Citations

Eugene Botkin was Nicholas II’s court physician from 1908 until the abolition of the monarchy. He accompanied the royal family into exile and shared their fate at Ekaterinburg in 1918. The son of a prominent St. Petersburg physician, he trained at the Universities of St. Petersburg, Berlin, and Heidelberg. As court physician, he participated in the management of the Tsarevich Alexei’s hemophilia, but most of his time was spent taking care of the Tsarina’s multiple psychosomatic ailments. A deep sense of duty, rendered him unable to part from the royal family during the difficult months of exile and imprisonment. During this period there were several episodes of imminent threat to his life, where despite having the opportunity to leave, he voluntarily decided to stay with the Romanovs. In up to three occasions he said his goodbyes to his children, only to find out the next day that the threat had been contained. Ironically, the last time he spoke to them he did not think they would be separated for long. In this study, we will analyze his life, in particular the events of his last days, and will explore the reasoning behind his selfless actions.

AbstractIntroductionBrugada syndrome (BrS) is associated with ventricular arrhythmia leading to sudden cardiac death. Risk stratification is challenging, as major arrhythmic events (MAEs) are rare. We assessed the utility of drug challenge testing in BrS by a systematic review and meta‐analysis.Methods and ResultsWe comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2019. Included studies compared the incidence of MAE between spontaneous and drug challenge–induced Type 1. Mixed‐effects Poisson regression was used to calculate the incidence rate ratio (IRR). Eighteen studies from 2006 to 2018 were included (4099 patients, mean follow‐up: 4.5 years). Pooled annual incidences of MAE in spontaneous, drug challenge induced (regardless of symptoms), asymptomatic drug challenge induced, and symptomatic drug challenge–induced Type 1 were 23.8 (95% confidence interval [CI]: 19.8–27.8), 6.5 (95% CI: 3.9–9.1), 2.1 (95% CI: −0.3 to 4.4), and 19.6 (95% CI: 9.9–29.3) per 1000 person‐years, respectively. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type 1 was not statistically different (IRR = 1.0; 95% CI: 0.6–1.7).ConclusionsThe incidence of MAE in drug challenge–induced Type 1 in asymptomatic patients is low. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type 1 was similar.

BACKGROUND: Transanal excision is the surgical treatment of choice for low-risk rectal pathology such as endoscopically unresectable polyps, very select early rectal cancers, as well as other benign and low-risk tumors. Robotic transanal minimally invasive surgery enhances the surgeon’s ability to work in the confined space of the rectum and helps overcome the limitations of other modalities for transanal excision. Large lesions that extend to the dentate line and cannot be excised transanally impart a particular challenge. Herein, we describe a hybrid robotic transanal minimally invasive surgery approach for excising large rectal lesions that extend to the dentate line and cannot be excised by utilizing traditional transanal techniques. TECHNIQUE: With the use of a standard transanal approach, the distal margin of the lesion is marked and lifted off of the internal sphincter muscle. The dissection is continued until above the anorectal ring, and a 5.5-cm transanal platform is introduced transanally. Insufflation with an 8-mm trocar is initiated and the robotic platform is docked transanally. A 1-cm circumferential proximal margin is marked, and the excision is continued robotically until en bloc resection of the lesion is completed. The defect is closed in a transverse fashion using barbed suture. For rare cases of circumferential or nearly circumferential full-thickness defects, interrupted barbed sutures are placed equidistant, the robot is undocked, the transanal platform is removed, and a handsewn coloanal anastomosis is performed allowing complete closure of the defect. RESULTS: A hybrid robotic transanal minimally invasive surgery approach to large and low-lying rectal lesions is feasible and safe, and it has advantages over standard transanal excision including enhanced ergonomics, dexterity, and optics, as well as reduced rates of specimen fragmentation. CONCLUSION: A hybrid robotic transanal minimally invasive surgery approach allows for complete resection of very large polyps, which would otherwise be extremely challenging with standard transanal approaches. See Video at http://links.lww.com/DCR/B231.

e17540 Background: The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after treatment with 2nd generation hormone therapy (2nd-HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing 2nd-HT. We sought to evaluate three common chemotherapy regimens in this setting. Methods: We retrospectively identified 150 patients with mCRPC with disease progression on enzalutamide or abiraterone. 92 patients were chemo-naïve, while 58 patients had previously received docetaxel chemotherapy prior to 2nd-HT. After failing 2nd-HT, 90 patients received docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). Favorable response was defined by ≥50% reduction in PSA level from baseline after a complete course of chemotherapy. Survival outcome was assessed for 30-month overall survival. Results: Mean (SD) age was 71.2 (8.28), 69.5(8.38) and 67.2 (8.36) for group (A), (B) and (C), respectively. Mean (SD) pre-chemotherapy PSA was 63.8 (138.18), 58.5 (118.15) and 53.7 (88.15) for group (A), (B) and (C), respectively. Mean (SD) Gleason score was 7.9 (1.1), 8.4 (0.88) and 8.1 (1.06) for group (A), (B) and (C), respectively. Patients in group (B) were 2.6 times more likely to have a favorable response compared to group (A) (OR = 2.625, 95%CI: 1.15 - 5.99) and almost 3 times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04 – 8.54) (p-value = 0.0442). We report a Hazard Ratio (HR) of 3.1 (95% CI 1.31-7.35; p = 0.0037) between patients in group (A) versus group (B), and a HR of 4.18 (95% CI 1.58-11.06; p = 0.0037) between patients in group (C) versus group (B). Thirty-month overall survival was 70.7%, 38.9%, and 30.3% for group (B), (A), and (C) respectively (p-value = 0.008). Conclusions: Our data demonstrate improved response and cancer-specific survival in patients with treatment-refractory mCRPC on docetaxel plus carboplatin compared to docetaxel or cabazitaxel alone. Selection bias is inherent in any retrospective study; however, our finding suggests that clinicians may consider docetaxel plus carboplatin in mCRPC patients who fail 2nd-HT. Further prospective studies are warranted.

5577 Background: Prostate specific antigen (PSA) has well-recognized limitations as a marker for treatment response and disease progression. A post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve mCRPC patients on enzalutamide had radiographic progression on conventional imaging with non-rising PSA. In this study, we sought to retrospectively compare PSA levels with C-11 choline positron emission tomography/ computed tomography (PET/CT) images in patients with m-CRPC on 2nd-HT with prior use of chemotherapy. Methods: We identified 123 patients with mCRPC on 2nd-HT following prior use of docetaxel chemotherapy (Abiraterone, n = 106; Enzalutamide, n = 17). Patients underwent serial PSA testing and C-11 choline PET/ CTs every 3–6 months. Disease progression was defined by the increase in blood pool corrected maximum standardized uptake value (SUVmax) of the index lesion on C-11 choline PET/CT scan. Suspicious lesions were confirmed by biopsy and/or conventional imaging. Results: Approximately 43% (n = 53) of patients had radiographic disease progression while on 2nd-HT. At time of radiographic progression, 60.4% of patients showed a parallel rise in PSA (Group-A), while 39.6% showed a paradoxical response; defined as radiographic progression with stable or down-trending PSA (Group-B). Median PSA at time of progression was 3.1 ng/ml for Group-A, and 1.3 ng/ml for Group-B (p-value = 0.0176). Median SUVmax was the same (4.9 Group-A, 4.6 Group-B; p-value = 0.6072). Bone-predominance progression was more significant in Group-B (90%) versus Group-A (65%) (p-value = 0.0309). The median time for radiographic progression was 9.5 months versus 3.9 months for Group-A and Group-B, respectively (Log-Rank = 0.0063). Conclusions: Metabolic imaging is a useful tool that should complement PSA in the evaluation of treatment response and disease progression in mCRPC patients on 2nd-HT, especially considering the paradoxical response observed in our data.

Dyn2 and α-actinin 4 interact directly to regulate invasive cell migration and the stabilization of invadopodia. Intriguingly, this is specific for α-actinin 4, and not the highly related protein α-actinin 1. These findings elucidate a novel mechanism of regulating cell migration, with important implications for invasive tumor cells.

Introduction: Brugada syndrome is associated with ventricular arrhythmia leading to sudden cardiac death. Risk stratification is challenging, as major arrhythmic events (MAE) are rare. We assessed the utility of drug challenge testing in Brugada syndrome by a systematic review and meta-analysis. Methods and results: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2019. Included studies compared the incidence of MAE between spontaneous and drug challenge induced Type-1. Data were combined using the random-effects, generic inverse variance method, to calculate pooled incidence and odds ratio (OR). Mixed-effects Poisson regression was used to calculated incidence rate ratio (IRR). Eighteen studies from 2006 to 2018 were included (4,099 patients, mean follow-up 4.5 years). Pooled annual incidences of MAE in spontaneous, drug challenge induced (regardless of symptoms), asymptomatic drug challenge induced, and symptomatic drug challenge induced Type-1 were 23.8 (95% confidence interval [CI]: 19.8-27.8), 6.5 (95% CI: 3.9-9.1), 2.1 (95% CI: -0.3-4.4), and 19.6 (95% CI: 9.9-29.3) per 1,000 person-years respectively. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type-1 was not statistically different (IRR=1.0, 95%CI: 0.6-1.7). The presence of ventricular tachyarrhythmia during drug challenge testing was a predictor of MAE (OR=3.73, 95% CI: 1.77-7.86, p=0.001). Conclusions: The incidence of MAE in drug challenge induced Type-1 in asymptomatic patients is low. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type-1 was similar. Ventricular tachyarrhythmia during drug challenge testing could be a useful risk marker for MAE in Brugada syndrome.

Abstract Imatinib mesylate (imatinib, Gleevec®, Novartis, Basel, Switzerland) inhibits T cells in vitro and in vivo (Dietz et al., Blood104: 1094–1099, 2004; Cwynarski et al., Leukemia18: 1332–1339, 2004). The drug blocks T cell cycle progression rather uniquely as it neither inhibits expression of CD69, an early marker of T cell activation, nor induces apoptosis. To characterize the molecular effects of imatinib leading to this mode of T-cell inhibition, we measured the changes in transcriptome (by Affymetrix U133 chips), proteome and phosphoproteome (by Western blotting, differential phosphoprotein expression and mass spectrometry). We found that phytohemagglutinin activated T cells pre-treated with imatinib had reduced expression of 983 transcripts and increased expression of 271 transcripts when compared to untreated PHA activated T cells by the factor of 1.5 or more (p<0.05). Among the prominently down-regulated transcripts were granzyme B, CTLA-4 and IL-2-receptor α-chain (CD25), all characteristic of activated T cells, as well as cyclins D2 and D3 and cyclin-dependent kinases 3, 4 and 7, the molecules regulating cell cycle progression. Among the up-regulated transcripts were Kruppel-like transcription factors 2 and 7, and p27, a finding compatible with the observed cell cycle inhibition. Furthermore, we selected and identified 30 proteins from 2-D gels that were up-regulated and/or hyperphosphorylated in imatinib treated activated T cells. Among these were four heterogeneous ribonucleoproteins, three lamins and γ-actin, all components of the nucleoskeleton at the interface of chromatin and inner nuclear membrane and involved in replication and transcription (Herrmann and Foisner, Cell. Mol. Life Sci.60: 1607–1612, 2003; Shumaker et al. Curr. Opinion Cell Biol.15: 358–366, 2003). Thus, imatinib-borne interference with T cell signal transduction affects the nuclear structure indicating for the first time that nucleoskeleton structural changes are associated with T cell activation status.

Abstract Aims Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS. Methods and results Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort. Conclusions Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome. Trial registration ClinicalTrials.gov number: NCT01947621.

TPS5093 Background: Globally, docetaxel remains the standard of care for metastatic CRPC; however, its use may be delayed until pts develop symptoms. The presence of infiltrating leukocytes in CRPC tumors suggests a natural antitumor immune response is occurring. This is supported by an overall survival (OS) benefit reported in men with asymptomatic or minimally symptomatic metastatic CRPC who received sipuleucel-T. Ipi, a monoclonal antibody that binds CTLA-4, augments antitumoral activity of cytotoxic immune cells. Ipi demonstrated OS benefit in two phase III trials for advanced melanoma, with side effects that were managed using product-specific treatment guidelines. In phase I/II trials in metastatic CRPC, Ipi has shown clinical activity (as measured by prostate-specific antigen [PSA] declines and RECIST response) with a similar toxicity profile to that observed in melanoma. This global (149 sites in 24 countries) phase III study (ClinicalTrials.gov identifier: NCT01057810) evaluates Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or minimally symptomatic CRPC without visceral metastases. Methods: The primary endpoint is OS; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The study is designed to detect a 9.3-month median difference (HR=0.7) in OS with 90% power and 0.05 two-sided significance. Pts are randomized at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or placebo as induction therapy. Eligible pts will receive maintenance therapy of blinded study drug every 12 weeks. The accrual goal is 600 pts randomized. Clinical trial information: NCT01057810. [Table: see text] [Table: see text]