-year event-free survival and overall survival for all patients were 75% and 91%, respectively. Conclusion: Primary testicular tumours follow a bimodal age distribution pattern. Majority of patients can be cured with platinum-based chemotherapy despite having advanced disease at presentation.

Neuroendocrine adaptations to starvation.

Famine and starvation have punctuated the evolutionary past of the human species. As such, we have developed hormonal responses to undernutrition that minimize energy expenditure on processes that are not critical for the survival of the individual, such as reproduction. In this review, we discuss neuroendocrine adaptations to starvation including hypogonadotropic hypogonadism, growth hormone resistance, hypercortisolemia, and the downregulation of the hypothalamic-pituitary-thyroid axis. We review the time-course of these adaptations by describing studies involving the short-term fasting of healthy individuals as well as studies describing the hormonal changes in states of chronic undernutrition, using individuals with anorexia nervosa as a model of chronic starvation. Lastly, we review representative clinical effects of chronic undernutrition.

The Outcome of Extremity Soft Tissue Sarcomas in Terms of Resection Margins: A Study From a Cancer Dedicated Center.

Introduction Extremity soft-tissue sarcomas are uncommon malignancies of mesenchymal tissue, it accounts for <1 % of cancers and has a high recurrence rate with positive resection margins and unplanned excision. This study aims to determine the influence of unplanned excision and resection margins on local recurrence, metastasis, and overall survival in soft tissue sarcoma of the extremities. Methods A retrospective review was conducted from January 2005 to December 2015 on all the patients with soft tissue sarcoma of the extremities. Age, sex, histopathology, site, tumor grade, biopsy type, recurrence, metastasis, and end outcome were analyzed. Kaplan-Meir curves were used for Survival analysis, and log-rank or the Cox proportional-hazards regression model was used for Significance analysis. The data were entered into SPSS version 20, and Statistical significance was set at a p-value ≤0.05. Results One hundred forty-five patients with soft tissue sarcoma of extremities were managed with a mean follow-up of 76.3+/-6.7 months. Undifferentiated pleomorphic sarcoma 47 (32.4%) was the most common pathology found in this cohort, followed by Synovial sarcoma 34 (23.4%) and Liposarcoma 19 (13.1%). The most common site of occurrence was lower extremity 102 (70.3%). All the patients had residual disease after unplanned excisions; 107 underwent R0 resection, while 38 underwent R1 resection. Five-year overall survival was 70.2 & 71.1 % for R1 & R0 resections, respectively, and 71.3% for excisional and 74.2% for incisional biopsy. The tumor grade significantly influences overall survival, while other variables were not found to affect Recurrence-free survival and metastasis-free survival. Conclusion The data indicates that the high-grade tumor has a negative influence on overall survival, while resection margins width and unplanned excision have no significant effect on local recurrence, Metastasis free survival, and overall survival; however, before excision, adequate planning and awareness among general surgeons is necessary to improve the surgical morbidity and financial burden over the health care facilities.

Review of Perioperative Care Pathway for Children With Renal Tumors.

Introduction Wilms tumor is the most common (90%) renal tumor in children. With the recent advances survival rate approaches 90%. This study was designed to identify factors associated with early recovery and hospital discharge, a step forward in the future development of early recovery after surgery (ERAS) protocol in children.  Methods A retrospective cohort study was conducted from May 2020 to February 2022 among children up to the age of 18-years with a diagnosis of primary malignant renal tumors who underwent radical nephrectomy. Baseline parameters (preoperative), intraoperative, and postoperative components were analyzed. A univariable and multivariable logistic regression model was used to identify the factors leading to early discharge. The data were entered into SPSS version 20 (IBM Inc., Armonk, USA), and a p-value ≤0.05 was statistically significant. Results A total of 44 patients with malignant renal tumors were managed with a mean age at diagnosis of 4.06±3.00 years. Twenty-six (59.1%) were male and 18 (40.9%) were female. All the patients received neoadjuvant chemotherapy. Wilms tumor was the most common pathology found in 41 (93.1%) patients; 19 (43.0 %) had stage I, 21 (47.7%) stage II, and four (9.1%) stage III disease. Thirty-four (77.3%) patients had a nasogastric tube placed postoperatively. Median blood loss (BL) was 40 ml (range: 5-250), and the median operative time was two hours (range: 1-4). The median postoperative day to mobilization was one day (range: 1-3), to clear liquids was two days (range: 1-3), and advanced to regular diet was three days (range: 2-5). The median postoperative day of discharge (from surgery to discharge) was four days (range: 2-7), with 31 (70.5%) patients discharged early. Conclusion Our findings indicate that early removal of tube, mobilization, and re-feedings were significantly associated with the early hospital discharge, while the other analyzed factors were not statistically significant. Furthermore, our findings are important in the future development and implementation of ERAS protocol in pediatric oncological resections.

Role of Serum Biomarkers in Early Detection of Non-Alcoholic Steatohepatitis and Fibrosis in West Virginian Children.

BACKGROUND: Obesity, an epidemic among West Virginia children, as well as insulin resistance (IR), is well-established contributors to nonalcoholic steatohepatitis (NASH). Progression of NASH can lead to hepatic fibrosis and cirrhosis, making early detection imperative. The standard for diagnosing NASH is histologically via liver biopsy, which is highly invasive and generally contraindicated in children. By studying serum biomarkers associated with NASH, we aim to identify high risk children who can benefit from a less invasive, alternative approach to the early detection of NASH. METHODS: Seventy one children were prospectively recruited and divided into 3 groups: normal weight without IR (control), obese without IR, and obese with IR. Serum samples were drawn for each patient and biomarker levels were assessed via ELISA kits. RESULTS: Obese without IR and obese with IR patients had significantly elevated levels of lipid metabolism and accumulation markers (FGF-21, NEFA, FATP5, ApoB), oxidative stress markers (dysfunctional HDL, 8-Isoprostane), inflammatory markers(dysfunctional HDL, CK-18) and apoptosis markers (CK-18) compared to control patients (p<0.02). Bilirubin (an antioxidant) was significantly decreased in the obese without IR and obese with IR patients compared to control (p<0.02). CONCLUSION: This study showed a correlation between obesity, IR, and biomarkers associated with NASH in pediatrics patients from West Virginia, with obese with IR patients showing the strongest correlation. These findings support the clinical application of these serum biomarkers as a less invasive method for early detection of NASH and hepatic fibrosis.

Enteric duplication in children: A case series.

BACKGROUND: Enteric duplication (ED) cysts include a wide variety of cystic lesions, which can involve any part of the gastrointestinal tract (GIT). They can be referred to foregut, midgut, hindgut derived, depending upon the portion of GIT involved. The main purpose of this study was to document the variety of presentation, investigations, and treatment options employed. PATIENTS AND METHODS: This was a retrospective study at Paediatric Surgery Department of Services Hospital, Lahore from August, 2011 to August, 2013. The details of all the patients, including gender, and age, presenting complaint, abdominal examination findings, diagnostic modality, site, type, associated malformations, surgical option, and outcome were analysed. RESULTS: A total of eight patients with histopathological diagnosis of EDs managed were included in the study. Of these eight patients, six were males and two were females, with an average age of 2.4 years. The main diagnostic tool used was ultrasound in almost all patients. The most commonly involved site was ileum in 5 of 8 (62.5%) patients. Two cases had gastric involvement, while one patient had involvement of the descending colon. Six of eight were of tubular type (75%), while remaining 2 (25%) were of cystic type. Excision was possible in all these patients. CONCLUSION: ED can present with a wide spectrum of symptomatology. It can present as mass abdomen, intestinal obstruction or even can mimic as hydrocoele. High index of suspicion is therefore required. Ultimate aim of treatment is excision of cyst with preservation of vascularity of native gut.

An epigastric heteropagus twin with ruptured giant omphalocele.

We present a case of heteropagus twins attached to the epigastric region. The neonate also had ruptured giant omphalocoele with most of gut and liver lying outside the abdominal cavity. Patient had uneventful surgery for separation of twins and repair of ruptured omphalocoele.

Ileal duplication cyst causing recurrent abdominal pain and melena.

Alimentary tract duplications are rare congenital anomalies. The presentation depends on their anatomical location, size and other characteristics. The most common variety is small bowel cystic duplication. We report a case of an eight years old girl who presented with recurrent abdominal pain and melena. Radioisotope technetium scan showed increased uptake of tracer in right lower abdomen and a diagnosis of Meckel's diverticulum made. At surgery a cystic, communicating, ileal duplication found which was resected along with adjacent gut. It is thus reiterated that while investigating children with recurrent abdominal pain and melena, gut duplications must be included in the differential diagnosis.

Repetitive transcranial magnetic stimulation (rTMS) in experimentally induced and chronic neuropathic pain: a review.

UNLABELLED: Repetitive transcranial magnetic stimulation (rTMS) is an emerging technology that has been demonstrated to be useful in the treatment of depression and potentially useful in the management of several neurologic conditions. More recently, increasing attention has been directed at evaluating its efficacy in the treatment of patients with chronic neuropathic pain. We first discuss the literature examining the efficacy of rTMS in trials of experimentally induced acute pain as well as among patients with chronic pain. Examining frequency data obtained from the available literature, we attempted to identify some of the parameters of rTMS that appear to be related to its analgesic effects. An overview of the mechanisms underlying its potential analgesic role is discussed; generally, the influences of rTMS on cortical, and, indirectly, subcortical, neurons may reduce pain transmission ascending from spinothalamic tracts, thereby mitigating pain. Finally, we discuss some of the methodological issues and limitations of available studies and offer recommendations for further research. PERSPECTIVE: The authors provide a comprehensive review of rTMS use in the treatment of neuropathic pain in the literature available to date. Although the clinical usefulness of rTMS in pain has, as yet, to be determined, it offers insights into the pathophysiologic processes involved in the maintenance and exacerbation of chronic pain.

The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites.

Fas (CD95/Apo-1) is a member of the tumor necrosis factor receptor family. Receptor binding results in activation of caspase 8, leading to activation of proapoptotic downstream molecules. We found that expression of Fas was up-regulated >10-fold in MCF-7 breast and HCT116 and RKO colon cancer cell lines after treatment with IC(60) doses of 5-fluorouracil (5-FU) and raltitrexed (RTX). Combined treatment with the agonistic Fas antibody CH-11 and either 5-FU or RTX resulted in a highly synergistic induction of apoptosis in these cell lines. Similar results were obtained for another antifolate, Alimta. Induction of thymidylate synthase expression inhibited Fas induction in response to RTX and Alimta, but not in response to 5-FU. Furthermore, thymidylate synthase induction abrogated the synergy between CH-11 and both antifolates but had no effect on the synergistic interaction between 5-FU and CH-11. Inactivation of p53 in MCF-7 and HCT116 cell lines blocked 5-FU- and antifolate-mediated up-regulation of Fas. Furthermore, Fas was not up-regulated in response to 5-FU or antifolates in the p53-mutant H630 colon cancer cell line. Lack of Fas up-regulation in the p53-null and -mutant lines abolished the synergistic interaction between 5-FU and CH-11. Interestingly, synergy was still observed between the antifolates and CH-11 in the p53-null HCT116 and p53-mutant H630 cell lines, although this was significantly reduced compared with the p53 wild-type cell lines. Our results indicate that Fas is an important mediator of apoptosis in response to both 5-FU and antifolates.

Identification of 5-fluorouracil-inducible target genes using cDNA microarray profiling.

The fluoropyrimidine 5-Fluorouracil (5-FU) is widely used in the treatment of cancer. To identify novel downstream mediators of tumor cell response to 5-FU, we used DNA microarray technology to identify genes that are transcriptionally activated by 5-FU treatment in the MCF-7 breast cancer cell line. Of 2400 genes analyzed, 619 were up-regulated by >3-fold. Highly up-regulated genes (>6-fold) with signal intensities of >3000 were analyzed by Northern blot. Genes that were consistently found to be up-regulated were spermine/spermidine acetyl transferase (SSAT), annexin II, thymosin-beta-10, chaperonin-10, and MAT-8. Treatment of MCF-7 cells with the antifolate tomudex and DNA-damaging agent oxaliplatin also resulted in up-regulation of each of these targets. The 5-FU-induced activation of MAT-8, thymosin-beta-10, and chaperonin-10 was abrogated by inactivation of p53 in MCF-7 cells, whereas induction of SSAT and annexin II was significantly reduced in the absence of p53. Moreover, each of these genes contained more than one potential p53-binding site, suggesting that p53 may play an important regulatory role in 5-FU-induced expression of these genes. In addition, we found that basal expression levels of SSAT, annexin II, thymosin beta-10, and chaperonin-10 were increased (by approximately 2-3-fold), and MAT-8 expression dramatically increased (by approximately 10-fold) in a 5-FU-resistant colorectal cancer cell line (H630-R10) compared with the parental H630 cell line, suggesting these genes may be useful biomarkers of resistance. These results demonstrate the potential of DNA microarrays to identify novel genes involved in mediating the response of tumor cells to chemotherapy.

The interaction of thymidylate synthase expression with p53-regulated signaling pathways in tumor cells.

Thymidylate synthase (TS) is a chemotherapeutic target for the fluoropyrimidine 5-fluorouracil (5-FU) and antifolate tomudex (TDX). Using the MCF-7 breast cancer line, we have developed a cell line with inducible TS expression termed M7TS90. Inducible TS expression in this line resulted in a moderate (approximately 3-fold) increase in 5-FU 50% inhibitory concentration at 72 hours (IC-50(72 h)) dose and a dramatic (approximately 24-fold) increase in the IC-50(72 h) dose of TDX, but did not affect chemosensitivity to cisplatin, oxaliplatin, irinotecan, and paclitaxel. In the absence of drug treatment, inducible TS expression had no effect on expression of the p53 tumor suppressor gene. However, TS induction abrogated p53, p21, Fas, and Bak induction in response to TDX, but not 5-FU. Similarly, downregulation of Bcl-2 was reversed by inducible TS expression in TDX, but not 5-FU-treated cells. Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX, but not 5-FU.

The role of thymidylate synthase induction in modulating p53-regulated gene expression in response to 5-fluorouracil and antifolates.

Thymidylate synthase (TS) is a critical target for chemotherapeutic agents such as 5-fluorouracil (5-FU) and antifolates such as tomudex (TDX),multitargeted antifolate, and ZD9331. Using the MCF-7 breast cancer line, we have developed p53 wild-type (M7TS90) and null (M7TS90-E6) isogenic lines with inducible TS expression (approximately 6-fold induction compared with control after 48 h). In the M7TS90 line, inducible TS expression resulted in a moderate approximately 3-fold increase in 5-FU IC-50(72 h) dose and a dramatic >20-fold increase in the IC-50(72 h) doses of TDX, multitargeted antifolate, and ZD9331. S-phase cell cycle arrest and apoptosis induced by the antifolates were abrogated by TS induction. In contrast, cell cycle arrest and apoptosis induced by 5-FU was unaffected by TS expression levels. Inactivation of p53 significantly increased resistance to 5-FU and the antifolates with IC-50(72 h) doses for 5-FU and TDX of >100 and >10 microM, respectively, in the M7TS90-E6 cell line. Furthermore, p53 inactivation completely abrogated the cell cycle arrest and apoptosis induced by 5-FU. The antifolates induced S-phase arrest in the p53 null cell line; however, the induction of apoptosis by these agents was significantly reduced compared with p53 wild-type cells. Both inducible TS expression and the addition of exogenous thymidine (10 microM) blocked p53 and p21 induction by the antifolates but not by 5-FU in the M7TS90 cell line. Similarly, inducible TS expression and exogenous thymidine abrogated antifolate but not 5-FU-mediated up-regulation of Fas/CD95 in M7TS90 cells. Our results indicate that in M7TS90 cells, inducible TS expression modulates p53 and p53 target gene expression in response to TS-targeted antifolate therapies but not to 5-FU.