Long-term efficacy of neoadjuvant-adjuvant targeted therapy in borderline resectable stage IIIB-D and IV melanoma.

BACKGROUND: Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. METHODS: Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. RESULTS: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p = .005) for RFS and HR = 0.33 (p = .002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR = 0.45; p = .022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. CONCLUSIONS: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. PLAIN LANGUAGE SUMMARY: Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.

Microencapsulation of Juniper and Black Pepper Essential Oil Using the Coacervation Method and Its Properties after Freeze-Drying.

Essential oils are mixtures of chemical compounds that are very susceptible to the effects of the external environment. Hence, more attention has been drawn to their preservation methods. The aim of the study was to test the possibility of using the classical model of complex coacervation for the microencapsulation of essential oils. Black pepper (Piper nigrum) and juniper (Juniperus communis) essential oils were dissolved in grape seed (GSO) and soybean (SBO) oil to minimize their loss during the process, and formed the core material. Various mixing ratios of polymers (gelatin (G), gum Arabic (GA)) were tested: 1:1; 1:2, and 2:1. The oil content was 10%, and the essential oil content was 1%. The prepared coacervates were lyophilized and then screened to obtain a powder. The following analyses were determined: encapsulation efficiency (EE), Carr index (CI), Hausner ratio (HR), solubility, hygroscopicity, moisture content, and particle size. The highest encapsulation efficiency achieved was within the range of 64.09-59.89%. The mixing ratio G/GA = 2:1 allowed us to obtain powders that were characterized by the lowest solubility (6.55-11.20%). The smallest particle sizes, which did not exceed 6 µm, characterized the powders obtained by mixing G/GA = 1:1. All powder samples were characterized by high cohesiveness and thus poor or very poor flow (CI = 30.58-50.27, HR = 1.45-2.01).

Cannabidiol affects breast meat volatile compounds in chickens subjected to different infection models.

No study has demonstrated the use of dietary Cannabis-derived cannabidiol (CBD) to alter the stress response in chickens or examined its effects on meat volatile compounds (VOCs). Here, we subjected chickens to dysbiosis via C. perfringens infection or Escherichia coli lipopolysaccharide (LPS) treatment and investigated the potential link between meat VOCs and cecal bacterial activity and the ameliorative effect of CBD. The cecal bacterial production of short-chain fatty acids (SCFAs) was closely correlated with meat VOCs. CBD supplementation reduced the formation of breast meat spoilage VOCs, including alcohols, trimethylamine and pentanoic acid, in the challenged birds, partly by decreasing cecal putrefactive SCFA production. Meat VOC/cecal SCFA relationships differed according to the challenge, and CBD attenuated the effects of C. perfringens infection better than the effects of LPS challenge on meat VOCs. These findings provide new insights into the interactions among bioactive agent supplementation, gut microbiota activity and meat properties in birds.

Green Technology for Pork Loin Wet Curing-Unconventional Use of Cow and Soy Milk Treated with Non-Thermal Atmospheric Plasma.

This study was conducted to evaluate the possibility of using plasma-activated cow and soy milk powders as a substitute for sodium nitrite for wet curing of pork meat (m. longissimus thoracis et lumborum). Pork loin slices were cured for 4 d at refrigerate conditions in four brines: water + salt (NC group), water + salt + sodium nitrite (PC group), water + salt + plasma-activated cow milk powder (B1 group), and water + salt + plasma-activated soy milk powder (B2 group). Importantly, brines from groups PC, B1, and B2 were characterized by the same concentration of NO2− ions (200 ppm). Results show that samples from B1 and B2 groups had significantly (p < 0.05) higher values of redness, nitrosylhemochrome content, and lower values of thiobarbituric acid reactive substances (TBARS) compared to samples from the NC group. At the same time, the groups cured with alternative curing agents were characterized by lower residual nitrite content with regard to groups cured with NaNO2. No significant differences (p ≥ 0.05) were found in pH and shear force values among the treatments. Finally, the aroma profile of the samples from groups B1 and B2 was similar to the aroma profile of the samples from the PC group (the aroma differed by a maximum of 1.73% in the case of brine containing plasma-activated cow milk powder) but differed significantly from the NC group (the aroma differed in 97.21%). Due to the higher nitrite depletion in the final product, while maintaining the quality parameters similar to traditionally cured pork loins, both alternative curing agents can be recommended, with a predominance of plasma-treated soy milk.

The Effect of Partial Substitution of Beef Tallow on Selected Physicochemical Properties, Fatty Acid Profile and PAH Content of Grilled Beef Burgers.

The objective of this study was to analyze the impact of partial replacement of beef tallow with sunflower, canola, linseed, olive oil and milk fat on physical properties, oxidation stability, fatty acid profile and PAHs (polycyclic aromatic hydrocarbons) content of beef burgers. Studies have shown a strong relationship between the fatty acid profile and the PAH content (especially of the heavy PAHs). The partial replacement of beef tallow with oils and milk fat (MF) contributed to a change in the fatty acid profile and a reduction in the hardness of the burgers. The highest PAH content was found in samples with canola oil (CO), which had the highest levels of monounsaturated fatty acids (MUFA), and in the control group (CON) without fat substitution, which had the highest levels of saturated fatty acids (SFA) and trans conformations. Substitution of animal fat with vegetable oils contributed to a change in the color of the burgers' surface, as there was a statistically significant increase in the L* color component and a decrease in the a* component. The burgers with canola oil (CO) and linseed oil (LO) were the most susceptible to oxidation, whereas the burgers with reduced fat content (CON_LOW FAT) were the most stable in terms of oxidation, where the malondialdehyde (MDA) content was 32.8% lower compared with the control group (CON). The studies confirm that partial replacement of beef tallow with vegetable oils and milk fat and reduction in fat content in burgers to be grilled can be an effective way to change their fatty acid profile and reduce the cyclization reaction of organic compounds leading to the formation of PAH. Correlation coefficient analysis showed that there is a relationship between fatty acid profile and the presence of selected PAHs in grilled beef burgers. The results of this study indicate that replacing beef tallow with vegetable oils is a promising approach in designing meat products with controlled PAH content.

Plasma-activated milk powder as a sodium nitrite alternative in pork sausages.

This study investigated the effect of plasma activated milk powder containing 1.3 g/kg nitrite as an alternative to sodium nitrite in stored pork sausages. Control samples (NC) did not contain a nitrite source, while the recipes of other treatments contained 100 ppm sodium nitrite (PC), 5% plasma activated milk powder (PAMP), and 5% plasma activated milk powder with 0.05% ascorbic acid (PAMP+AA). The obtained results showed both experimental groups were characterized by higher values of residual nitrite, nitrosylhemochrome and redness as well as similar or lower values of thiobarbituric acid reactive substances and total aerobic plate count compared to PC group after the storage period. Using ascorbic acid promoted reduction of nitrite content and extended the color stability of the samples compared to PAMP group without deteriorating the oxidative and microbiological quality of the product. Finally, sausages cured using the proposed alternative method exhibited higher cooking yield, lighter color, better texture, and different aroma profile (PCA) than those with sodium nitrite.

Application of atmospheric pressure cold plasma activated plant protein preparations solutions as an alternative curing method for pork sausages.

This study was performed to determine the effect of plasma-activated solutions of protein preparations of selected plants, as an alternative nitrite source, on the quality characteristics of pork sausages. The used solutions contained 500 ppm nitrite. Sausages without nitrite (NC), with 75 ppm sodium nitrite (PC), and with solutions of soy (E1), pea (E2) and lentil (E3) preparations (100 g/kg of meat ingredients) were manufactured and stored for 8 days. The results showed that after processing sausages from E1, E2 and E3 groups showed similar nitrite content as PC group (20.69-21.89 mg nitrite/kg; P ≥ 0.05). Performed analyses (residual nitrite, nitrosylhemochrome content, a* values, thiobarbituric acid reactive substances, total aerobic plate count) suggested also that addition of nitrite through solutions of soy and pea plasma-activated preparations extended the shelf life of sausages comparable to sodium nitrite without a negative effect on aroma (PCA), as was reported for some other sources of nitrite.

Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism.

Secreted extracellular vesicles (EVs) influence the tumor microenvironment and promote distal metastasis. Here, we analyzed the involvement of melanoma-secreted EVs in lymph node pre-metastatic niche formation in murine models. We found that small EVs (sEVs) derived from metastatic melanoma cell lines were enriched in nerve growth factor receptor (NGFR, p75NTR), spread through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Remarkably, sEVs enhanced lymphangiogenesis and tumor cell adhesion by inducing ERK kinase, nuclear factor (NF)-κB activation and intracellular adhesion molecule (ICAM)-1 expression in lymphatic endothelial cells. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased lymph node metastasis and extended survival in pre-clinical models. Furthermore, NGFR expression was augmented in human lymph node metastases relative to that in matched primary tumors, and the frequency of NGFR+ metastatic melanoma cells in lymph nodes correlated with patient survival. In summary, we found that NGFR is secreted in melanoma-derived sEVs, reinforcing lymph node pre-metastatic niche formation and metastasis.

Combined Preoperative Hypofractionated Radiotherapy With Doxorubicin-Ifosfamide Chemotherapy in Marginally Resectable Soft Tissue Sarcomas: Results of a Phase 2 Clinical Trial.

PURPOSE: There is no standard treatment for marginally resectable soft tissue sarcomas (STSs) of the extremities and trunk wall, and current approaches produce unsatisfactory results. We hypothesized that the combination of doxorubicin-ifosfamide (AI) chemotherapy and 5 × 5 Gy hypofractionated radiotherapy can generate a higher ratio of limb-sparing or conservative surgeries with negative microscopic margins (R0) and acceptable treatment toxicity. METHODS AND MATERIALS: We conducted a single-arm prospective clinical trial. Treatment combined 1 cycle of AI with subsequent 5 × 5 Gy radiotherapy within 1 week, followed by 2 cycles of AI and surgery. The primary endpoint was to assess the number of patients in whom en bloc R0 resection was achieved. RESULTS: Forty-six patients met the eligibility criteria. Three patients had resectable lung metastases at baseline. Forty-two received the planned protocol treatment. In 2 patients, the treatment was prematurely stopped because of the toxicity of chemotherapy. One patient died of septic shock because of severe bone marrow suppression after the second AI cycle; a second death was not related to treatment for STS. Three patients underwent amputation. In 72% of patients in the intention-to-treat analysis, we achieved en bloc R0 resections. Grade 3+ Common Terminology Criteria for Adverse Events 4.03 chemotherapy toxicity requiring dose reduction or treatment interruption occurred in 15 patients. Wound complications occurred in 18 patients, but they were severe in only 6 patients. CONCLUSIONS: Preoperative AI combined with 5 × 5 Gy radiotherapy is a promising method for the management of marginally resectable STS. This protocol enables a high ratio of R0 limb-sparing or conservative surgeries. Further evaluation of this strategy is warranted.

Influence of Plant Extract Addition to Marinades on Polycyclic Aromatic Hydrocarbon Formation in Grilled Pork Meat.

Marinating is one of the most common methods of pre-processing meat. Appropriate selection of marinade ingredients can influence the physicochemical properties of the meat and can reduce the level of polycyclic aromatic hydrocarbons (PAHs) in the final product. The effects of the inclusion of natural plant extracts such as bay leaf (BL), black pepper (BP), turmeric (TU), jalapeno pepper (JP) and tamarind paste (TA) in marinades on the physicochemical properties of grilled pork neck were studied. The addition of spice extracts to marinades increased the proportion of colour components L* and b*. The use of TU, TA, JP, MX and C marinades lowered the hardness and pH of the meat. The highest phenolic compound levels were observed in the case of the mixture of all extracts (MX) and JP marinades, and the highest total antioxidant capacity was exhibited by the BL and MX marinades. The highest PAH content was recorded in the CON marinade (Σ12PAH 98.48 ± 0.81 µg/kg) and the lowest in the JP marinade (4.76 ± 0.08 µg/kg), which had the strongest, statistically significant reducing effect (95% reduction) on PAH levels. Analysis of correlation coefficients showed a relationship between the total antioxidant capacity of the marinades and the PAH content in grilled pork.

Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma.

Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.

Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and BRAF V600E mutation.

Liquid biopsies from cancer patients have the potential to improve diagnosis and prognosis. The assessment of surrogate markers of tumor progression in circulating extracellular vesicles could be a powerful non-invasive approach in this setting. We have characterized extracellular vesicles purified from the lymphatic drainage also known as exudative seroma (ES) of stage III melanoma patients obtained after lymphadenectomy. Proteomic analysis showed that seroma-derived exosomes are enriched in proteins resembling melanoma progression. In addition, we found that the BRAFV600E mutation can be detected in ES-derived extracellular vesicles and its detection correlated with patients at risk of relapse.

The sensory quality of allergen-controlled, fat-reduced, salt-reduced pork-ostrich sausages during storage.

BACKGROUND: New meat products tailored to consumer health should be characterised by reduced sodium, fat and cholesterol contents and other health-promoting benefits. However, the food sector's greatest challenge is allergen-free production. Consumers are not willing to compromise the sensory quality of meat products for health. The aim of the present study was to analyse the influence of the storage time on the physical properties and consumer acceptance of allergen-controlled, fat-reduced, salt-reduced pork-ostrich sausages. The study focused on pork-ostrich sausages produced in accordance with a new patented technology, which focused on eliminating cross-contamination on-line in the plant, eliminating cross-contamination after preparation, and eliminating spices with high allergy potential. The production was focused on reducing fat (by approximately 50%) and salt (by approximately 30%) levels. RESULTS: No changes in the texture parameters of the sausage were observed during storage time; however, some changes in colour were observed. There were no significant differences in sensory consumer acceptability of pork-ostrich sausage after 14 days of storage; thus, it may be stated that the instrumentally assessed differences in colour did not influence consumer acceptance. CONCLUSION: The applied fat and NaCl reduction in the pork-ostrich sausages contributed to high consumer ratings and was not correlated with saltiness acceptability. © 2017 Society of Chemical Industry.

The synthesis, mass spectrometric properties and identification of some N,N-di-(ß-arylisopropyl)formamides related to the synthesis of ring-modified amphetamines.

This study examines the electron impact (EI) induced mass spectrometric behavior of several N,N-di-(ß-arylisopropyl)formamides, which are connected to the Leuckart synthesis of some amphetamine analogues. Emphasis is laid on the fragmentation paths, which are common for all compounds under investigation and may be used in construction of the prediction scheme useful for identification of similar impurities, especially in absence of desirable authentic material. On the basis of this scheme several new N,N-di-(ß-arylisopropyl)formamides have been identified in selected amphetamine analogues synthesized by the Leuckart method, including 4-methylthioamphetamine (4-MTA), 4-fluoroamphetamine (4-FA), 4-methylamphetamine, 3-trifluoromethylamphetamine, 3,4-methylenedioxyamphetamine (MDA), 2,5-dimethoxyamphetamine (2,5-DMA), 2,4,5- and 3,4,5-trimethoxyamphetamines (2-TMA and 3-TMA).