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Gilbert's syndrome (GS) is a benign hereditary disorder of bilirubin metabolism due to a mutation in the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) gene which results in hyperbilirubinaemia and related complications mainly cholelithiasis. It can be co-inherited along with sickle cell anaemia, thalassaemias and other haemoglobinopathies including glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis and cystic fibrosis. More than 100 mutations have been reported in UGT1A1 gene and the most common as insertion of extra (TA) nucleotides in the promoter region of TATA box. The more the number of TA repeats, the higher is the bilirubin levels. These mutations result in a 10%–35% reduction in the UGT1A1 enzyme activity resulting in mild to moderate unconjugated hyperbilirubinaemia and related complications. For diagnosis the mode of inheritance is more important than testing in the patients. However; the inheritance pattern of GS differs in ethnicities. For early diagnosis to prevent worsening of the symptoms and for timely management one should be aware of the inheritance pattern in patient. In this systemic analysis we studied the association between complications in GS with the genotypes and complications. It was found that TA7/7 is more significant in GS with sickle cell disease (SCD) group when compared to healthy controls with 2.2% chances of having this genotype in GS with SCD than healthy controls. The significance of having TA7/7 genotype is similar in GS with SCD and α-thalasaemia group. However, there is a high recommendation to carry out multicentre studies and conduct meta-analyses for establishing universal recommendations.

Background: UGT1A1 polymorphisms should be considered when using irinotecan-containing regimens, especially in patients with a double-variant-type (DV), including homozygous for UGT1A1*28 and UGT1A1*6 and heterozygous for both UGT1A1*28 and UGT1A1*6. We investigated the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) (irinotecan 80 mg/m2) in patients having DV. Methods: Patients with advanced pancreatic cancer who had received FOLFIRINOX between January 2015 and December 2019 were included in this study. Non-DV patients received the standard mFOLFIRINOX (irinotecan 150 mg/m2) as first-line (non-DV1) or second-line therapy (non-DV2); however, DV patients received mFOLFIRINOX (irinotecan 80 mg/m2) as the second-line therapy (DV2). We retrospectively evaluated the safety and efficacy of the lowered irinotecan dose in the DV2 group relative to the non-DV1 (safety) or non-DV2 (safety and efficacy) groups. Results: A total of 235 patients were eligible for this study with 118 patients in the non-DV1, 106 in the non-DV2, and 11 in the DV2 groups. Major grade 3–4 adverse events were neutropenia (33.9, 31.1, and 18.2%) and febrile neutropenia (6.8, 3.8, and 9.1%) in the non-DV1, non-DV2, and DV2 groups, respectively. The median progression-free survival was 3.4 months in the non-DV2 group, and 4.4 months in the DV2 group. The overall survival from the date of starting second-line chemotherapy was 8.8 months in the non-DV2 group and 11.5 months in the DV2 group. Conclusions: Based on our findings, the safety and efficacy of mFOLFIRINOX (irinotecan 80 mg/m2) in DV patients were comparable with the standard mFOLFIRINOX (irinotecan 150 mg/m2) in non-DV patients. [ABSTRACT FROM AUTHOR]

Gilbert's syndrome (GS) is a benign hereditary disorder of bilirubin metabolism due to a mutation in the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) gene which results in hyperbilirubinaemia and related complications mainly cholelithiasis. It can be co-inherited along with sickle cell anaemia, thalassaemias and other haemoglobinopathies including glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis and cystic fibrosis. More than 100 mutations have been reported in UGT1A1 gene and the most common as insertion of extra (TA) nucleotides in the promoter region of TATA box. The more the number of TA repeats, the higher is the bilirubin levels. These mutations result in a 10%-35% reduction in the UGT1A1 enzyme activity resulting in mild to moderate unconjugated hyperbilirubinaemia and related complications. For diagnosis the mode of inheritance is more important than testing in the patients. However; the inheritance pattern of GS differs in ethnicities. For early diagnosis to prevent worsening of the symptoms and for timely management one should be aware of the inheritance pattern in patient. In this systemic analysis we studied the association between complications in GS with the genotypes and complications. It was found that TA7/7 is more significant in GS with sickle cell disease (SCD) group when compared to healthy controls with 2.2% chances of having this genotype in GS with SCD than healthy controls. The significance of having TA7/7 genotype is similar in GS with SCD and α-thalasaemia group. However, there is a high recommendation to carry out multicentre studies and conduct meta-analyses for establishing universal recommendations. [ABSTRACT FROM AUTHOR]

Abstract Background Uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) is a predictive biomarker for the side-effects of irinotecan chemotherapy, which reduces the volume of tumors harboring UGT1A1 polymorphisms. We aimed to determine whether UGT1A1 polymorphisms can predict progression-free survival in patients with local cervical cancer treated with irinotecan chemotherapy. Methods We retrospectively analyzed the data of 51 patients with cervical cancer treated at a single institution between 2010 and 2015. All patients were diagnosed with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IB1, IB2, IIA, or IIB squamous cell carcinoma, underwent radical hysterectomy, and received irinotecan chemotherapy as neoadjuvant and/or adjuvant treatment. All patients were examined for irinotecan side effects using UGT1A1 tests. Conditional inference tree and survival analyses were performed considering the FIGO stage, age, the UGT1A1 status, and the number of metastatic lymph nodes to determine primary factors associated with progression-free survival. Results The tree-structured survival model determined high recurrence-risk factors related to progression-free survival. The most relevant factor was ≥2 metastatic lymph nodes (p = 0.004). The second most relevant factor was UGT1A1 genotype (p = 0.024). Among patients with ≤1 metastatic lymph node, those with UGT1A1 polymorphisms benefited from irinotecan chemotherapy and demonstrated significantly longer progression-free survival (p = 0.020) than those with wild-type UGT1A1. Conclusions Irinotecan chemotherapy might be beneficial in patients with cervical cancer, UGT1A1 polymorphisms, and ≤ 1 metastatic lymph nodes.

Abstract Background Gilbert syndrome (GS) is an autosomal recessive inherited disorder of bilirubin glucuronidation which has not been investigated in Egypt. This longitudinal study investigated the frequency, clinical course, genetic profile and health related quality of life in Egyptian adults. Methods An initial cross-sectional study was conducted to assess the frequency of Gilbert syndrome among Egyptian adults. Subjects fulfilling the criteria of GS were enrolled into the study and prospectively followed for the clinical features, risk factors for hyperbilirubinemia, health related quality of life [Short form-36 Health Survey version 2 (SF-36v2) and Chronic Liver Disease Questionnaire (CLDQ)], vitamins assessment and UGT1A1 polymorphisms. Results One hundred and one subjects fulfilled the criteria of GS with a prevalence of 8.016%. Recurrent jaundice was the only presentation in 47 (56.627%) GS subjects and jaundice was associated with abdominal pain, dyspepsia or loss of appetite in 54 (53.465%) subjects. A significant difference in 25-Hydroxyvitamin D3 levels was detected between GS patients and control subjects (P 12 h, pregnancy, and low calorie weight losing plans, systemic infections, and intensive physical effort. During jaundice attacks, subjects with GS had significant differences in vitality, role emotional, social functioning, worry and general health domains of the SF-36v2 and CLDQ compared to controls. The homozygous polymorphism A(TA)7TAA was the most frequent polymorphism in Egyptians with GS. Conclusion Gilbert syndrome is a frequent inherited disorder in Egypt. In a substantial percentage of subjects with GS, episodes of jaundice are associated with other symptoms and nutritional deficiencies which result in impairment of HRQOL. Screening, counseling, monitoring and individualized health care are recommended for subjects with GS in the setting of anesthesia, pregnancy, treatment with DAAs, deliveries, surgery and weight loss plans.

Background: Uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) is a predictive biomarker for the side-effects of irinotecan chemotherapy, which reduces the volume of tumors harboring UGT1A1 polymorphisms. We aimed to determine whether UGT1A1 polymorphisms can predict progression-free survival in patients with local cervical cancer treated with irinotecan chemotherapy.Methods: We retrospectively analyzed the data of 51 patients with cervical cancer treated at a single institution between 2010 and 2015. All patients were diagnosed with 2009 International Federation of Gynecology and Obstetrics (FIGO) stage IB1, IB2, IIA, or IIB squamous cell carcinoma, underwent radical hysterectomy, and received irinotecan chemotherapy as neoadjuvant and/or adjuvant treatment. All patients were examined for irinotecan side effects using UGT1A1 tests. Conditional inference tree and survival analyses were performed considering the FIGO stage, age, the UGT1A1 status, and the number of metastatic lymph nodes to determine primary factors associated with progression-free survival.Results: The tree-structured survival model determined high recurrence-risk factors related to progression-free survival. The most relevant factor was ≥2 metastatic lymph nodes (p = 0.004). The second most relevant factor was UGT1A1 genotype (p = 0.024). Among patients with ≤1 metastatic lymph node, those with UGT1A1 polymorphisms benefited from irinotecan chemotherapy and demonstrated significantly longer progression-free survival (p = 0.020) than those with wild-type UGT1A1.Conclusions: Irinotecan chemotherapy might be beneficial in patients with cervical cancer, UGT1A1 polymorphisms, and ≤ 1 metastatic lymph nodes. [ABSTRACT FROM AUTHOR]

Background: Gilbert syndrome (GS) is an autosomal recessive inherited disorder of bilirubin glucuronidation which has not been investigated in Egypt. This longitudinal study investigated the frequency, clinical course, genetic profile and health related quality of life in Egyptian adults.Methods: An initial cross-sectional study was conducted to assess the frequency of Gilbert syndrome among Egyptian adults. Subjects fulfilling the criteria of GS were enrolled into the study and prospectively followed for the clinical features, risk factors for hyperbilirubinemia, health related quality of life [Short form-36 Health Survey version 2 (SF-36v2) and Chronic Liver Disease Questionnaire (CLDQ)], vitamins assessment and UGT1A1 polymorphisms.Results: One hundred and one subjects fulfilled the criteria of GS with a prevalence of 8.016%. Recurrent jaundice was the only presentation in 47 (56.627%) GS subjects and jaundice was associated with abdominal pain, dyspepsia or loss of appetite in 54 (53.465%) subjects. A significant difference in 25-Hydroxyvitamin D3 levels was detected between GS patients and control subjects (P <  00001). Twelve subjects with GS developed significant unconjugated bilirubinemia during direct antiviral therapy (DAAs) therapy for HCV despite achieving sustained virologic response. Pregnancy was associated with significant exacerbation of unconjugated bilirubin which persisted through pregnancy. Risk factors for clinical jaundice included general anesthesia, pregnancy, fasting > 12 h, pregnancy, and low calorie weight losing plans, systemic infections, and intensive physical effort. During jaundice attacks, subjects with GS had significant differences in vitality, role emotional, social functioning, worry and general health domains of the SF-36v2 and CLDQ compared to controls. The homozygous polymorphism A(TA)7TAA was the most frequent polymorphism in Egyptians with GS.Conclusion: Gilbert syndrome is a frequent inherited disorder in Egypt. In a substantial percentage of subjects with GS, episodes of jaundice are associated with other symptoms and nutritional deficiencies which result in impairment of HRQOL. Screening, counseling, monitoring and individualized health care are recommended for subjects with GS in the setting of anesthesia, pregnancy, treatment with DAAs, deliveries, surgery and weight loss plans. [ABSTRACT FROM AUTHOR]

Purpose: Irinotecan is effective for metastatic colorectal cancer (mCRC). SN-38 is an active metabolite of irinotecan, which is formed by carboxylesterase and inactivated by UDP-glucuronyltransferase (UGT) 1A1. The UGT enzyme activity is reduced in patients with homozygous mutation in UGT1A1 genes (*6/*6, *28/*28 and *6/*28); thus dose reduction is required for prevention of severe adverse events associated with irinotecan. The present study was designed to investigate the relationship between UGT1A1 polymorphisms and the incidence of adverse events or the therapeutic effect in mCRC patients who received irinotecan.Methods: Sixty-three mCRC patients who received irinotecan during January 2014 and May 2018 were the subjects of this study. The incidence of adverse events, including diarrhea and neutropenia, and the therapeutic effect of irinotecan were compared among homozygous group, heterozygous group and wild-type group. The initial dose of irinotecan was 150 mg/m2 in the heterozygous group and wild-type group, while the dose was reduced by 20% (120 mg/m2) in the homozygous group.Results: The UGT1A1 polymorphisms occurred in 15.9%, 33.3%, and 50.8% for homozygous group, heterozygous group, and wild-type group, respectively. The average dose of irinotecan during overall cycles was not significantly different among three groups, despite the reduction of initial dose in homozygous group. There were no significant differences in the incidence rates of adverse events, tumor response, or time to treatment failure among three groups.Conclusion: The present study demonstrated that dose reduction by 20% ensured safety and efficacy of irinotecan in mCRC patients with homozygous mutation in UGT1A1 genes. [ABSTRACT FROM AUTHOR]

Introduction: The development of antibody-drug conjugates (ADCs) have revolutionized treatment for breast cancer. Sacituzumab govitecan (SG), a Trop2-targeted ADC, has demonstrated remarkable efficacy in triple-negative breast cancer (TNBC) and hormone receptor-positive metastatic breast cancer., Areas Covered: We summarize the evidence for SG use in the treatment of metastatic breast cancer, discuss the toxicity profile, and present strategies to manage adverse events., Expert Opinion: Hematologic toxicities are frequently observed with SG therapy. Neutropenia, reported in up to 72% of cases, often requires dose reductions or delays. Granulocyte colony-stimulating factor can be helpful in managing and preventing this toxicity. Anemia is another common toxicity and patients may require transfusions of packed red blood cells. Gastrointestinal toxicities are also common. A tailored regimen of prophylactic antiemetics (2-3 agents) should be initiated before SG infusion. For diarrhea, infectious workup should be considered on a case-by-case basis; patients should start loperamide and fluid/electrolyte replacement if necessary. Severe diarrhea associated with cholinergic syndrome should prompt the administration of atropine. Fatigue occurs in approximately half of the patients receiving SG, and <50% of patients experience complete alopecia during treatment. The approval of SG has significantly improved treatment outcomes; however, effective management of the toxicities is critical to optimize patient care and treatment adherence.

Glucuronidation, mediated by the UDP-glucuronosyltransferase 1A1 ( UGT1A1) enzyme, is an important metabolic process during which steroids are converted to more easily excreted compounds in steroid target tissues, such as the prostate. The aim of our study was to investigate the possible correlation between UGT1A1 promoter gene polymorphism and benign prostatic hyperplasia. 421 blood samples were obtained from 138 consecutive patients diagnosed with benign prostatic hypeplasia (BPH group) and 283 healthy volunteers (control group). A(TA)6TAA promoter polymorphism of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/7, heterozygous 6/7 and normal homozygous 6/6) were identified. No significant differences were observed between the BPH group and controls regarding the genotyping distribution of the three UGT1A1 promoter genotypes ( P = 0.39). Also, no association was found between overall disease risk and the presence of the polymorphic homozygous genotype ( TA( 7) /TA) 7) vs. TA( 6) /TA( 7) +  TA( 6) /TA( 6)) ( P = 0.31). Our data suggest that the TA repeat polymorphism of UGT1A1 is not associated with increased BPH risk susceptibility in Caucasian men. [ABSTRACT FROM AUTHOR]