Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer.

Cisplatin-based combination chemotherapy is the foundation for treatment of advanced bladder cancer (BlCa), but many patients develop chemoresistance mediated by increased Akt and ERK phosphorylation. However, the mechanism by which cisplatin induces this increase has not been elucidated. Among six patient-derived xenograft (PDX) models of BlCa, we observed that the cisplatin-resistant BL0269 express high epidermal growth factor receptor, ErbB2/HER2 and ErbB3/HER3. Cisplatin treatment transiently increased phospho-ErbB3 (Y1328), phospho-ERK (T202/Y204) and phospho-Akt (S473), and analysis of radical cystectomy tissues from patients with BlCa showed correlation between ErbB3 and ERK phosphorylation, likely due to the activation of ERK via the ErbB3 pathway. In vitro analysis revealed a role for the ErbB3 ligand heregulin1-ß1 (HRG1/NRG1), which is higher in chemoresistant lines compared to cisplatin-sensitive cells. Additionally, cisplatin treatment, both in PDX and cell models, increased HRG1 levels. The monoclonal antibody seribantumab, that obstructs ErbB3 ligand-binding, suppressed HRG1-induced ErbB3, Akt and ERK phosphorylation. Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.

Postoperative Day 1 Discharge in Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction.

With high success rates of autologous breast reconstruction, the focus has shifted from flap survival to improved patient outcomes. Historically, a criticism of autologous breast reconstruction has been the length of hospital stay. Our institution has progressively shortened the length of stay after deep inferior epigastric artery perforator (DIEP) flap reconstruction and began discharging select patients on postoperative day 1 (POD1). The purpose of this study was to document our experience with POD1 discharges and to identify preoperative and intraoperative factors that may identify patients as candidates for earlier discharge. Methods: An institutional review board-approved, retrospective chart review of patients undergoing DIEP flap breast reconstruction from January 2019 to March 2022 at Atrium Health was completed, consisting of 510 patients and 846 DIEP flaps. Patient demographics, medical history, operative course, and postoperative complications were collected. Results: Twenty-three patients totaling 33 DIEP flaps were discharged on POD1. The POD1 group and the group of all other patients (POD2+) had no difference in age, ASA score, or comorbidities. BMI was significantly lower in the POD1 group (P = 0.039). Overall operative time was significantly lower in the POD1 group, and this remained true when differentiating into unilateral operations (P = 0.023) and bilateral operations (P = 0.01). No major complications occurred in those discharged on POD1. Conclusions: POD1 discharge after DIEP flap breast reconstruction is safe for select patients. Lower BMI and shorter operative times may be predictive in identifying patients as candidates for earlier discharge.

The Virtual Interview Experience: Advantages, Disadvantages, and Trends in Applicant Behavior.

Residency programs and applicants were forced to hold virtual interviews during the 2020-2021 application cycle. Inability to evaluate a program and/or applicant in person has intangible drawbacks. However, there are obvious advantages: cost, convenience, and comfort. Do the advantages outweigh the disadvantages? How have applicant behaviors changed to learn about programs in a virtual-only interview process? Methods: A survey was distributed to 302 applicants to a single plastic surgery residency program during the 2020 application cycle. Demographics, social media presence and utilization, and experience with the virtual application and interview process were analyzed. A 2018 survey from our institution was compared with a subset of questions for longitudinal analysis. Results: Seventy-six respondents (25.2%) completed the survey. Most applicants (88.2%) spent less than $1000 during the interview and application cycle. Over half (56.6%) did not receive letters of recommendation from outside their home program. A significant minority (27.6%) of applicants attended more than one interview in a single day. Compared to 2018, applicants in 2021 were significantly more likely to access alternative digital resources (forums/discussion boards, social media, and podcasts) when learning about programs. Average number of interviews remains in the range of pre-COVID studies, but the percentage of interviews attended increased. Conclusions: Applicants spent substantially less money on interviews and relied on alternative digital sources to learn about residency programs. This study objectively quantifies the advantages of virtual interviews. Disadvantages include inability to assess "fit" and lack of nonverbal communication.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Bilateral Diffuse Pseudoangiomatous Stromal Hyperplasia Necessitating Mastectomy.

Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon, benign breast lesion often diagnosed incidentally and frequently mistaken for fibroadenoma given similar radiographic appearance. Histopathology classically reveals diffuse, dense fibrous stromal background with a complex network of spindle cells forming slit-like spaces, giving it the appearance of angiomatous proliferation. Surgical excision is generally not necessary. Here we present two unusual cases of PASH: an adolescent patient with bilateral rapid onset of symptoms, and a premenopausal patient with bilateral, diffuse, recurrent PASH. Both required mastectomy. We aim to highlight the variable nature of presentation and briefly review current management options.

Comparative Cancer Cell Signaling in Muscle-Invasive Urothelial Carcinoma of the Bladder in Dogs and Humans.

Muscle-invasive urothelial carcinoma (MIUC) is the most common type of bladder malignancy in humans, but also in dogs that represent a naturally occurring model for this disease. Dogs are immunocompetent animals that share risk factors, pathophysiological features, clinical signs and response to chemotherapeutics with human cancer patients. This review summarizes the fundamental pathways for canine MIUC initiation, progression, and metastasis, emerging therapeutic targets and mechanisms of drug resistance, and proposes new opportunities for potential prognostic and diagnostic biomarkers and therapeutics. Identifying similarities and differences between cancer signaling in dogs and humans is of utmost importance for the efficient translation of in vitro research to successful clinical trials for both species.

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes.

To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.

The Triangular Dart Flap: A Reconstructive Option for Soft Tissue Defects.

INTRODUCTION: Reconstruction of soft tissue defects after skin cancer excision remains a challenge. Options for reconstruction are numerous, including primary repair, local tissue rearrangement, and skin grafts, among others. In this series, the authors present a novel technique: The triangular dart flap. This is a single-stage tissue rearrangement that uses the redundant tissue of the dog-ear to aid in the closure of these wounds. METHODS: A retrospective review was conducted of all patients undergoing local tissue rearrangements by the senior author from 2009 to 2018. Factors were collected and analyzed, including age, size and cause of defect, comorbidities, smoking history, and postoperative complications. RESULTS: Twenty-four patients underwent reconstruction with a triangular dart flap for repair of malignant defects. Mean defect size was 7.3 cm2 (0.8-20 cm2), and mean repair size was 29.7 cm2 (6-80 cm2). Initial pathology included basal cell carcinoma (45.8%), melanoma in situ (29.2%), and squamous cell carcinoma (16.7%), among others. Location varied widely among face and extremities. Anesthesia was predominantly local only (79.1%). There were no major complications, and 5 (20.8%) minor complications. CONCLUSIONS: The triangular dart flap is a novel single-stage procedure, generally performed under local anesthesia only, for correction of Mohs defects. By using the redundant tissue of dog-ears to better approximate the wound edges, a tension-free primary closure can be achieved in sensitive areas, such as the nasal tip.

Social media impact in the Match: A survey of current trends in the United States.

BACKGROUND: Applicants to integrated plastic and reconstructive surgery (PRS) residency in the United States spend exorbitant amounts of time and money throughout the interview process. Outside of first-hand experience through a visiting rotation, applicants utilize various resources in learning about a program. Today's applicants are "Millennials," the demographic cohort raised during the information age and proficient with digital technology. The authors evaluated whether programs have a presence on social media, and whether applicants are following these accounts. METHODS: An online survey was sent to applicants to a single integrated plastic surgery program evaluating basic demographics, social media utilization, and sources of information accessed throughout the residency application process. A manual search of popular social media platforms (Instagram, Facebook, and Twitter) was performed in October 2019. Accounts affiliated with integrated PRS programs were identified and analyzed. RESULTS: Eighty-four of 222 applicants (37.8%) completed the survey. Ninety-six percent of applicants were within the Millennial demographic. Ninety-six percent of applicants had some form of social media presence, with Facebook (90%) and Instagram (87%) being the most popular platforms. Seventy-three percent of applicants reported following a PRS residency social media account. As of October 2019, 59 integrated residency programs (73%) have active Instagram accounts. CONCLUSIONS: Applicants still rely on the program website when researching potential residencies, but social media is being rapidly adopted by programs. Program social media accounts should be used as a dynamic form of communication to better inform applicants of program strengths and weaknesses.

Academics in the Pandemic: Early Impact of COVID-19 on Plastic Surgery Training Programs.

The COVID-19 global pandemic has impacted plastic surgery training in the United States, requiring unprecedented measures to prepare for potential surges in critically ill patients. This study investigates how plastic surgery programs responded to this crisis, as well as how successful these changes were, through a survey of program directors and of residents at academic training programs in the United States. METHODS: Two separate anonymous online surveys were conducted via REDCap between April 16 and June 4, 2020. The first survey was distributed to program directors, and the second was distributed to plastic surgery residents. Resident responses were then subdivided for an analysis between geographic regions. RESULTS: Of the 59 program director responses (43.7%), the majority of programs implemented a platoon approach for resident coverage. A minority did the same for attending coverage. In total, 92% transitioned to virtual didactics only. Plastic surgery residents covered alternative services at 25% of responding institutions, and an additional 68% had a plan in place for responding to personnel shortages. Overall, residents were satisfied with their program's response in a variety of categories. When subdivided based on geographic region, respondents in the Northeast and Northwest were less satisfied with resident wellness, personal and loved ones' safety, and program communication. CONCLUSIONS: With the possibility of a "second wave," successful methods of academic programs adapting to the pandemic should be communicated to reduce the future impact. Increased frequency of communications between program directors and residents can improve mental health and wellness of the resident population.

The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy.

The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD-and the current state of the available compounds in clinical development.

The p14ARF tumor suppressor restrains androgen receptor activity and prevents apoptosis in prostate cancer cells.

Prostate cancer (PCa) is characterized by a unique dependence on optimal androgen receptor (AR) activity where physiological androgen concentrations induce proliferation but castrate and supraphysiological levels suppress growth. This feature has been exploited in bipolar androgen therapy (BAT) for castrate resistant malignancies. Here, we investigated the role of the tumor suppressor protein p14ARF in maintaining optimal AR activity and the function of the AR itself in regulating p14ARF levels. We used a tumor tissue array of differing stages and grades to define the relationships between these components and identified a strong positive correlation between p14ARF and AR expression. Mechanistic studies utilizing CWR22 xenograft and cell culture models revealed that a decrease in AR reduced p14ARF expression and deregulated E2F factors, which are linked to p14ARF and AR regulation. Chromatin immunoprecipitation studies identified AR binding sites upstream of p14ARF. p14ARF depletion enhanced AR-dependent PSA and TMPRSS2 transcription, hence p14ARF constrains AR activity. However, p14ARF depletion ultimately results in apoptosis. In PCa cells, AR co-ops p14ARF as part of a feedback mechanism to ensure optimal AR activity for maximal prostate cancer cell survival and proliferation.

Initial Experience With Autologous Skin Cell Suspension for Treatment of Deep Partial-Thickness Facial Burns.

Facial burns present a challenge in burn care, as hypertrophic scarring and dyspigmentation can interfere with patients' personal identities, ocular and oral functional outcomes, and have long-term deleterious effects. The purpose of this study is to evaluate our initial experience with non-cultured, autologous skin cell suspension (ASCS) for the treatment of deep partial-thickness (DPT) facial burns. Patients were enrolled at a single burn center during a multicenter, prospective, single-arm, observational study involving the compassionate use of ASCS for the treatment of large total BSA (TBSA) burns. Treatment decisions concerning facial burns were made by the senior author. Facial burns were initially excised and treated with allograft. The timing of ASCS application was influenced by an individual's clinical status; however, all patients were treated within 30 days of injury. Outcomes included subjective cosmetic parameters and the number of reoperations within 3 months. Five patients (4 males, 1 female) were treated with ASCS for DPT facial burns. Age ranged from 2.1 to 40.7 years (mean 18.2 ± 17.3 years). Average follow-up was 231.2 ± 173.1 days (range 63-424 days). Two patients required reoperation for partial graft loss within 3 months in areas of full-thickness injury. There were no major complications and one superficial hematoma. Healing and cosmetic outcomes were equivalent to, and sometimes substantially better than, outcomes typical of split-thickness autografting. Non-cultured, ASCS was successfully used to treat DPT facial burns containing confluent dermis with remarkable cosmetic outcomes. Treatment of DPT burns with ASCS may be an alternative to current treatments, particularly in patients prone to dyspigmentation, scarring sequelae, and with limited donor sites.

Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase.

BACKGROUND: Despite overexpression of the ErbB (EGFR/HER2/ErbB3/ErbB4) family in castration-resistant prostate cancer (CRPC), some inhibitors of this family, including the dual EGFR/HER2 inhibitor lapatinib, failed in Phase II clinical trials. Hence, we investigated mechanisms of lapatinib resistance to determine whether alternate ErbB inhibitors can succeed. METHODS: The CWR22 human tumour xenograft and its CRPC subline 22Rv1 and sera from lapatinib-treated CRPC patients from a previously reported Phase II trial were used to study lapatinib resistance. Mechanistic studies were conducted in LNCaP, C4-2 and 22Rv1 cell lines. RESULTS: Lapatinib increased intratumoral HER2 protein, which encouraged resistance to this treatment in mouse models. Sera from CRPC patients following lapatinib treatment demonstrated increased HER2 levels. Investigation of the mechanism of lapatinib-induced HER2 increase revealed that lapatinib promotes HER2 protein stability, leading to membrane localisation, EGFR/HER2 heterodimerisation and signalling, elevating cell viability. Knockdown of HER2 and ErbB3, but not EGFR, sensitised CRPC cells to lapatinib. At equimolar concentrations, the recently FDA-approved pan-ErbB inhibitor dacomitinib decreased HER2 protein stability, prevented ErbB membrane localisation (despite continued membrane integrity) and EGFR/HER2 heterodimerisation, thereby decreasing downstream signalling and increasing apoptosis. CONCLUSIONS: Targeting the EGFR axis using the irreversible pan-ErbB inhibitor dacomitinib is a viable therapeutic option for CRPC.

Timing of Free Flaps for Traumatic Wounds of the Lower Extremity: Have Advances in Perioperative Care Changed the Treatment Algorithm?

BACKGROUND: Despite the landmark study by Godina 30 years ago, opinions still vary within the literature about the management of complex traumatic wounds in the lower extremity. We present a large series of lower extremity reconstructions with vascularized free tissue and examine the perioperative factors that influenced the success of these cases. METHODS: We reviewed 88 patients with free flap reconstruction of traumatic lower extremity wounds over 8 years. Primary outcomes were flap infections, flap loss, total flap-specific complications, and total recipient site complications. Independent variables specific to perioperative care including time to flap coverage, injury classification, exposed or infected hardware, prior osteomyelitis, use of wound vacuum-assisted closure (VAC) therapy, and concurrent polytrauma were investigated to establish their influence on primary outcomes. Each independent variable was assessed using Chi-square or Fisher's exact test and was included in a logistic regression analysis to establish significance. RESULTS: Of the 88 patients, 8 had flap loss, 8 had flap infections, and a total of 23 had primary adverse outcomes. Timing of the reconstruction, VAC use, injury classification, prior hardware or wound status, or presence of polytrauma had no statistically significant impact on the primary outcomes. Injury classification/severity on total recipient site complications (p = 0.051) and flap-specific complications (p = 0.073) trended toward significance; however, subgroup analysis did not achieve significance. Logistic regression of any recipient site complication including all independent variables similarly showed no significance. CONCLUSION: Although the original study by Godina suggests early coverage is critical to optimize outcomes, in the modern era of advanced wound care, our study adds to a growing body of evidence that supports the de-emphasis of the 72-hour reconstruction interval. Our current management is focused on more effectively coordinating efficient peritraumatic and perioperative care on an individualized basis in the often very complicated polytrauma patient.

Obatoclax, a BH3 Mimetic, Enhances Cisplatin-Induced Apoptosis and Decreases the Clonogenicity of Muscle Invasive Bladder Cancer Cells via Mechanisms That Involve the Inhibition of Pro-Survival Molecules as Well as Cell Cycle Regulators.

Several studies by our group and others have determined that expression levels of Bcl-2 and/or Bcl-xL, pro-survival molecules which are associated with chemoresistance, are elevated in patients with muscle invasive bladder cancer (MI-BC). The goal of this study was to determine whether combining Obatoclax, a BH3 mimetic which inhibits pro-survival Bcl-2 family members, can improve responses to cisplatin chemotherapy, the standard of care treatment for MI-BC. Three MI-BC cell lines (T24, TCCSuP, 5637) were treated with Obatoclax alone or in combination with cisplatin and/or pre-miR-34a, a molecule which we have previously shown to inhibit MI-BC cell proliferation via decreasing Cdk6 expression. Proliferation, clonogenic, and apoptosis assays confirmed that Obatoclax can decrease cell proliferation and promote apoptosis in a dose-dependent manner. Combination treatment experiments identified Obatoclax + cisplatin as the most effective treatment. Immunoprecipitation and Western analyses indicate that, in addition to being able to inhibit Bcl-2 and Bcl-xL, Obatoclax can also decrease cyclin D1 and Cdk4/6 expression levels. This has not previously been reported. The combined data demonstrate that Obatoclax can inhibit cell proliferation, promote apoptosis, and significantly enhance the effectiveness of cisplatin in MI-BC cells via mechanisms that likely involve the inhibition of both pro-survival molecules and cell cycle regulators.

Politics in the Consulting Room.

The recent presidential campaign and election have had a strong impact on many patients and clinicians. This guest column and its introduction by Dr Eric Plakun, who edits the psychotherapy section of the journal, note the inevitability that we will all self-disclose, while describing some of the pros and cons and impacts of self-disclosure of a clinician's political perspectives.

The Sternum-Nipple Distance is Double the Nipple-Inframammary Fold Distance in Macromastia.

BACKGROUND: Reduction mammaplasty is one of the most commonly performed plastic surgery operations. For a majority of techniques, the most common long-term complication is pseudoptosis. It has previously been proposed that upper breast suspensory ligaments (SL) are weaker than lower breast SL. We tested this hypothesis through anthropometry of the proxies for upper and lower SL strength: the sternal notch-nipple (SN-N) distance and the nipple-inframammary fold (N-IMF) distance, respectively. METHODS: An institutional review board-approved retrospective review of patients undergoing reduction mammoplasty in an academic faculty practice between 2008 and 2015 was conducted. Patient demographics included age, race, and body mass index (BMI); patient comorbidities included smoking status, diabetes, and hypertension. Breast anthropometric measurements included SN-N and N-IMF. Sternal notch-nipple was used as the primary metric of the upper SL strength, whereas N-IMF was used as the primary metric of the lower SL strength. Intraoperative details included reduction technique and resection mass. Postoperative complications were recorded, including nipple areola complex necrosis and hematoma. Linear regression analysis was performed with the primary endpoint of the relationship between SN-N and N-IMF distance in macromastia. RESULTS: Data from 208 patients, totaling 400 individual breast measurements, were collected. The mean SN-N length was 35.1 cm, mean N-IMF length was 16.0 cm, and mean resection weight was 1094 g. Linear regression found that N-IMF distance could be predicted as 45% of the SN-N distance (N-IMF = 0.454 * SN-N). This was a strong relationship, demonstrated by univariate analysis of SN-N and N-IMF (R, 0.624; P < 0.001). A Wise pattern was used in 89.9% of cases; an inferior pedicle was used in 83.7% of cases. Nipple areola complex necrosis occurred in 15 breasts (3.75%). Sternal notch-nipple (R, 0.127; P = 0.011) and N-IMF (R, 0.119; P = 0.017) were both predictive of nipple areola complex necrosis (Table 4). CONCLUSIONS: In our series, the N-IMF distance increased 0.45 cm for every 1 cm increase in the SN-N distance. This relationship strengthens our primary hypothesis that the lower pole ligaments stretch at a significantly slower rate than the upper pole ligaments. Taking this into consideration, we suggest that surgeons seeking to minimize pseudoptosis rates should favor techniques that minimally disrupt the lower SL.

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.