Long-Term Survival of Dental Implants in Irradiated Patients.

The surgical ablation of head and neck cancer followed by radiotherapy often leads to unfavorable functional and aesthetic outcomes. Studies have demonstrated that these outcomes can significantly impact quality of life. Dental implants play a crucial role in rehabilitation by facilitating the use of suprastructures and obturators. However, the long-term survival of dental implants in patients who have undergone radiotherapy remains uncertain, raising several questions. These include determining the optimal timing for dental implantation (before or after radiotherapy), identifying the radiotherapy threshold for implant loss, and considering the role of hyperbaric oxygen therapy. These and other related concerns will be addressed in the following article.

Improved nasal trumpet: "In-house" device to promote the healing of skin grafts in the anterior nasal nostril.

This technical note addresses the complexities of reconstructive surgery for malignant skin lesions in the lower nasal aperture and pericolumellar region. Traditional solutions, such as free skin grafts, face challenges in maintaining attachment to the surgical site without adequate support. Nasal packing, a common approach, obstructs the nasal opening and compromises air passage, hindering ventilation. The use of a nasal trumpet has proven beneficial in maintaining nasal patency in various cases, but it falls short of addressing the specific challenges posed by reconstructive surgery. The proposed solution involves a novel device comprising a nasal cannula, surgical sponge, and fine mesh gauze with 3% bismuth tribromophenate. This combination serves a triple purpose: the nasal cannula facilitates air passage, the surgical sponge applies controlled pressure around the nasal opening to aid graft adhesion, and the gauze with bismuth tribromophenate promotes wound healing and prevents infection. The assembled device is inserted into the nostril, anchored to the patient's skin with silk stitches. This innovative approach offers a practical solution for maintaining nasal patency, promoting graft adherence, and supporting wound healing in reconstructive surgery.

Long-Term Outcomes Following Definitive or Adjuvant Proton Radiotherapy for Adenoid Cystic Carcinoma.

Purpose: Adenoid cystic carcinoma (ACC) is a rare malignancy accounting for 1% of all head and neck cancers. Treatment for ACC has its challenges and risks, yet few outcomes studies exist. We present long-term outcomes of patients with ACC of the head and neck treated with proton therapy (PT). Materials and Methods: Under an institutional review board-approved, single-institutional prospective outcomes registry, we reviewed the records of 56 patients with de novo, nonmetastatic ACC of the head and neck treated with PT with definitive (n = 9) or adjuvant PT (n = 47) from June 2007 to December 2021. The median dose to the primary site was 72.6 gray relative biological equivalent (range, 64-74.4) delivered as either once (n = 19) or twice (n = 37) daily treatments. Thirty patients received concurrent chemotherapy. Thirty-one patients received nodal radiation, 30 electively and 1 for nodal involvement. Results: With a median follow-up of 6.2 years (range, 0.9-14.7), the 5-year local-regional control (LRC), disease-free survival, cause-specific survival, and overall survival rates were 88%, 85%, 89%, and 89%, respectively. Intracranial extension (P = .003) and gross residual tumor (P = .0388) were factors associated with LRC rates. While the LRC rate for those with a gross total resection was 96%, those with subtotal resection or biopsy alone were 81% and 76%, respectively. The 5-year cumulative incidence of clinically significant grade ≥3 toxicity was 15%, and the crude incidence at the most recent follow-up was 23% (n = 13). Conclusion: This is the largest sample size with the longest median follow-up to date of patients with ACC treated with PT. PT can provide excellent disease control for ACC of the head and neck with acceptable toxicity. T4 disease, intracranial involvement, and gross residual disease at the time of PT following either biopsy or subtotal resection were significant prognostic features for worse outcomes.

Can the Malnutrition Universal Screening Tool (MUST) Predict Healing Complications Following Microvascular Reconstruction of the Head and Neck?

Study Design: Retrospective cohort study. Objective: Malnutrition has been found to have negative effects on the immune system and inflammatory responses, impairing the wound healing process. Free flap failure is a serious complication in patients undergoing microvascular reconstruction, as it increases patient morbidity, length of stay in the hospital, patient, and hospital costs, as well as causes the need for further surgical interventions1. Malnutrition is estimated to be present in 35-50% of head and neck cancer patients with higher rates in those experiencing hypo-oropharyngeal disease. This is often caused by functional and pain limitations from due to disease burden causing odynophagia and dysphagia. The Malnutrition Universal Screening Tool (MUST) is recommended for risk screening and provides three scores for risk classification: high, intermediate, and low2. We argue that the use of MUST as a preoperative assessment tool is useful to predict postoperative surgical site infection and delayed wound healing in patients that will undergo reconstruction with free flaps for head and neck defects. Methods: A retrospective cohort study was designed to include all subjects who underwent head and neck microvascular free tissue transfer at a single institution between 2013 and 2019. Primary and secondary reconstructions were included, for benign or malignant pathology, osteonecrosis, osteomyelitis, congenital defects, and trauma. The nutritional risk was evaluated using MUST, which analyzes body mass index, weight loss, and acute disease effect, to classify patients as low, intermediate, and high risk. We further divided the subjects into two comparison groups- low-intermediate and high risk. The primary outcome was surgical site complications and delayed wound healing. Data was analyzed as frequencies and means with standard deviations, as well as Fisher's exact test and t-test. P-values <0.05 were considered statistically significant. Analyses were done utilizing IBM SPSS Statistics Version 29. Results: 131 subjects were included for data analysis, with 54 being considered low MUST risk, 12 intermediate risk (66 low-intermediate), and 65 were high risk. The mean BMI overall was 25.5 ±5.3, and 27.2 in the low-intermediate group, and 23.7 in the high-risk group. Eighty-two subjects experienced <5-pound weight loss in the preceding 6 months to surgery, while 17 lost between 5-10 pounds, and 23 lost 10< pounds. Cancer/osteonecrosis was the etiology for 54 (82%) subjects of the low-intermediate group, and 61 (92%) of the high-risk group (P = .089). The subjects classified in High-risk group according to the MUST score had 11% more surgical site complications (P = .120) and 13.7% more delayed wound healing and dehiscence(P = .09); only 3 subjects in the study presented total flap loss and they were all in the High-risk group. Surgical site complication, delayed wound healing rates and partial or total flap loss were not increased by any specific medical comorbidity or history such as radiation or chemotherapy. Conclusions: In conclusion, Subjects with high MUST score had increased complications and poor wound healing, and subjects with acute disease effect that induces a phase of nil per os for > 5 day have higher risk of total flap loss and surgical site complication.

Comparison of the outcomes of split thickness skin graft versus thickness skin graft for closure of the radial forearm free flap donor site: A systematic review.

BACKGROUND: Radial forearm free flap (RFFF) donor site closure is traditionally performed with split thickness skin grafts (STSG), which can be associated with poor aesthetics, wrist stiffness, paresthesia, reduced strength, and tendon exposure. Full thickness skin grafts (FTSG) are potentially beneficial as they provide a more durable coverage, and the skin graft donor site can be closed primarily, which is more aesthetic. The aim of this systematic review is to compare the outcomes of STSG versus FTSG for closure of the RFFF donor site. METHODS: A systematic review was performed, following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The primary objective was to answer: do subjects undergoing RFFF harvest, utilizing FTSG to close the RFFF donor site, compared to STSG, achieve superior aesthetics at the RFFF donor site? Included papers compared FTSG and STSG with statistical data. Means were compared with t-test and proportions with Fisher's exact test. RESULTS: The initial search resulted in 1851 studies. After applying the inclusion/exclusion criteria, the search resulted in eight studies, with 366 total skin grafts, 197 STSG and 169 FTSG. Six studies evaluated aesthetics utilizing a Likert scale, with the scaled average aesthetic score for FTSG being 7.9/10 compared to 6.9/10 for STSG (p < .001). Tendon exposure was measured in five studies, with a rate of 13.1% for STSG versus 10.6% for FTSG (p = .555). No significant difference in function was observed, however, methods to quantify function were heterogeneous. CONCLUSION: FTSG compared to STSG, resulted in statistically significant improved aesthetics, with comparable rates of tendon exposure and function.

Association between tonsillectomy and oropharyngeal cancer risk: a retrospective cohort study.

BACKGROUND: The purpose of this retrospective cohort study is to describe the association between the history of tonsillectomy and the risk of oropharyngeal squamous cell carcinoma (OPSSC), using a large cohort of patients. MATERIALS AND METHODS: We performed a retrospective cohort study with 3620 patients diagnosed with OPٍSCC from 2010 to 2021. We utilized the University of Florida patients' registry i2b2 system. Three subsets of OPSSC were defined, base of tongue(BOT) cancer, tonsillar cancer, and other OPSSC. Tumor demographics and history of tonsillectomy were collected. Odds ratio for OPSSC were assessed utilizing a logistic regression model with adjusting for gender, race, and age. P < 0.05 was deemed significant. RESULTS: Of the 3620 OPSSC patients were BOT cancer (N = 964), tonsillar cancer (N = 995), and other OPSSC (N = 1661). There was a statistically significant reduction in tonsillar cancer and BOT cancer odds ratio in patients with a history of tonsillectomy vs. patients without tonsillectomy (0.086 and 0.117), respectively, with a P value < .0001. The odds ratio of OPSSC in patients with a history of tonsillectomy vs. patients without tonsillectomy is 1.031. CONCLUSION: This study showed that the OPSSC and previous history of tonsillectomy are associated. Our results showed a significant reduction in BOT and tonsillar cancer risk in patients with a history of tonsillectomy and an insignificant decrease in other OPSSC. This study could emphasize the importance of the development of future clinical trials to investigate the role of prophylactic tonsillectomy as a secondary preventive strategy to reduce OPSSC.

Mathematical Modeling of Vessel Geometry and Circumference in Microvascular Surgery.

Introduction: Microvascular anastomosis has traditionally been executed with a perpendicular transection through the vessel at the widest diameter to increase circumference and thus increase blood flow while decreasing resistance. In Chen's 2015 article, it was suggested that an "open Y" would improve vessel size match, and Wei and Mardini discuss angled transections of the vessels. This project aims to explore the geometric configurations feasible at the anastomotic transection and mathematically model the resulting hypothetical increases in circumference. Materials and Methods: The mathematical models were theoretically developed by our team. The formulas model increases in circumference of the transection at different distances in relation to the bifurcation of a blood vessel, as well as changes in circumference at different transection angulations. An in vitro exploration as to the anastomotic feasibility of each geometric cut was completed on ten poultry tissue specimens. Results: The mathematical models demonstrated the change in vessel circumference, with multiple geometric designs calculated, best shown through diagrams. For example, if the vessel width is 1 mm, the distance from the increasing vessel diameter to the final bifurcation is 1 mm, and the bifurcation angle is 45°, the circumference of the transected vessel increases by 82.8%. Models of transections at different angulations, for instance 30°, 45°, and 60°, yield an increase in elliptical circumference of 8.0%, 22.5%, and 58.1%, respectively. Additional derivations calculate the elliptical circumference at any angle in a single vessel, and at any angle in a bifurcating vessel. Conclusion: The theoretical and clinical aim of this project is to increase awareness of the anastomotic creativity and mathematically demonstrate the optimal anastomotic geometry, which has not been objectively explored to our knowledge. An in vivo study would further support clinical improvements, with the aim to map postoperative fluid dynamics through the geometric anastomoses.

Exosomes modified with anti-MEK1 siRNA lead to an effective silencing of triple negative breast cancer cells.

Triple negative breast cancer (TNBC) is a highly heterogenous disease not sensitive to endocrine or HER2 therapy and standardized treatment regimens are still missing. Therefore, development of novel TNBC treatment approaches is of utmost relevance. Herein, the potential of MAPK/ERK downregulation by RNAi-based therapeutics in a panel of mesenchymal stem-like TNBC cell lines was uncovered. Our data revealed that suppression of one of the central nodes of this signaling pathway, MEK1, affects proliferation, migration, and invasion of TNBC cells, that may be explained by the reversion of the epithelial-mesenchymal transition phenotype, which is facilitated by the MMP-2/MMP-9 downregulation. Moreover, an exosome-based system was successfully generated for the siRNA loading (iExoMEK1). Our data suggested absence of modification of the physical properties and general integrity of the iExoMEK1 comparatively to the unmodified counterparts. Such exosome-mediated downregulation of MEK1 led to a tumor regression accompanied by a decrease of angiogenesis using the chick chorioallantoic-membrane model. Our results highlight the potential of the targeting of MAPK/ERK cascade as a promising therapeutic approach against TNBC.

Eosinophilic Variant of Granulomatosis With Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a multisystemic necrotizing vasculitis with a special tropism to the respiratory tract and the kidneys. Although uncommon, GPA may be associated with hypereosinophilia and limited organ involvement. In these cases, American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria may be insufficient to establish the diagnosis. We described a limited form of GPA, hypereosinophilia, and predominant skin involvement.

Comparative Assessment of Total Versus Hemi Glossectomy Defects Reconstructed With Anterolateral Thigh Free Flap.

BACKGROUND: Free tissue transfers for reconstruction following tongue resection has become standard practice. PURPOSE: This study sought to evaluate volume shrinkage of the anterolateral thigh free (ALTF) reconstructing tongue defects at 6 months postoperative. The aim was to estimate a shrinkage factor for ALTF reconstructing hemi and total glossectomy. STUDY DESIGN, SETTING, SAMPLE: This was an IRB-approved retrospective cohort study conducted at the head and neck service at the University of Florida, College of Medicine, Jacksonville (FL). This study targeted patients with tongue cancer from January 2018 to April 2022. INCLUSION CRITERIA: patients with tongue squamous cell carcinoma (SCC) who were surgically treated by either hemi or total glossectomy and reconstructed with ALTF. Patients had to have a postoperative computer tomography scans at 1 and 6 months post-surgery. Patients with constant body mass index during 6 months postreconstruction. Additionally, the patients were to have been treated with adjuvant radiotherapy. EXCLUSION CRITERIA: patients with recurrent tongue cancer and those who weren't reconstructed or managed with other treatment modalities. PREDICTOR VARIABLE: Type of tongue resection hemi versus total glossectomy for treatment of tongue SCC. MAIN OUTCOME VARIABLE: Shrinkage percentage of ALTF reconstructing tongue defects at 6 months postoperatively. COVARIATES: Age and gender. ANALYSES: Paired t-test and student t-test with level of significance P ≤ .05 were used to statistically analyze ALTF volume changes at 1 and 6 months postoperatively and ALTF shrinkage percentage at 6 months postreconstruction, respectively. RESULTS: We identified 85 patients who were treated for tongue SCC during the time period of study. Out of the 85 patients, 11 patients were reconstructed with an ALTF. Eight males and 3 females with a mean age of 62.3 years old. Six patients had total glossectomy and 5 had hemi glossectomy. Patients with hemi glossectomy had a significant difference in mean average flap shrinkage of 39.6%, while in those with total glossectomy had 17.7% (P = .004). CONCLUSION AND RELEVANCE: According to our results, we recommend that the flap size should be larger than the defect to adjust for volume shrinkage (1.4 times and 1.2 times for cases of hemi and total glossectomy, respectively).

Silver nanoparticles exert toxic effects in human monocytes and macrophages associated with the disruption of Δψm and release of pro-inflammatory cytokines.

Silver nanoparticles (AgNP) are the most widely produced type of nanoparticles due to their antimicrobial and preservative properties. However, their systemic bioavailability may be considered a potential hazard. When AgNP reach the bloodstream, they interact with the immune cells, contributing to the onset and development of an inflammatory response. Monocytes and macrophages play a pivotal role in our defense system, but the interaction of AgNP with these cells is still not clear. Therefore, the main objective of this work was to assess the cytotoxic and pro-inflammatory effects induced by 5, 10, and 50 nm AgNP coated with polyvinylpyrrolidone (PVP) and citrate, in concentrations that could be attained in vivo (0-25 µg/mL), in human monocytes isolated from human blood and human macrophages derived from a monocytic cell line (THP-1). The effects of PVP and citrate-coated AgNP on cell viability, mitochondrial membrane potential, and cytokines release were evaluated. The results evidenced that AgNP exert strong harmful effects in both monocytes and macrophages, through the establishment of a strong pro-inflammatory response that culminates in cell death. The observed effects were dependent on the AgNP concentration, size and coating, being observed more pronounced cytotoxic effects with smaller PVP coated AgNP. The results showed that human monocytes seem to be more sensitive to AgNP exposure than human macrophages. Considering the increased daily use of AgNP, it is imperative to further explore the adverse outcomes and mechanistic pathways leading to AgNP-induced pro-inflammatory effects to deep insight into the molecular mechanism involved in this effect.

Subcellular compartmentalization of aluminum reduced its hazardous impact on rye photosynthesis.

Aluminum (Al) toxicity limits crops growth and production in acidic soils. Compared to roots, less is known about the toxic effects of Al in leaves. Al subcellular compartmentalization is also largely unknown. Using rye (Secale cereale L.) Beira (more tolerant) and RioDeva (more sensitive to Al) genotypes, we evaluated the patterns of Al accumulation in leaf cell organelles and the photosynthetic and metabolic changes to cope with Al toxicity. The tolerant genotype accumulated less Al in all organelles, except the vacuoles. This suggests that Al compartmentalization plays a role in Al tolerance of Beira genotype. PSII efficiency, stomatal conductance, pigment biosynthesis, and photosynthesis metabolism were less affected in the tolerant genotype. In the Calvin cycle, carboxylation was compromised by Al exposure in the tolerant genotype. Other Calvin cycle-related enzymes, phoshoglycerate kinase (PGK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), triose-phosphate isomerase (TPI), and fructose 1,6-bisphosphatase (FBPase) activities decreased in the sensitive line after 48 h of Al exposure. Consequentially, carbohydrate and organic acid metabolism were affected in a genotype-specific manner, where sugar levels increased only in the tolerant genotype. In conclusion, Al transport to the leaf and compartmentalization in the vacuoles tolerant genotype's leaf cells provide complementary mechanisms of Al tolerance, protecting the photosynthetic apparatus and thereby sustaining growth.

Glucose-Functionalized Silver Nanoparticles as a Potential New Therapy Agent Targeting Hormone-Resistant Prostate Cancer cells.

Purpose: Silver nanoparticles (AgNPs) have shown great potential as anticancer agents, namely in therapies' resistant forms of cancer. The progression of prostate cancer (PCa) to resistant forms of the disease (castration-resistant PCa, CRPC) is associated with poor prognosis and life quality, with current limited therapeutic options. CRPC is characterized by a high glucose consumption, which poses as an opportunity to direct AgNPs to these cancer cells. Thus, this study explores the effect of glucose functionalization of AgNPs in PCa and CRPC cell lines (LNCaP, Du-145 and PC-3). Methods: AgNPs were synthesized, further functionalized, and their physical and chemical composition was characterized both in water and in culture medium, through UV-visible spectrum, dynamic light scattering (DLS), transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR). Their effect was assessed in the cell lines regarding AgNPs' entering pathway, cellular proliferation capacity, ROS production, mitochondrial membrane depolarization, cell cycle analysis and apoptosis evaluation. Results: AgNPs displayed an average size of 61nm and moderate monodispersity with a slight increase after functionalization, and a round shape. These characteristics remained stable when redispersed in culture medium. Both AgNPs and G-AgNPs were cytotoxic only to CRPC cells and not to hormone-sensitive ones and their effect was higher after functionalization showing the potential of glucose to favor AgNPs' uptake by cancer cells. Entering through endocytosis and being encapsulated in lysosomes, the NPs increased the ROS, inducing mitochondrial damage, and arresting cell cycle in S Phase, therefore blocking proliferation, and inducing apoptosis. Conclusion: The nanoparticles synthesized in the present study revealed good characteristics and stability for administration to cancer cells. Their uptake through endocytosis leads to promising cytotoxic effects towards CRPC cells, revealing the potential of G-AgNPs as a future therapeutic approach to improve the management of patients with PCa resistant to hormone therapy or metastatic disease.

Active Neutralizing Mats for Corrosive Chemical Storage.

Laboratories and industries that handle chemicals are ubiquitously prone to leakages. These may occur in storage rooms, cabinets or even in temporary locations, such as workbenches and shelves. A relevant number of these chemicals are corrosive, thus commercial products already exist to prevent material damage and injuries. One strategy consists of the use of absorbing mats, where few display neutralizing properties, and even less a controlled neutralization. Nevertheless, to the authors' knowledge, the commercially available neutralizing mats are solely dedicated to neutralizing acid or alkali solutions, never both. Therefore, this work describes the development and proof of a completely novel concept, where a dual component active mat (DCAM) is able to perform a controlled simultaneous neutralization of acid and alkali leakages by using microencapsulated active components. Moreover, its active components comprise food-grade ingredients, embedded in nonwoven polypropylene. The acid neutralizing mats contain sodium carbonate (Na2CO3) encapsulated in sodium alginate microcapsules (MC-ASC). Alkali neutralizing mats possess commercial encapsulated citric acid in hydrogenated palm oil (MIRCAP CT 85-H). A DCAM encompasses both MC-ASC and MIRCAP CT 85-H and was able to neutralize solutions up to 10% (v/v) of hydrochloric acid (HCl) and sodium hydroxide (NaOH). The efficacy of the neutralization was assessed by direct titration and using pH strip measurement tests to simulate the leakages. Due to the complexity of neutralization efficacy evaluation based solely on pH value, a thorough conductivity study was performed. DCAM reduced the conductivity of HCl and NaOH (1% and 2% (v/v)) in over 70%. The composites were characterized by scanning electron microscopy (SEM), differential calorimetry (DSC) and thermogravimetric analysis (TGA). The size of MC-ASC microcapsules ranged from 2 µm to 8 µm. Finally, all mat components displayed thermal stability above 150 °C.

Classification and Staging of Melanoma in the Head and Neck.

The rates of melanoma continue to rise, with recent estimates have shown that 18% to 22% of new melanoma cases occur within the head and neck in the United States each year. The mainstay of treatment of nonmetastatic primary melanomas of the head and neck includes the surgical resection and management of regional disease as indicated. Thorough knowledge of the classification and staging of melanoma is paramount to evaluate prognosis, determine the appropriate surgical intervention, and assess eligibility for adjuvant therapy and clinic trials. The traditional clinicopathologic classification of melanoma is based on morphologic aspects of the growth phase and distinguishes 4 of the most common subtypes as defined by the World Health Organization: superficial spreading, nodular, acral lentiginous, and lentigo maligna melanoma. The data used to derive the AJCC TNM Categories are based on superficial spreading melanoma and nodular subtypes. Melanoma is diagnosed histopathologically following initial biopsy that will assist with classifying the tumor to guide treatment. Classification is based on tumor thickness and ulceration (T stage, Breslow Staging), Regional Lymph Node Involvement (N Stage), and presence of metastasis (M Stage). Tumor thickness (Breslow thickness) and ulceration are 2 independent prognostic factors that have been shown to be the strongest predictors of survival and outcome. Clark level of invasion and mitotic rate are no longer incorporated into the current AJCC staging system, but still have shown to be important prognostic factors for cutaneous melanoma. For patients with metastatic (Stage IV) disease Lactate Dehydrogenase remains an independent predictor of survival. The Maxillofacial surgeon must remain up to date on the most current management strategies in this patient population. Classification systems and staging provide the foundation for clinical decision making and prognostication for the Maxillofacial surgeon when caring for these patients.

Targeted liposomal doxorubicin/ceramides combinations: The importance to assess the nature of drug interaction beyond bulk tumor cells.

One of the major assets of anticancer nanomedicine is the ability to co-deliver drug combinations, as it enables targeting of different cellular populations and/or signaling pathways implicated in tumorigenesis and thus tackling tumor heterogeneity. Moreover, drug resistance can be circumvented, for example, upon co-encapsulation and delivery of doxorubicin and sphingolipids, as ceramides. Herein, the impact of short (C6) and long (C18) alkyl chain length ceramides on the nature of drug interaction, within the scope of combination with doxorubicin, was performed in bulk triple-negative breast cancer (TNBC) cells, as well as on the density of putative cancer stem cells and phenotype, including live single-cell tracking. C6- or C18-ceramide enabled a synergistic drug interaction in all conditions and (bulk) cell lines tested. However, differentiation among these two ceramides was reflected on the migratory potential of cancer cells, particularly significant against the highly motile MDA-MB-231 cells. This effect was supported by the downregulation of the PI3K/Akt pathway enabled by C6-ceramide and in contrast with C18-ceramide. The decrease of the migratory potential enabled by the targeted liposomal combinations is of high relevance in the context of TNBC, due to the underlying metastatic potential. Surprisingly, the nature of the drug interaction assessed at the level of bulk cancer cells revealed to be insufficient to predict whether a drug combination enables a decrease in the percentage of the master regulators of tumor relapse as ALDH+/high putative TNBC cancer stem cells, suggesting, for the first time, that it should be extended further down to this level.