Bowel Anastomosis After or Before HIPEC: A Comparative Study in Patients Undergoing CRS+HIPEC for Peritoneal Surface Malignancy.

BACKGROUND: Anastomotic leak after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) remains a dreaded complication. There is no consensus statement regarding the optimal timing for bowel anastomoses to perform after or before HIPEC. METHODS: Patients who underwent CRS+HIPEC and had at least one bowel anastomosis were retrospectively analyzed to evaluate if timing of anastomosis done after or before HIPEC had an impact on bowel complication rates (anastomotic leak and perforation). RESULTS: From 2013 to 2019, 214 of 370 patients underwent CRS+HIPEC and had at least one bowel anastomosis. Of these 214 patients, 104 and 110 patients had anastomosis after and before HIPEC, respectively. A total of 324 anastomoses were performed, with a mean of 0.87 anastomoses per patient (range 1-4). The incidence of anastomotic leaks was comparable between the pre- and post-HIPEC groups (3.6% vs. 4.8%; p > 0.05), as was the bowel complication rate (7.6% vs. 7.2%). After multivariate analysis, prior surgical score >1 (odds ratio [OR] 4.3), recurrent cancers (OR 7.4), and more than two anastomosis (OR 3.8) were considered independent risk factors for bowel complications. CONCLUSION: Anastomosis of the bowel performed after or before HIPEC does not affect bowel complication rates (leak/perforation). Higher prior surgical score, surgery for recurrent cancers, and more than two bowel anastomosis are independent risk factors for predicting bowel complications. Prehabilitation, standardization of steps, immediate attention and repair of serosal tears, and thorough inspection of the bowel before closure helps to decrease bowel complications. The timing of anastomosis can be at the discretion of the surgeon.

Sentinel node mapping using indocyanine green and near-infrared fluorescence imaging technology for endometrial cancer: A prospective study using a surgical algorithm in Indian patients.

BACKGROUND: Indocyanine green (ICG) fluorescence with high-definition, three-dimensional imaging systems is emerging as the latest strategy to reduce trauma and improve surgical outcomes during oncosurgery. MATERIALS AND METHODS: This is a prospective study involving 100 patients with carcinoma endometrium who underwent robotic-assisted Type 1 pan-hysterectomy, with ICG-directed sentinel lymph node (SLN) biopsy from November 2017 to December 2019. The aim was to assess the feasibility and diagnostic accuracy of SLN algorithm and to evaluate the location and distribution of SLN in pelvic, para-aortic and unusual areas and the role of frozen section. RESULTS: The overall SLN detection rate was 98%. Bilateral detection was possible in 92% of the cases. Right side was detected in 98% of the cases and left side was visualised in 92% of the cases. Complete node dissection was done where SLN mapping failed. The most common location for SLN in our series was obturator on the right hemipelvis and internal iliac on the left hemipelvis. SLN in the para-aortic area was detected in 14% of cases. In six cases, SLN was found in atypical locations, that is pre-sacral area. Eight patients had SLN positivity for metastasis and underwent complete retroperitoneal lymphadenectomy. Comparison of final histopathological report with frozen section reports showed no false negatives. CONCLUSIONS: SLN mapping holds a great promise as a modern staging strategy for endometrial cancer. In our experience, cervical injection was an optimal method of mapping the pelvis. ICG showed a high overall detection rate, and bilateral mapping appears to be a feasible alternative to the more traditional methods of SLN mapping in patients with endometrial cancer. The ICG fluorescence imaging system is simple and safe and may become a standard in oncosurgery in view of its staging and anatomical imaging capabilities. This approach can reduce the morbidity, operative times and costs associated with complete lymphadenectomy while maintaining prognostic and predictive information.

Enhanced Recovery After Surgery (ERAS) in gynecologic oncology: an international survey of peri-operative practice.

INTRODUCTION: Enhanced Recovery After Surgery (ERAS) programs have been shown to improve clinical outcomes in gynecologic oncology, with the majority of published reports originating from a small number of specialized centers. It is unclear to what degree ERAS is implemented in hospitals globally. This international survey investigated the status of ERAS protocol implementation in open gynecologic oncology surgery to provide a worldwide perspective on peri-operative practice patterns. METHODS: Requests to participate in an online survey of ERAS practices were distributed via social media (WhatsApp, Twitter, and Social Link). The survey was active between January 15 and March 15, 2020. Additionally, four national gynecologic oncology societies agreed to distribute the study among their members. Respondents were requested to answer a 17-item questionnaire about their ERAS practice preferences in the pre-, intra-, and post-operative periods. RESULTS: Data from 454 respondents representing 62 countries were analyzed. Overall, 37% reported that ERAS was implemented at their institution. The regional distribution was: Europe 38%, Americas 33%, Asia 19%, and Africa 10%. ERAS gynecologic oncology guidelines were well adhered to (>80%) in the domains of deep vein thrombosis prophylaxis, early removal of urinary catheter after surgery, and early introduction of ambulation. Areas with poor adherence to the guidelines included the use of bowel preparation, adoption of modern fasting guidelines, carbohydrate loading, use of nasogastric tubes and peritoneal drains, intra-operative temperature monitoring, and early feeding. CONCLUSION: This international survey of ERAS in open gynecologic oncology surgery shows that, while some practices are consistent with guideline recommendations, many practices contradict the established evidence. Efforts are required to decrease the variation in peri-operative care that exists in order to improve clinical outcomes for patients with gynecologic cancer globally.

Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability.

A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.

Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF1) receptor antagonists.

A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.

Design, synthesis, and evaluation of phenylglycinols and phenyl amines as agonists of GPR88.

Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties.

Potential CRF1R PET imaging agents: 1-fluoroalkylsubstituted 5-halo-3-(arylamino)pyrazin-2(1H)-ones.

A series of pyrazinones were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients are discussed herein.

Cytoreductive Surgery with HIPEC as Primary Treatment for Advanced Epithelial Ovarian Carcinoma: Upfront or Interval-ISPSM Collaborative Study.

Cytoreductive surgery with HIPEC has shown promising results in the interval setting of advanced epithelial ovarian cancer. Its role in upfront setting has not yet been established. All eligible patients underwent CRS-HIPEC as per institution protocol. Relevant data was collected prospectively in institutional HIPEC registry and analyzed retrospectively for the study period from February 2014 to February 2020. Out of 190 patients, 80 underwent CRS-HIPEC in upfront setting and 110 in interval setting. The median age was 54 ± 7.45 years, upfront group had higher PCI (14.1 ± 8.75 vs. 9.6 ± 5.2. 2), and required longer duration of surgery (10.6 ± 1.73 vs. 8.4 ± 1.71 h) had more blood loss (1025 ± 668.76 vs. 680 ± 302.23 ml). The upfront group required more diaphragmatic resections, bowel resections, and multivisceral resections. The overall G3-G4 morbidity was comparable (25.4% vs. 27.3%), upfront group had more surgical morbidity (20% vs. 9.1%) whereas interval group had more medical morbidity, i.e., electrolyte imbalance and hematological. After a median follow-up of 43 months, median DFS was 33 months in the upfront vs. 30 months in the interval group, p = 0.75, median OS was 46 months interval group and was not yet achieved in upfront group.(p = 0.13). Four-year OS was 85% vs. 60%. In patients of advanced EOC upfront CRS HIPEC showed promising outcomes and trend towards better survival with similar morbidity and mortality. The upfront group had more surgical morbidity whereas interval group had more medical morbidity. Multiinstitutional randomized studies are needed to define patient selection and study morbidity patterns and compare the outcomes between CRS-HIPEC in the upfront and interval setting for advanced epithelial ovarian cancer.

Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-b]pyridazines as Glycogen Synthase Kinase-3ß (GSK-3ß) Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3ß has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo[1,2-b]pyridazine derivatives that were evaluated as GSK-3ß inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3ß inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3ß inhibitor that significantly lowered levels of phosphorylated tau.

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various other diseases, including mood disorders, type 2 diabetes, and cancer. There is considerable evidence indicating that GSK-3ß in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated tau protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model.

[18F](R)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(4-(2-fluoroethoxy)-2,5-dimethyl phenylamino)pyrazin-2(1H)-one: introduction of N3-phenylpyrazinones as potential CRF-R1 PET imaging agents.

Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [(18)F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments.

PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras.

In the recent past, proteolysis-targeting chimera (PROTAC) technology has received enormous attention for its ability to overcome the limitations of protein inhibitors and its capability to target undruggable proteins. The PROTAC molecule consists of three components, a ubiquitin E3 ligase ligand, a linker, and a target protein ligand. The application of this technology is rapidly gaining momentum, especially in cancer therapy. In this review, we first look at the history of degraders, followed by a section on the ubiquitin proteasome system (UPS) and E3 ligases used in PROTAC development. PROTACs are dependent on the UPS for degradation of target proteins. We further discuss the scope and design of degraders and mitigation strategies for overcoming the hook effect seen with degraders. As PROTACs do not follow Lipinski's 'Rule of 5', these molecules face drug metabolism and pharmacokinetic challenges. A detailed section on absorption, distribution, metabolism, and excretion of degraders is provided wherein we discuss methodologies and strategies to surmount the challenges faced by these molecules. For understanding PROTAC-mediated degradation, the characterization and measurement of protein levels in cells is important. Currently used techniques and recent advancements in assessment tools for degraders are discussed. Furthermore, we examine the challenges and emerging technologies that need to be focused on in order to competently develop potent degraders. Many companies are working in this area of emerging new modality and a few PROTACs have already entered clinical trials; the details of the trials are included in this review.

Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.

Discovery of Non-Nucleotide Small-Molecule STING Agonists via Chemotype Hybridization.

The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2',3'-cGAMP (1) (an endogenous STING activator ligand) and other closely related cyclic dinucleotides (CDNs). While these efforts have successfully identified novel CDNs that have progressed into the clinic, their utility is currently limited to patients with solid tumors that STING agonists can be delivered to intratumorally. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model.

Development and validation of LC/MS/MS method for Triciribine and its monophosphate metabolite in plasma and RBC: Application to mice pharmacokinetic studies.

Triciribine (TCN) is a tricyclic nucleoside analog of adenosine and an inhibitor of Akt kinase. Triciribine 5'-monophosphate (TCNP) is a water-soluble analog of Triciribine and has progressed to Phase I and II clinical trials in oncology. TCNP is also an endogenous anabolite of TCN similar to other nucleoside phosphates. Clinical development of TCNP has been hampered by high pharmacokinetic variability due to complex interplay of TCN-TCNP conversion and reconversion in plasma, erythrocytes (RBC) and peripheral organs. TCN has been demonstrated to be an efficacious agent in mice models of acute lung injury at low doses (0.5 mg/kg/day) although its pharmacokinetic-pharmacodynamic (PK/PD) relationship remained unclear. We have developed and validated a sensitive, specific and robust LC/MS/MS assay for quantitation of TCN and TCNP in plasma and RBC. Using a simple protein precipitation method, quantitation of these analytes was accomplished with recoveries exceeding 85% and with a run time of 4 min. This assay was used to determine the pharmacokinetic parameters of TCN and TCNP in mice after single dose intravenous administration at 1, 3 and 10 mg/kg. TCNP accumulates in RBC, has low clearance and a half-life of 18 to 23 h. Unlike other nucleoside phosphates, TCNP was found to be relatively stable in mice plasma serving as a secondary depot. TCN levels were low and with high clearance relative to hepatic blood flow. A combination of sustained levels of TCNP in RBC and plasma serves as a depot for TCN to elicit robust therapeutic activity in acute lung injury mice models.

A multi-targeting pre-clinical candidate against drug-resistant tuberculosis.

FNDR-20081 [4-{4-[5-(4-Isopropyl-phenyl)- [1,2,4]oxadiazol-3-ylmethyl]-piperazin-1-yl}-7-pyridin-3-yl-quinoline] is a novel, first in class anti-tubercular pre-clinical candidate against sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). In-vitro combination studies of FNDR-20081 with first- and second-line drugs exhibited no antagonism, suggesting its compatibility for developing new combination-regimens. FNDR-20081, which is non-toxic with no CYP3A4 liability, demonstrated exposure-dependent killing of replicating-Mtb, as well as the non-replicating-Mtb, and efficacy in a mouse model of infection. Whole genome sequencing (WGS) of FNDR-20081 resistant mutants revealed the identification of pleotropic targets: marR (Rv0678), a regulator of MmpL5, a transporter/efflux pump mechanism for drug resistance; and Rv3683, a putative metalloprotease potentially involved in peptidoglycan biosynthesis. In summary, FNDR-20081 is a promising first in class compound with the potential to form a new combination regimen for MDR-TB treatment.

Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain.

Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of µ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.

Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.

Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.

Comparative biotransformation of pyrazinone-containing corticotropin-releasing factor receptor-1 antagonists: minimizing the reactive metabolite formation.

(S)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1H)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0-7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.

Synthesis and structure-activity relationships of N3-pyridylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists.

A series of N(3)-pyridylpyrazinones was investigated as corticotropin-releasing factor-1 receptor antagonists. It was observed that the binding affinity of analogues containing a pyridyl group was influenced not only by the substitution pattern on the pyridyl group, but also by the pK(a) of the pyridyl nitrogen. Analogues containing a novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group were among the most potent N(3)-pyridylpyrazinones synthesized. The synthesis and SAR of N(3)-pyridylpyrazinones is described herein.