Irreversible electroporation (Nanoknife® treatment) in the field of hepatobiliary surgery: Current status and future perspectives.

PURPOSE: We aimed to provide an overview of current understanding on the potential use of irreversible electroporation (IRE) in the field of hepatobiliary surgery with a focus on current results in hepatic and pancreatic cancers, its limitations, and its current directions. METHODS: Through a review of the literature we have gathered the key articles and trials that are shaping our understanding of the current status of IRE and its prospective uses, and organized them in an easily understandable format showcasing the most up to date results. RESULTS: IRE appears to be comparable in effectiveness and postoperative pain to the more established thermal ablation methods, while having the benefit of avoiding their detrimental thermal effects. In liver cancer, IRE was shown to be efficacious with low levels of local recurrences and only minimal complications. In pancreatic cancer it proved to have significant survival benefits but more significant (although rare) complications compared to the ones seen when IRE is used in liver cancer. Current evidence suggests a promising future for IRE, but clinical randomized control trials, and further developments of treatment protocols are required to come to more stable conclusions on the effectiveness and safety of IRE. CONCLUSIONS: IRE is proving to be an adequate method for the treatment of tumors of the pancreas and liver in cases where traditional methods are unavailable. It has been proven particularly efficacious in patients with masses in close proximity to vital structures such as vessels, as well as major biliary and hepatic structures where thermal methods of ablation would cause significant complications.

Perioperative use of iloprost in cardiac surgery patients diagnosed with heparin-induced thrombocytopenia-reactive antibodies or with true HIT (HIT-reactive antibodies plus thrombocytopenia): An 11-year experience.

Thrombocytopenia and thromboembolism(s) may develop in heparin immune-mediated thrombocytopenia (HIT) patients after reexposure to heparin. At the Onassis Cardiac Surgery Center, 530 out of 17,000 patients requiring heart surgery over an 11-year period underwent preoperative HIT assessment by ELISA and a three-point heparin-induced platelet aggregation assay (HIPAG). The screening identified 110 patients with HIT-reactive antibodies, out of which 46 were also thrombocytopenic (true HIT). Cardiac surgery was performed in HIT-positive patients under heparin anticoagulation and iloprost infusion. A control group of 118 HIT-negative patients received heparin but no iloprost during surgery. For the first 20 patients, the dose of iloprost diminishing the HIPAG test to ≤5% was determined prior to surgery by in vitro titration using the patients' own plasma and donor platelets. In parallel, the iloprost "target dose" was also established for each patient intraoperatively, but before heparin administration. Iloprost was infused initially at 3 ng/kg/mL and further adjusted intraoperatively, until ex vivo aggregation reached ≤5%. As a close correlation was observed between the "target dose" identified before surgery and that established intraoperatively, the remaining 90 patients were administered iloprost starting at the presurgery identified "target dose." This process significantly reduced the number of intraoperative HIPAG reassessments needed to determine the iloprost target dose, and reduced surgical time, while maintaining similar primary clinical outcomes to controls. Therefore, infusion of iloprost throughout surgery, under continuous titration, allows cardiac surgery to be undertaken safely using heparin, while avoiding life-threatening iloprost-induced hypotension in patients diagnosed with HIT-reactive antibodies or true HIT.

Effectiveness of Virtual Reality Vs Guided Imagery on mood changes in cancer patients receiving chemotherapy treatment: A crossover trial.

PURPOSE: To test whether Virtual Reality (VR) can benefit cancer patients from their interaction with an immersive environment, on their mood and their biophysical parameters, compared to those who will experience a Guided Imagery (GI) intervention. METHODS: This was a randomized crossover trial with 50 cancer patients on active chemotherapy treatment, who were randomized to one of two treatment sequences VR-GI or GI-VR. Patients were assessed for Mood Changes, using POMS questionnaire, for three symptoms (Nausea, Pain and Feeling Sick), using three questions from FACT-G questionnaire, and Bio-physical parameters (Blood Pressure, Heart Rate, Oxygen Saturation). Linear Mixed Effect Models were used for the statistical analysis. RESULTS: Patients experienced a better effect of mood state, for all the sub-scales of mood, after the VR intervention compared to GI, regardless of the sequence (p < 0⋅05). No effectiveness was found for Nausea, Pain and Feeling Sick symptoms. Statistically significant improvements were found on the Bio-physical parameters for the VR intervention (p < 0⋅05). CONCLUSION: VR intervention based on mood induction strategies is a feasible and effective procedure for promoting positive mood in cancer patients during chemotherapy. Ways to integrate such innovative technologies in clinical practice need to be explored by health care professionals. TRIAL REGISTRATION NUMBER: NCT02392728.

A randomised controlled feasibility trial to evaluate Lawsonia inermis (henna)'s effect on palmar-plantar erythrodysesthesia induced by capecitabine or pegylated liposomal doxorubicin.

PURPOSE: To test the effectiveness of henna in the management of palmar-plantar erythrodysesthesia (PPE) in patients receiving treatment with capecitabine or pegylated liposomal doxorubicin (PLD). METHOD: This was a randomized controlled feasibility study in three specialized tertiary cancer centers with 56 patients with a PPE grade 1 or above and various cancer diagnoses. The intervention included the local application of henna to the affected areas. The control group followed the same process with a henna inert. Primary outcome was PPE grade and secondary outcomes were the EORTC QLQ-C30, PPE-related QoL (HFS-14), activities of daily living (ECOG) and pain. Patients in both groups were assessed at baseline and then weekly at four follow-ups. RESULTS: PPE grade in the intervention group (1-3.8%) was lower compared to the control group (4-13.38%) and also lower levels of pain were reported by the patients in the intervention group (2.46 ± 1.17) compared to the control (5.57 ± 2.01). ECOG status in the intervention group was improved compared to the control (p = 0.039). The intervention group, experienced higher Global Health Status (p ≤ 0.008), Physical function (p ≤ 0.001), Emotional Function (p = 0.029), Social function (p ≤ 0.001) and lower Fatigue (p ≤ 0.001) and Pain (p ≤ 0.001) compared to the Control group. A statistically significant interaction was found between Group and Time over the weekly measurements of HFS-14 scores (F = 5,009, p ≤ 0.002) indicating the significant effect of the intervention throughout the weekly assessments. CONCLUSION: The trial provided preliminary evidence on henna's effectiveness for treating PPE during treatment with capecitabine or PLD, with lower PPE grades, better performance status and better HRQoL observed in the henna group. CLINICALTRIALS. GOV IDENTIFIER: NCT01751893.

A pilot randomized double-blind, placebo-controlled study on the effects of the topical application of pyridoxine on palmar-plantar erythrodysesthesia (PPE) induced by capecitabine or pegylated liposomal doxorubicin (PLD).

PURPOSE: Palmar-Plantar Erythrodysesthesia (PPE) is a dose-limiting adverse event that commonly occurs with capecitabine and Pegylated Liposomal Doxorubicin-PLD treatment. The study aimed to test the effectiveness of a Pyridoxine (B6) treatment protocol in the management of PPE in patients receiving treatment with capecitabine or pegylated liposomal doxorubicin. METHODS: This was a pilot randomized double-blind, placebo-controlled study. Patients receiving capecitabine or pegylated liposomal doxorubicin with PPE grade 1 or above were randomly allocated to receive pyridoxine or placebo. The PPE grade, Quality of Life-QoL, Pain and patients' activities of daily living were assessed. RESULTS: Thirty patients were assigned in the Control and 24 in the Intervention group. No statistically significant difference was found in the PPE grade between baseline and week 6 in the 2 groups (p = 0.263). The control group exhibited worst PPE-associated QoL and higher PAIN levels between baseline and week 6. Respectively, the intervention group showed improved PPE-associated QoL and lower PAIN levels. At week 6, the ECOG status in the Intervention group was improved compared to the control (p = 0.018). Patients in the Intervention group experienced better Global Health Status (p = 0.012), Physical (p = 0.003), Emotional (p = 0.008), and Social function (p < 0.001), lower Fatigue (p = 0.001) and Pain (p = 0.006) compared to Control. CONCLUSION: Topical pyridoxine was not shown to have an effect on the treatment of PPE. However, results demonstrated its effectiveness on health related QoL, QoL-associated with PPE and pain levels. Due to the high attrition rate further validation of these results in a larger population is warranted. CLINICALTRIALS. GOV IDENTIFIER: NCT02625415.

Initial experience with neoadjuvant FOLFIRINOX as first line therapy for locally advanced pancreatic cancer.

The prevalence of pancreatic ductal adenocarcinoma (PDAC) is increasing in the western world, being currently on of the leading causes of mortality. Surgical resection provides best chances of cure but, unfortunately, less than 20% of the patients are eligible for curative intent surgery at the time of diagnosis. Chemotherapeutic agents such as FOLFIRINOX have been used in patients with metastatic or locally advanced disease showing survival benefit. METHODS: In this pilot study, we present an early initial experience with neoadjuvant FOLFIRINOX as first line therapy for locally advanced and non resectable PDAC highlighting the toxicity and complete resection rates as well as overall survival. RESULTS: Roughly every patient experienced toxicity according to ECOG criteria with a median recorded event up to 6, most of them grade I and grade II. One third of the patients had downsizing of tumor, however only 43.3% of them ended up having resectable disease. A R0 resection was achieved in 10 of the patients (76.9%). Median follow up for the entire study was 14 months. Fourteen patients (46.6%) had stable disease and 7 (23.3%) had tumor-related death. Approximately 30% of the patients were in remission by the end of follow up. Considering the above results patients that had good response to FOLFIRINOX and underwent R0 surgical treatment had increased their median survival to 30 months compared to those who did not have oncological tumor resection (13 months). CONCLUSIONS: FOLFIRINOX is an effective treatment regimen that manages to convert unresectable -at diagnosis PDAC- to resectable with increased survival. However, due to high toxicity, treatment is only feasible in selected patients and requires close monitoring.

Pharmacogenomic Testing to Guide Personalized Cancer Medicine Decisions in Private Oncology Practice: A Case Study.

Innovative tumor profiling methodologies are utilized to elucidate the pharmacogenomic landscape of tumor cells in order to support the molecularly guided delivery of therapeutics. Indeed, improved clinical outcomes are achieved in oncology practice by providing the physicians with expert-guided, standardized, and easily interpretable knowledge, translated from molecular profiling analysis to support clinical decision-making. However, there is still limited utilization of the technology especially in small private oncology practices. In this work, we analyzed how molecularly guided interventions in 17 consented cancer patients led to an overall improvement of disease response rates in a private oncology center. The precision medicine strategy was based on the OncoDEEP™ profiling solutions and focused on finding clinically actionable relationships between tumor biomarkers and drug responses. The obtained data support the notion that (a) following the pharmacogenomic-derived recommendations favorably impacted cancer therapy progression, and (b) the earlier profiling followed by the delivery of molecularly targeted therapy led to more durable and improved pharmacological response rates. Moreover, we report the example of a patient with metastatic gastric adenocarcinoma who, based on the molecular profiling data, received an off-label therapy that resulted in a complete response and a current cancer-free maintenance status. Overall, our data provide a paradigm on how molecular tumor profiling can improve decision-making in the routine private oncology practice.

Diagnosis and management of isolated pituitary metastasis from adenocarcinoma of unknown origin presenting as loss of libido.

Pituitary gland metastasis from primary tumours is uncommon on its own. Rarely, some of these primary tumours may be of unknown origin. This metastasis to the pituitary gland could manifest as diabetes insipidus, cranial nerve palsies, headaches, fatigue and other symptoms. In rare cases, it could present as loss of libido. We describe here this rare presentation, loss of libido, examine the diagnosis and management undertaken, and provide a systematic review of the literature for similar cases.

Preoperative detection and management of immune heparin-induced thrombocytopenia in patients undergoing heart surgery with iloprost.

OBJECTIVE: The objective of this study was to evaluate our protocol for the identification and management of patients with immune heparin-induced thrombocytopenia undergoing cardiac surgery. METHODS: Among 1518 patients who underwent cardiac surgery between June 1998 and May 2001, 32 (2.1%) presented with platelet counts less than 150,000/mm3 preoperatively or a history of prolonged (>3 days) intravenous exposure to heparin or both. These 32 patients were evaluated with an enzyme-linked immunosorbent assay for antibodies against heparin-platelet factor 4 complex. Platelets of patients with detected antibodies were tested with the prostacyclin analog iloprost for inhibition of heparin aggregation and determination of the inhibiting concentration and corresponding intravenous infusion rate of iloprost. Patients with antibodies received heparin after complete platelet inhibition with iloprost infusion. Hypotension was prevented or treated with intravenous noradrenaline. Ten randomly selected patients with similar preoperative characteristics, no previous extended exposure to heparin, and normal platelet counts served as controls. RESULTS: Ten of the 32 patients (group A, 31.3%) and none of the controls had antibodies against heparin-platelet factor 4 complex. Patients in group A underwent surgery with iloprost (6-24 ng.kg(-1).min(-1)) and had their blood pressure maintained at greater than 95 mm Hg with norepinephrine infusion (1-4 microg.kg(-1).min(-1)). Operative mortality was zero. There were no thrombotic complications or bleeding requiring exploration. One patient in group A bled 1310 mL/6 hours but did not need exploration. There was no difference in postoperative blood loss and morbidity between groups. Platelet counts were reduced by 12.5% +/- 8.7% (group A) and 38.1% +/- 15.2% (control) (P <.001) 1 hour postoperatively and reached preoperative values by the fifth postoperative day. CONCLUSIONS: Immune heparin-induced thrombocytopenia can be detected preoperatively among patients with a low platelet count or a history of prolonged heparin exposure or both. Cardiac surgery can be safely undertaken using iloprost-induced platelet inhibition during heparinization.

A prospective, double-blind study on the efficacy of the bioline surface-heparinized extracorporeal perfusion circuit.

BACKGROUND: We evaluated the newly introduced Bioline heparin coating and tested the hypothesis that surface heparinization limited to the oxygenator and the arterial filter will ameliorate systemic inflammation and preserve platelets during cardiopulmonary bypass (CPB). METHODS: In a prospective double-blind study, 159 patients underwent coronary revascularization using closed-system CPB with systemic heparinization, mild hypothermia (33 degrees C), a hollow-fiber oxygenator, and an arterial filter. The patients were randomly divided in three groups. In group A (controls, n = 51), surface heparinization was not used. In group B (n = 52), the extracorporeal circuits were totally surface-heparinized with Bioline coating. In group C (n = 56), surface heparinization was limited to oxygenator and arterial filter. RESULTS: No significant difference was noted in patient characteristics and operative data between groups. Operative (30-day) mortality was zero. Platelet counts dropped by 12.3% of pre-CPB value among controls at 15 minutes of CPB, but were preserved in groups B and C throughout perfusion (p = 0.0127). Platelet factor 4, plasmin-antiplasmin levels, and tumor necrosis factor-alpha increased more in controls during CPB than in groups B or C (p = 0.0443, p = 0.0238 and p = 0.0154 respectively). Beta-thromboglobulin, fibrinopeptide-A, prothrombin fragments 1 + 2, factor XIIa levels, bleeding times, blood loss, and transfusion requirements were similar between groups. Intensive care unit stay was shorter in groups B and C than in controls (p = 0.037). CONCLUSIONS: Surface heparinization with Bioline coating preserves platelets, ameliorates the inflammatory response and is associated with a reduced fibrinolytic activity during CPB. Surface heparinization limited to the oxygenator and the arterial filter had similar results as totally surface-heparinized circuits.

Neutrophil depletion reduces myocardial reperfusion morbidity.

BACKGROUND: We tested the hypothesis that depletion of neutrophil leukocytes from the cardioplegic and the initial myocardial reperfusion perfusates reduces clinical indices of reperfusion injury in patients undergoing elective coronary artery bypass. METHODS: We studied 160 consecutive patients who underwent standard coronary revascularization with cardiopulmonary bypass. Patients with recent myocardial infarction or coronary angioplasty were excluded. Cold blood cardioplegia was used. Just before aortic unclamping, the hearts were perfused retrograde with 250 mL of normothermic cardioplegic solution and 750 mL of blood (pump perfusate). Patients were randomly assigned to two groups. In 80 patients (treated), neutrophils and platelets were removed from all cardiac perfusate during aortic crossclamping with leukocyte filtration. In the remaining 80 patients (control group), leukocyte filtration was not used. RESULTS: There was no significant difference between groups in age, sex, severity of disease, and number of bypass grafts implanted. Treated patients showed lower prevalence of low cardiac index and reperfusion ventricular fibrillation and lower levels of creatinine kinase MB isoenzyme and troponin I early postoperatively (p < 0.05). CONCLUSIONS: Neutrophil-filtered blood cardioplegia/reperfusion significantly reduced clinical and biochemical indices of myocardial reperfusion injury after elective coronary revascularization with cardiopulmonary bypass.

Clinical effectiveness of leukocyte filtration during cardiopulmonary bypass in patients with chronic obstructive pulmonary disease.

BACKGROUND: We tested the hypothesis that leukocyte filtration during pulmonary reperfusion preserves pulmonary function and results in improved oxygenation after cardiopulmonary bypass (CPB) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In a prospective, randomized study, the treatment group consisted of 20 patients with COPD from consecutive open-heart procedures. A primed leukocyte filter was connected to the arterial line downstream of the standard arterial filter but was excluded from circulation. Circulated blood was directed through the leukocyte filter approximately 10 minutes before aortic cross-clamp removal and at early reperfusion for up to 30 minutes. These patients were compared to 20 additional COPD patients (controls) on whom systemic leukocyte filtration was not used during open-heart surgery. RESULTS: There was no significant difference in gender, age, left ventricular ejection fraction, type of procedure, aortic cross-clamp time, perfusion time, preoperative FEV1 and preoperative respiratory index (Pao2/FiO2 ratio) between treatment and control groups. The respiratory index changed in the treatment group by +9.8% of baseline after completion of CPB, by -14.2% upon arrival in the intensive care unit (ICU), and by -19.6% 12 hours later, whereas in the control group, it changed by -14.5% (p < 0.05), -27.7%, and -24%, respectively. Leukocyte-depleted patients required shorter intubation time (20.4 +/- 16.1 hours), ICU stay (46.2 +/- 40.1 hours) and length of hospitalization (8.3 +/- 2.8 days) than controls (29.5 +/- 21.9 hours, p < 0.05; 75.5 +/- 34.9 hours, p < 0.005; and 10.4 +/- 3.5 days, p < 0.05, respectively). Surgical (30-day) mortality was zero in both groups. CONCLUSIONS: In COPD patients having CPB, systemic leukocyte depletion at early reperfusion was associated with better oxygenation, shorter intubation time, and shorter ICU and hospital stays. Leukocyte filtration during CPB most likely preserves pulmonary function by ameliorating pulmonary reperfusion injury.