Tumor lysate particle only vaccine (TLPO) vs. Tumor lysate particle-loaded, dendritic cell vaccine (TLPLDC) to prevent recurrence in resected stage III/IV melanoma patients: Results of a phase I/IIa trial.

BACKGROUND: The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from dendritic cells (DC) loaded ex vivo with autologous tumor lysate (TL). TLPLDC has been shown to decrease recurrence in resected Stage III/IV melanoma patients in a Phase IIb trial. The TL particle only (TLPO) vaccine is produced by loading of yeast cell wall particles with autologous TL and direct injection allowing for in vivo DC loading. We have compared the TLPO and TLPLDC vaccines in an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine. METHODS: Patients rendered clinically disease-free after surgery were randomized 2:1 to receive the TLPO or TLPLDC vaccine and followed for recurrence and death. Patients had scheduled intradermal inoculations at 0, 1, 2, 6, 12, and 18 months after enrollment. Kaplan-Meier and log-rank analysis were used to compare disease-free survival (DFS) and overall survival (OS) in an intention-to-treat (ITT) analysis. RESULTS: Sixty-three patients were randomized, 43 TLPO and 20 TLPLDC. Patients randomized to the TLPO arm were more likely to be female (37.2% vs. 10.0 %, p = 0.026), but otherwise no significant clinicopathological differences were identified. No differences in related adverse events (AE) were found between treatment arms. At a median follow-up of 20.5 months, the DFS (60.8% vs. 58.7 %, p = 0.714) and OS (94.6% vs. 93.8 %, p = 0.966) were equivalent between the TLPO and TLPLDC groups, respectively. No statistical differences were found in subgroup analyses between vaccine types, which accounted for receipt of immunotherapy and the use of G-CSF pre-blood draw. CONCLUSIONS: In a randomized, double-blind Phase I/IIa trial, there were no differences in DFS or OS in resected Stage III/IV melanoma patients receiving adjuvant TLPO versus TLPLDC vaccines. Given manufacturing advantages, further efficacy testing of TLPO is warranted in a Phase III trial.

The benefit of adjuvant chemotherapy following pancreaticoduodenectomy for pancreatic adenocarcinoma depends on response to neoadjuvant therapy.

BACKGROUND: The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. METHODS: The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. RESULTS: After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). CONCLUSION: Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.

Impact of Clinician Subjectivity on the Assessment of Dry Eye Disease Prevalence in a UK Public Health Care Patient Population.

Purpose: To understand the impact of subjectivity on diagnosis rates of dry eye disease (DED) in an unbiased population. Patients and Methods: A multicenter study enrolled 818 subjects with complete report forms (465 females, 67.1 ± 16.7 years, 353 males, 65.0 ± 15.9 years). Subjects were evaluated for staining, TBUT, tear osmolarity, meibomian gland disease, and OSDI. Results: Physicians diagnosed 48.7% of subjects as having DED, ranging from 42.9% to 62.3% between sites. Positivity rates for staining (≥ grade 1) ranged from 41.3% to 84.1% (mean = 0.8 ± 0.9 grade), TBUT (<10s) ranged from 39.1% to 61.6% (mean = 10.4 ± 6.6 seconds), osmolarity (>308 mOsm/L) ranged from 63.7% to 72.4% (mean = 319.7 ± 20.8), MGD grading ranged from 28.9% to 51.3% (mean = 0.5 ± 0.7), and symptoms measured by OSDI ranged from 57.6% to 71.0% (mean = 23.5 ± 20.5) between sites. Tear osmolarity was the most consistent between sites (max/min positivity = 114%), followed by OSDI (123%), TBUT (158%), MGD (178%), and staining (204%). DED markers were uncorrelated (average r2 = 0.05 ± 0.07). A substantial number of subjects (N = 110) exhibited positive symptoms (OSDI = 32.4 ± 15.7) and hyperosmolarity (338.1 ± 20.1 mOsm/L) but no other obvious signs of DED (MGD grade = 0.2 ± 0.4, TBUT = 13.5 ± 7.0 seconds, staining grade = 0.4 ± 0.5). Conclusion: Subjective signs of DED varied considerably, whereas objective measurements of OSDI and osmolarity were the most consistent between sites. A large proportion of subjects exhibited high symptoms and hyperosmolarity but no other obvious signs of dry eye disease, most of whom were undiagnosed by clinical assessment without access to the osmolarity measurement.

Robotic Mitral Valve Repair for Degenerative Mitral Regurgitation.

BACKGROUND: Contemporary national utilization and comparative safety data of robotic mitral valve repair for degenerative mitral regurgitation compared with nonrobotic approaches are lacking. The study aimed to characterize national trends of utilization and outcomes of robotic mitral repair of degenerative mitral regurgitation compared with sternotomy and thoracotomy approaches. METHODS: Patients undergoing intended mitral repair of degenerative mitral regurgitation in The Society of Thoracic Surgeons Adult Cardiac Surgery Database between 2015 and 2021 were examined. Mitral repair was performed in 61,322 patients. Descriptive analyses characterized center-level volumes and outcomes. Propensity score matching separately identified 5540 pairs of robotic vs thoracotomy approaches and 6962 pairs of robotic vs sternotomy approaches. Outcomes were operative mortality, composite mortality and major morbidity, postoperative length of stay, and conversion to mitral replacement. RESULTS: Through the 7-year study period, 116 surgeons across 103 hospitals performed mitral repair robotically. The proportion of robotic cases increased from 10.9% (949 of 8712) in 2015 to 14.6% (1274 of 8730) in 2021. In both robotic-thoracotomy and robotic-sternotomy matched pairs, mortality and morbidity were not significantly different, whereas the robotic approach had lower conversion (1.2% vs 3.1% for robotic-thoracotomy and 1.0% vs 3.7% for robotic-sternotomy), shorter length of stay, and fewer 30-day readmissions. Mortality and morbidity were lower at higher-volume centers, crossing the national mean mortality and morbidity at a cumulative robotic mitral repair case of 40. CONCLUSIONS: Robotic mitral repair is a safe and effective approach and is associated with comparable mortality and morbidity, a lower conversion rate, a shorter length of stay, and fewer 30-day readmissions than thoracotomy or sternotomy approaches.

Predictors and benefits of multiagent chemotherapy for pancreatic adenocarcinoma: Timing matters.

INTRODUCTION: Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS). METHODS: The National Cancer Database was queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model. RESULTS: A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%; odds ratio [OR]: 0.59; p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18; 95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95% CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001). CONCLUSION: Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.

Robotic mitral valve re-repair with removal of transcatheter mitral valve repair clips.

We demonstrate a totally endoscopic and percutaneous approach to robotic mitral valve re-repair after the failure of transcatheter edge-to-edge repair.

What Does Minimally Invasive Mitral Valve Surgery Really Mean? Defining Totally Endoscopic Mitral Valve Surgery Through Meta Analysis.

INTRODUCTION: Minimally invasive approaches to mitral valve surgery are being performed with increasing frequency; however, many of these procedures still involve rib spreading and large incisions. The heterogeneity of self-reported "minimally invasive" approaches limits analysis of outcomes. This review aims to formally define totally endoscopic mitral valve surgery (TEMVS) and assess outcomes. MATERIALS AND METHODS: A comprehensive literature search in Pub-Med, Cochrane Library, and EMBASE was used to find studies reporting outcomes on totally endoscopic mitral valve surgery. "Totally endoscopic" was defined as incisions less than 3cm and the avoidance of rib spreading. The primary outcome was 30-day mortality and secondary endpoints included postoperative myocardial infarction (MI), stroke, early reoperation, wound infection, renal failure, and prolonged ventilation. Perioperative patient characteristics were also recorded and analyzed. RESULTS: Thirty-three studies (6031 patients) were included in our meta-analysis. The 30-day mortality rate was 0.33%, p=0.88. The most frequent complications were early reoperation (2.12%, p=0.44) and prolonged ventilation (1.46% p=<0.01). Rates of MI, stroke, and renal failure were each less than 1%. Patient characteristics including age, body mass index (BMI), and ejection fractions were also analyzed. CONCLUSIONS: We propose a formal definition of TEMVS, which is performed through incisions less than 3cm and without rib spreading. Thirty-day mortality and other adverse sequelae of TEMVS are uncommon.

Cost and Clinical Outcomes Evaluation Between the Endoaortic Balloon and External Aortic Clamp in Cardiac Surgery.

OBJECTIVE: Endoaortic balloon occlusion facilitates cardioplegic arrest during minimally invasive surgery (MIS). Studies have shown endoclamping to be as safe as traditional aortic clamping. We compared outcomes and hospital costs of endoclamping versus external aortic occlusion in a large administrative database. METHODS: There were 52,882 adults undergoing eligible cardiac surgery (October 2015 to March 2020) identified in the Premier Healthcare Database. Endoclamp procedures (n = 419) were 1:3 propensity score matched to similar procedures using external aortic occlusion (n = 1,244). Generalized linear modeling measured differences in in-hospital complications (major adverse renal and cardiac events, including mortality, new-onset atrial fibrillation, acute kidney injury [AKI], myocardial infarction [MI], postcardiotomy syndrome, stroke/transient ischemic attack [TIA], and aortic dissection) and length of stay (LOS). RESULTS: The mean age was 63 years, and 53% were male (n = 882). The majority (93%, n = 1,543) were mitral valve procedures, and 17% of procedures (n = 285) were robot-assisted. Total hospitalization costs were not statistically significantly different between the 2 groups ($52,158 vs $49,839, P = 0.06). The median LOS was significantly shorter in the endoclamp group (incident rate ratio = 0.87, P < 0.001). Mortality, atrial fibrillation, AKI, and stroke/TIA were similar between the 2 groups. MI and postcardiotomy syndrome were lower in the endoclamp group (odds ratio [OR] = 0.14, P = 0.006, and OR = 0.27, P = 0.005). There were no aortic dissections in the endoclamp group. CONCLUSIONS: Aortic endoclamping in MIS was associated with similar costs, shorter LOS, no dissections, and comparably low mortality and stroke rates when compared with external clamping in this hospital billing dataset. These results demonstrate the clinical safety and efficacy of endoaortic balloon clamping in a real-world setting. Further studies are warranted.

Ferredoxin C2 is required for chlorophyll biosynthesis and accumulation of photosynthetic antennae in Arabidopsis.

Ferredoxins (Fd) are small iron-sulphur proteins, with sub-types that have evolved for specific redox functions. Ferredoxin C2 (FdC2) proteins are essential Fd homologues conserved in all photosynthetic organisms and a number of different FdC2 functions have been proposed in angiosperms. Here we use RNAi silencing in Arabidopsis thaliana to generate a viable fdC2 mutant line with near-depleted FdC2 protein levels. Mutant leaves have ~50% less chlorophyll a and b, and chloroplasts have poorly developed thylakoid membrane structure. Transcriptomics indicates upregulation of genes involved in stress responses. Although fdC2 antisense plants show increased damage at photosystem II (PSII) when exposed to high light, PSII recovers at the same rate as wild type in the dark. This contradicts literature proposing that FdC2 regulates translation of the D1 subunit of PSII, by binding to psbA transcript. Measurement of chlorophyll biosynthesis intermediates revealed a build-up of Mg-protoporphyrin IX, the substrate of the aerobic cyclase. We localise FdC2 to the inner chloroplast envelope and show that the FdC2 RNAi line has a disproportionately lower protein abundance of antennae proteins, which are nuclear-encoded and must be refolded at the envelope after import.

Endoaortic balloon occlusion versus transthoracic cross-clamp for totally endoscopic robotic mitral valve surgery: a retrospective cohort study.

Endoaortic balloon occlusion (EABO) and transthoracic cross-clamping have been shown to have comparable safety profiles for aortic occlusion in minimally invasive mitral valve surgery (MIMVS). However, few studies have focused exclusively on the totally endoscopic robotic approach. We sought to compare outcomes for patients undergoing totally endoscopic robotic mitral valve surgery with aortic occlusion via EABO and transthoracic clamping after a period where EABO was unavailable required us to use the transthoracic clamp. Retrospective review identified 113 patients who underwent robotic mitral valve surgery at our facility between 2019 and 2021 with EABO (n = 71) or transthoracic clamping (n = 42). Relevant data were extracted and compared. Preoperative characteristics were similar other than a higher rate of coronary artery disease [EABO: 69.0% (49/71) vs clamp: 45.2% (19/42), p = .02] and chronic lung disease [EABO: 38.0% (27/71) vs clamp: 9.5% (4/42), p < .01] in the EABO group. Median percutaneous cardiopulmonary bypass time, operative time, and cross-clamp time were comparable. Similar rates of postoperative bleeding complications were observed, and no aortic complications were observed. One patient in each group underwent conversion to an open approach. 30-day mortality and readmission rates were comparable. EABO and transthoracic clamp were associated with similar bleeding and aortic outcomes, and mortality and readmission rates were comparable at thirty days postoperatively. Our findings support the comparable safety of the two techniques, which is well documented in studies encompassing all MIMVS techniques, within the specific context of the totally endoscopic robotic approach.

Phase II Trial of Nelipepimut-S Peptide Vaccine in Women with Ductal Carcinoma In Situ.

NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in CTL responses between groups and between pre-vaccination and 1-month post-operation were analyzed using a two-sample t test or Wilcoxon rank sum test. The incidence and severity of adverse events were compared between groups. Overall, 45 patients were registered; 20 patients were HLA-A2 negative, 7 declined participation, 1 withdrew, and 4 failed screening for other reasons. The remaining 13 were randomized to NeuVax (n = 9) or GM-CSF alone (n = 4). Vaccination was well-tolerated with similar treatment-related toxicity between groups with the majority (>89%) of adverse events being grade 1. The percentage of NPS-specific CTLs increased in both arms between baseline (pre-vaccination) and 1-month post-operation. The increase was numerically greater in the NPS+GM-CSF arm, but the difference was not statistically significant. NPS+GM-CSF is safe and well-tolerated when given preoperatively to patients with DCIS. In patients with HLA-A2-positive DCIS, two inoculations with NPS+GM-CSF can induce in vivo immunity and a continued antigen-specific T-cell response 1-month postsurgery. PREVENTION RELEVANCE: This trial showed that vaccination of patients with HLA-A2-positive DCIS with NeuVax in the preoperative setting can induce a sustained antigen-specific T-cell response. This provides proof of principle that vaccination in the preoperative or adjuvant setting may stimulate an adaptive immune response that could potentially prevent disease recurrence.

Feasibility of Robotic Mitral Valve Repair Using Barbed Nonabsorbable Sutures: A Preliminary Single-Center Experience.

OBJECTIVE: Barbed nonabsorbable sutures have been widely adopted for tissue closure in noncardiac robotic surgery to improve intraoperative efficiency. Here, we examine the profile in robotic mitral valve repair (rMVR), which utilized barbed nonabsorbable sutures. To our knowledge, this is the first report to describe clinical outcomes for rMVR with barbed nonabsorbable sutures. METHODS: A retrospective review identified 90 patients who underwent rMVR using barbed nonabsorbable sutures at our center between 2019 and 2021. The primary outcome measure was dehiscence, while other relevant outcomes included 30-day readmission and 30-day mortality. RESULTS: In addition to fixation of the mitral annuloplasty band, barbed nonabsorbable sutures were employed commonly in concomitant pericardiectomy closure (100.0%, 90 of 90), atriotomy closure (100.0%, 90 of 90), and left atrial appendage closure (if eligible; 98.8%, 83 of 84). One patient who underwent mitral valve annuloplasty using only barbed nonabsorbable suture required reoperation for annuloplasty ring dehiscence. Immediate postoperative ring dehiscence was not observed in any patients after the routine reinforcement of barbed nonabsorbable sutures with everting pledgeted polyester sutures, and no additional patients required reoperation for suture-related complications. Clinical signs of dehiscence were not observed after pericardiectomy, atriotomy, or left atrial appendage closure with barbed nonabsorbable sutures. The 30-day readmission rate was 3.3% (3 of 90), and 30-day mortality was 0% (0 of 90). CONCLUSIONS: These data suggest the initial feasibility of barbed nonabsorbable sutures in robotic cardiac surgery, specifically within rMVR. Further research is necessary to explore the long-term safety and efficacy profile of such approach.

Feasibility of Postoperative Day One or Day Two Discharge After Robotic Cardiac Surgery.

INTRODUCTION: The robotic platform reduces the invasiveness of cardiac surgical procedures, thus facilitating earlier discharge in select patients. We sought to evaluate the characteristics, perioperative management, and early outcomes of patients who underwent postoperative day 1 or 2 (POD1-2) discharge after robotic cardiac surgery at our institution. METHODS: Retrospective review of 169 patients who underwent robotic cardiac surgery at our facility between 2019 and 2021 identified 57 patients discharged early on POD1 (n = 19) or POD2 (n = 38) and 112 patients who underwent standard discharge (POD3 or later). Relevant data were extracted and compared. RESULTS: In the early discharge group, median patient age was 62 [IQR: 55, 66] (IQR = interquartile range) years, and 70.2% (40/57) were male. Median Society of Thoracic Surgeons predictive risk of mortality score was 0.36 [IQR: 0.25, 0.56] %. The most common procedures performed were mitral valve repair [66.6%, (38/57)], atrial mass resection [10.5% (6/57)], and coronary artery bypass grafting [10.5% (6/57)]. The only significant differences between the POD1 and POD2 groups were shorter operative time, higher rate of in-operating room extubation, and shorter ICU length of stay in the POD1 group. Lower in-hospital morbidity and comparable 30-day mortality and readmission rates were observed between the early and standard discharge groups. CONCLUSIONS: POD1-2 discharge after various robotic cardiac operations afforded lower morbidity and similar 30-day readmission and mortality rates compared to discharge on POD3 or later. Our findings support the feasibility of POD1-2 discharge after robotic cardiac surgery for patients with low preoperative risk, an uncomplicated postoperative course, and appropriate postoperative management protocols.

A New Frontier: No Working Port for Robotic Mitral Valve Repair.

A 61-year-old male presented via referral for mitral regurgitation and was deemed an appropriate robotic surgery candidate for complex mitral valve repair with the maze procedure and patent foramen ovale and left atrial appendage closures, using all percutaneous cannulation. We report upon the first case in the literature that describes the use of only 4 robotic ports, with no working port used.

Tumor infiltrating lymphocytes as an endpoint in cancer vaccine trials.

Checkpoint inhibitors have invigorated cancer immunotherapy research, including cancer vaccination. Classic early phase trial design and endpoints used in developing chemotherapy are not suited for evaluating all forms of cancer treatment. Peripheral T cell response dynamics have demonstrated inconsistency in assessing the efficacy of cancer vaccination. Tumor infiltrating lymphocytes (TILs), reflect the local tumor microenvironment and may prove a superior endpoint in cancer vaccination trials. Cancer vaccines may also promote success in combination immunotherapy treatment of weakly immunogenic tumors. This review explores the impact of TILs as an endpoint for cancer vaccination in multiple malignancies, summarizes the current literature regarding TILs analysis, and discusses the challenges of providing validity and a standardized implementation of this approach.

Endoaortic Balloon Occlusion in Totally Endoscopic and Percutaneous Robotic Cardiac Surgery.

Previous studies have shown that the endoaortic balloon occlusion (EABO) can provide satisfactory aortic cross-clamping with comparable surgical outcomes to thoracic aortic clamping in the setting of minimally invasive and robotic cardiac surgery. We described our approach to EABO use in totally endoscopic and percutaneous robotic mitral valve surgery. Preoperative computed tomography angiography is required to evaluate the quality and size of the ascending aorta, identify access sites for peripheral cannulation and endoaortic balloon insertion, and screen for other vascular anomalies. Continuous bilateral upper extremity arterial pressure and cranial near-infrared spectroscopy monitoring are essential to detect obstruction of the innominate artery due to distal balloon migration. Transesophageal echocardiography is needed for continuous monitoring of balloon positioning and antegrade cardioplegia delivery. Direct fluorescent visualization of the endoaortic balloon on the robotic camera allows for verification of balloon and efficient repositioning if needed. The surgeon should assess hemodynamic and imaging information simultaneously during the balloon inflation and delivery of antegrade cardioplegia. Aortic root pressure, systemic blood pressure, and balloon catheter tension affect the position of the inflated endoaortic balloon in the ascending aorta. The surgeon should eliminate all slack in the balloon catheter and lock it into position to prevent proximal balloon migration after the completion of antegrade cardioplegia. Using scrupulous preoperative imaging assessment and continuous intraoperative monitoring, the EABO can achieve adequate cardiac arrest in totally endoscopic robotic cardiac surgery, even in patients with previous sternotomy without compromise of surgical outcomes.