The effect of mind-body intervention on lymphocyte doubling time and treatment free survival in treatment-naïve chronic lymphocytic leukemia patients.

INTRODUCTION: Mind-Body Intervention (MBI) serves as supportive aid in oncology. We hypothesized that MBI could impact the progression of Chronic Lymphocytic Leukemia (CLL) in the 'watch and wait' (w&w) phase. METHODS: MBI was utilized in a non-randomized prospective controlled study between 02/2020-02/2022 in 76 treatment-naïve CLL patients in the w&w phase (37 intervention and 39 control patients). The primary and secondary endpoints were prolongation of Lymphocyte Doubling Time (LDT) and treatment-free survival (TFS). The prolongation of LDT was compared at 0, 180, 360, and 540 days using paired t-tests. TFS was compared between intervention and control groups using the log-rank test. Cox proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for TFS in the intervention group compared to the control, stratified by the study covariates. RESULTS: MBI prolonged LDT at all time points, including at day 360 (Median of 2.47 years; CI 1.05-3.9; p= 0.001). TFS at 18 months was longer in the intervention group compared to the control group (HR 0.23; CI 0.06-0.79, p=0.01). CONCLUSIONS: MBI was associated with prolonged LDT and TFS in patients with CLL in the w&w phase. These results provide a basis for a larger randomized-control trial.

Comparing a novel wide field of view laparoscope with conventional laparoscope while performing laparoscopic cholecystectomy.

BACKGROUND: The limited 70° field of view (FoV) used in standard laparoscopy necessitates maneuvering the laparoscope to view the ports, follow the surgical tools, and search for a target region. Complications related to events that take place outside the FoV are underreported. Recently, a novel laparoscopic system (SurroundScope, 270Surgical) was reported to dramatically expand the FoV from 70 to 270°. This study focuses on differences in performing laparoscopic cholecystectomy using the SurroundScope compared to the standard laparoscope. METHODS: Forty-four laparoscopic surgeries were performed and video recorded. A subanalysis of 21 Cholecystectomies was performed and compared to 21 Cholecystectomies, performed with the standard laparoscope during the study period by the same surgeon. RESULTS: No accidental or intraoperative adverse events occurred when using the SurroundScope. Subanalysis of 21 Cholecystectomies revealed shorter fog/smoke cleaning times using the SurroundScope compared to the standard scope (1.45 ± 5.08 sec vs. 54.95 ± 137.77 sec, p = 0.0454). Furthermore, operations performed with the SurroundScope had a shorter trocar placement duration (85.0 ± 40.9 sec vs. 111.3 ± 70.5 sec; p = 0.077), shorter time to achieve critical view of safety (9.5 ± 4.14 min vs. 15.8 ± 11.87 min; p = 0.015), and shorter procedure duration (31.9 ± 10.4 min vs. 42.9 ± 22 min; p = 0.025). In post-operative evaluations, the surgeon noted that tools could be continuously followed and ports were visible without camera manipulation. Also, the surgeon agreed that the procedure could be better planned due to the wide FoV and that surgical workflow was improved. Furthermore, the surgeon agreed that the procedure was safer using the SurroundScope. CONCLUSIONS: Initial results demonstrate the advantages of the SurroundScope over standard laparoscopy. By expanding the FoV, visualization is improved, the procedure is more efficient, significantly shorter and most important, patient safety, per surgeons' testimonials is improved. Further investigation to quantify these benefits in a larger group of patients and among various surgical procedures should be considered.

Effects of wide-angle laparoscopy on surgical workflow in laparoscopic cholecystectomies.

INTRODUCTION: Laparoscopy is now the gold standard approach to many surgical procedures thanks to its many advantages. Minimizing distractions is essential to a safe and successful surgery and an undisrupted surgical workflow. The SurroundScope, a wide angle (270°) laparoscopic camera system has the potential to decrease surgical distractions and increase workflow. METHODS: Forty-two laparoscopic cholecystectomies were performed by a single surgeon, 21 with the SurroundScope and 21 with standard angle laparoscope. Video recordings of surgeries were reviewed for calculating the number of entries of surgical tools into the field of view, relative time of tools and ports viewed in surgical field and number of times camera was removed due to fog or smoke. RESULTS: The usage of the SurroundScope resulted in a significantly lower number of entries to the field of view compared to the standard scope (58.50 versus 102; P < 0.0001). Usage of SurroundScope resulted in a significantly higher appearance ratio of tools, with a value of 1.87 compared to 1.63 for standard scope (P-value < 0.0001), and the appearance ratio of ports was also significantly higher, measuring 1.84 compared to 0.27 for the standard scope (P-value < 0.0001). In addition, the SurroundScope had to be removed and reinserted due to smoke or fog in only 2 cases (9.5%), compared to 12 cases (57.1%) in the standard scope group (P-value < 0.01). CONCLUSIONS: The SurroundScope camera system improves surgical workflow in laparoscopic cholecystectomy. This conceivably increase the safety of the operation due to the utilization of the wide-angle view and "chip on the tip" technology.

Robust antibody response after a third BNT162b2 vaccine compared to the second among immunocompromised and healthy individuals, a prospective longitudinal cohort study.

PURPOSE: As protection from COVID-19 following two doses of the BNT162b2 vaccine showed a time dependent waning, a third (booster) dose was administrated. This study aims to compare the antibody response following the third dose versus the second and to evaluate post-booster seroconversion. METHODS: A prospective observational study conducted in Maccabi Healthcare Services. Serial SARS-CoV-2 Spike IgG tests, 1,2,3 and 6 months following the second vaccine dose and one month following the third were obtained. Neutralizing antibody levels were measured in a subset of participants. Per individual SARS-CoV-2 Spike IgG titer ratios were calculated one month after the booster administration compared to titers one month following the second dose and prior to booster. RESULTS: Among 110 participants,56 (51%) were women. Mean age was 61.7 ± 1.9 years and 66 (60%) were immunocompromised. One month after third dose, IgG titers were induced 7.83 (95 %CI 5.25-11.67) folds and 2.40 (95 %CI 1.90-3.03) folds compared to one month after the second, in the immunocompromised and immunocompetent groups, respectively. Of the 17 immunocompromised participants who were seronegative after the second dose, 4 (24%) became seropositive following the third. Comparing the titers prior to the third dose, an increase of 50.7 (95 %CI 32.5-79.1) fold in the immunocompromised group and 25.7 (95 %CI 19.1-34.7) fold in and immunocompetent group, was observed. CONCLUSION: A third BNT162b2 vaccine elicited robust humoral response, superior to the response observed following the second, among immunocompetent and immunocompromised individuals.

The introduction of wide-angle 270° laparoscopy through a novel laparoscopic camera system.

BACKGROUND: Laparoscopy has enjoyed improvements over the last three decades primarily in achieving high definition, but the 70° field of view (FOV) remains unchanged. Complications related to events that take place out of the FOV continue to be reported. Additional problems leading to poor visualization are fogging and smoke accumulation. A novel laparoscopic system (SurroundScope, 270Surgical) was developed and dramatically expands the FOV from the 70° to 270° by adding side cameras at the distal tip of the laparoscope, while LED illumination eliminates fogging and improves smoke effects. This study describes the initial clinical experience with SurroundScope and its potential advantages over traditional laparoscopy. METHODS: SurroundScope was studied at Bnai Zion Medical Center in Israel and the Minnesota Institute for Minimally Invasive Surgery in America. 27 laparoscopic surgeries were performed, and at the end of each procedure, evaluations were completed by all surgeons and camera holders. RESULTS: All 27 cases were completed successfully without adverse events. No injuries occurred as a result of surgical tool manipulation outside of the central frame while 133 potentially adverse events were identified on side frames. There was no fogging across the 27 cases. The impact of smoke was negligible in all cases, as laparoscope removal or venting was never necessary. Surgeon respondents indicated that tools could be followed from the port to the site of surgery without camera manipulation. Most surgeons strongly agreed that the potential to identify bleeding was improved. Camera holders strongly agreed that the ergonomics were improved and that they moved the camera less than with a standard laparoscope. CONCLUSIONS: Initial results demonstrate numerous advantages for SurroundScope as compared to traditional laparoscopy. The important benefits of expanded FOV, complete lack of fogging, and negligible smoke may improve patient safety, reduce adverse events and the duration of surgery. Further investigation to quantify these benefits is recommended.

Safety and efficacy of the BNT162b mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.

Management and Outcome of Venous Thrombosis in Patients with Myeloproliferative Neoplasms: Data from the Israeli MPN Working Group.

The BCR-ABL-negative myeloproliferative neoplasms (MPN) are associated with high incidence of venous thrombosis and a significant rate of recurrent events, but there is no consensus regarding their management. In this retrospective study, we analyzed 96 patients with MPN-related venous thrombosis. The index venous thrombosis occurred at a median age of 58 years (IQR 37-71), with 58% of the events involving unusual sites. Patients who were on antiplatelet agents at the time of index thrombosis tended to be older than patients who were not receiving antiplatelets at the time of index thrombosis. The majority of index thromboses occurring after the diagnosis of MPN had uncontrolled blood counts at the time of event and were not receiving antithrombotic agents. Following the thrombotic episode, 75% of patients received long-term anticoagulation. At a median follow-up of 3.4 years, the recurrence rate was 14%. Thrombophilia was significantly more prevalent among patients with recurrent thrombosis compared to patients without recurrence (p < 0.01). Patients who developed a recurrent event early were more likely to have thrombophilia (either inherited or antiphospholipid antibodies), and controlled blood counts, and were likely to receive anticoagulation at the time of recurrence compared to patients with later recurrences. Thrombophilia may contribute to venous thrombosis recurrence, especially early after the index venous thrombosis. Suboptimal anticoagulation and blood count control are factors associated with late venous thrombosis recurrence.

Dual BRAF/MEK blockade restores CNS responses in BRAF-mutant Erdheim-Chester disease patients following BRAF inhibitor monotherapy.

BACKGROUND: Erdheim-Chester disease (ECD), a rare inflammatory myeloid neoplasm, is known to be fundamentally reliant on the constitutive activation of the MAPK signaling pathway in the majority of patients. Consequently, inhibition of the V600E-mutant BRAF kinase has proven to be a safe and efficacious long-term therapeutic strategy for BRAF-mutant ECD patients. Nevertheless, in a subset of patients with CNS disease, the efficacy of long-term treatment may diminish, facilitating suboptimal responses or disease progression. METHODS: We retrospectively describe 3 BRAF-mutant ECD patients whose treatment with Vemurafenib was upgraded to Vemurafenib/Cobimetinib due to either disease progression, insufficient response, or unacceptable toxicity. CNS response to therapy was evaluated using magnetic resonance imaging (MRI) and extra-cranial disease was monitored using 18F-fludeoxyglucose positron emission tomography/computed tomography (PET/CT). RESULTS: Three patients with a mean age of 52.6 years were treated with Vemurafenib for a mean duration of 26.6 months (range: 6-52). Monotherapies were upgraded to Vemurafenib/Cobimetinib dual therapy. The combination therapy was administered for a mean duration of 21 months (range: 19-23). All patients exhibited clinical and neurological improvement. Regression of lesions on MRI was noted in 2 patients. Both patients characterized by a PET-avid disease responded to the biological treatment regimen with complete metabolic remissions. CONCLUSION: Dual inhibition of BRAF and downstream MEK may be a safe and effective therapeutic strategy for BRAF-mutant ECD patients for whom BRAF inhibitor therapy proved insufficient and as such appropriate for the long-term management of CNS disease in ECD.

[PRACTICAL ADVICE FOR THE APPROPRIATE USE OF DIRECT ORAL ANTICOAGULANTS].

INTRODUCTION: The direct oral anticoagulants (DOACs) are a class of drugs used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for prevention and treatment of venous thrombo-embolism. They are as effective and are safer than the vitamin K antagonists that were the oral drugs previously used for this purpose. The DOACs are convenient to use because of their fixed dose-response relationship which makes routine monitoring of drug levels unnecessary. Further, they have no food interactions and relatively few drug interactions. A number of practical considerations related to the routine clinical use of the DOACs have become apparent. These include choosing the appropriate drug and importantly dose-based on patient characteristics, managing the use of DOACs peri-operatively and the appropriate management of the acutely bleeding DOAC-treated patient. Recent controlled and observational studies provide guidance for dealing with these clinical situations thus enhancing the efficacy and safety of DOAC treatment in routine clinical practice.

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.

Hemorrhagic complications in patients treated with anticoagulant doses of a low molecular weight heparin (enoxaparin) in routine hospital practice.

Low molecular weight heparins (LMWHs) are a rapidly growing class of anticoagulant drug. Their efficacy has been demonstrated in several clinical settings where they are rapidly becoming the anticoagulant of choice. Controlled clinical studies in patients with deep vein thrombosis, pulmonary embolism, and unstable angina have documented that the frequency of major hemorrhage is 0.5-4%. The purpose of the study was to determine the frequency of minor and major hemorrhage occurring in patients receiving anticoagulant doses of an LMWH (enoxaparin) during routine clinical practice. A prospective, observational study of consecutive patients receiving enoxaparin 1 mg/kg twice daily for at least 24 hours in five internal medicine wards of a university teaching hospital was performed. Five hundred forty-nine patients were studied. The mean age was 67.5+/-15.5 years and the mean duration of enoxaparin therapy was 3.8+/-1.5 days. Hemorrhage was documented in a total of 94 patients (17.3%). Major hemorrhage occurred in 14 patients (2.6%), injection-site hemorrhage occurred in 55 patients (10%), and minor hemorrhage (noninjection site) was documented in 25 patients (4.7%). There were two deaths attributed to hemorrhage. Patients with major hemorrhage were older than patients with minor or no hemorrhage (75.5+/-10.4 versus 66.8+/-15.2 years; p=0.03) and occurred in patients receiving enoxaparin for a longer period (5.14+/-3.8 days) than those with minor (4+/-2.5 days) or no hemorrhage (2.9+/-2.1 days). Major hemorrhage was significantly associated with impaired renal function, chronic liver disease, and concomitant treatment with warfarin or a proton pump inhibitor. Enoxaparin used in anticoagulant doses in unselected medical patients is not associated with more major hemorrhagic complications than observed in controlled clinical trials. Major hemorrhage may be more likely in older patients, in patients with chronic liver disease and impaired renal function, in patients receiving prolonged enoxaparin therapy, and in patients receiving warfarin or proton pump inhibitors.

The effect of plasma depletion of platelet concentrates on platelet aggregation and phosphatidylserine expression.

Plasma-reduced platelet concentrates are commonly administered to prevent febrile transfusion reactions and to avoid fluid overload in neonates. Because little is known about the influence of centrifugation and resuspension on functional aspects of platelets, we examined the effects of plasma-reduction on platelet aggregation and platelet-dependent thrombin generation. Our results show that plasma reduction and resuspension of the platelet pellet in saline or plasma results in a significant reduction in platelet aggregation to a combination of the platelet agonists adenosine diphosphate and epinephrine (p < 0.001). In contrast, when a combination of the more potent agonists collagen and thrombin was used, platelet aggregation was maintained. Likewise, no decline was observed in platelet-dependent thrombin generation as measured by the functional prothrombinase assay or Annexin V binding. We conclude that centrifugation and resuspension of platelets to render the concentrate plasma-free, as a routine procedure in blood banking, variably affects in vitro platelet aggregability but does not significantly affect platelet-dependent thrombin generation.