Brassiere Cup Size Agreement between Patients and Plastic Surgeons: Do Surgeons and Patients Speak the Same Size Language?

Patients undergoing plastic surgery of the breasts often communicate their size expectations as a brassiere cup size. However, multiple factors may cause a miscommunication between the surgeon and patient when brassiere cup size is used as a measure of results. The aim of this study was to determine the degree of agreement between disclosed and estimated brassiere cup size and also interrater agreement. Methods: Three-dimensional (3D) scans of 32 subjects were evaluated by 10 plastic surgeons estimating cup size using the American brassiere system. The surgeons were blinded to all parameters, including the 3D surface software-derived volume measures of the Vectra scan. The 3D scans of the anterior torsos were viewed. The plastic surgeons' estimations were compared with the cup sizes stated by the subjects (disclosed cup size), using simple and weighted Kappa statistics. Results: Agreement between the estimated and disclosed brassiere sizes was only slight (0.1479 ± 0.0605) using a simple Kappa analysis. Even when a Fleiss-Cohen-weighted comparison was used, only moderate agreement (0.6231 ± 0.0589) was found. The interrater agreement intraclass correlation coefficient was 0.705. Rater accuracy varied. The percentage of time spent in cosmetic practice and gender were not significantly correlated with accuracy. Conclusions: Agreement between cup size disclosed by subjects and estimates by plastic surgeons was low. A miscommunication between the surgeon and patient may occur when using brassiere sizes to communicate wishes and estimates in procedures that involve changes in breast volume.

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.

Beyond the 21-cm Notch-to-nipple Myth: Golden Proportions in Breast Aesthetics.

BACKGROUND: The 21-cm notch-to-nipple distance has been accepted without academic scrutiny as a key measure in breast aesthetics. The Fibonacci sequence and phi ratio occur frequently in nature. They have previously been used to assess aesthetics of the face, but not the breast. This study aims to assess if the static 21-cm measure or the proportional phi ratio is associated with ideal breast aesthetics. METHOD: Subclavicular-breast height and breast width were used to calculate the aesthetic ratio. Subjects were subsequently aesthetically rated. A one-sample t-test was used to determine if the ratio for each breast differed from phi. Breast scores with one, both, or no breasts were compared with an optimal phi ratio. Analysis of variance was performed. Tukey-Kramer adjustment for multiple comparisons was used when pairwise comparisons were conducted. RESULTS: Five subjects (14%) had bilateral optimal phi ratio breasts. Four subjects (11%) had one breast with an optimal phi ratio. Subjects with bilateral optimal phi ratios had significantly higher overall breast scores than those with only one optimal breast (Δ = 0.86, P = 0.025) or no optimal breast (Δ = 0.73, P = 0.008). Distance from optimal Fibonacci nipple position was moderately to strongly correlated with aesthetic score (-0.630, P = 0.016). No correlation was found between 21-cm notch-to-nipple distance and aesthetic score. CONCLUSION: The bilateral optimal phi ratio is correlated with high overall aesthetic scores, as is the optimal Fibonacci nipple position. No correlation was found between 21-cm notch-to-nipple distance and overall aesthetic score.

Tracing: A Simple Interpretation Method for the DIEP Flap CT Angiography to Help Operative Decision-making.

CT angiography (CTA) is an established technique that allows preoperative planning in DIEP flap reconstruction. However, innovative technological developments with extensive amounts of information require processing of data. It also requires user knowledge to interpret findings. Descriptions by radiologists are many times disappointingly limited to caliber and exit points of the perforator from the rectus fascia. Many DIEP flap surgeons similarly fail to utilize the CTA to its full extent. This is likely due to information overload. By tracing the DIEA on the CTA on a computer screen, using an ordinary ballpoint pen and a white sheet of paper, the surgeon can create a stylistic map of the dissectional-path of the DIEA. The map illustrates unusual branching patterns, perforator caliber and location, interconnections between individual perforators (or lack thereof), length of intramuscular dissection, and also rectus abdominis muscle intersections. The mapping can help in the choice of perforator(s) and may also speed up decision-making during surgical dissection. A penciled map also eases a round-table discussion, if multiple surgeons are involved in the operation. The map can also easily be brought to the operating room for guidance. Tracing is a user-friendly, time-efficient, intuitive, low-cost, and low-tech method that generates data that are easy to interpret, easy to share, and easy to discuss with other surgeons. The method is also not dependent on a radiologist for interpretation.

An Aesthetic Factor Priority List of the Female Breast in Scandinavian Subjects.

Background: There is little consensus about the relative determinative value of each individual factor in female breast aesthetics. When performing breast surgery with an aesthetic goal, certain factors will be more important than others. The purpose of this study was to make an aesthetic factor rank list to determine the relative contributions to overall breast aesthetics. Method: Volunteers were scanned using the 3-dimensional Vectra system. Ten Scandinavian plastic surgeons rated 37 subjects, using a validated scoring system with 49 scoring items. The correlation between specific aesthetic factors and overall breast aesthetic scores of the subjects were calculated using Pearson's r, Spearman's ρ, and Kendall's τ. Results: A very strong correlation was found between overall breast aesthetic score and lower pole shape (0.876, P < 0.0001). This was also true for upper pole shape (0.826, P < 0.0001) and breast height (0.821, P < 0.0001). A strong correlation was found between overall breast aesthetic score and nipple position (0.733, P < 0.0001), breast size (0.644, P < 0.0001), and breast width (0.632, P < 0.0001). Factors that were only moderately correlated with aesthetic score were intermammary distance (0.496, P = 0.002), nipple size and projection (0.588, P < 0.0001), areolar diameter (0.484, P < 0.0001), and areolar shape (0.403, P < 0.0001). Perceived symmetry was a weak factor (0.363, P = 0.027). Conclusions: Aesthetic factors of the female breast can be ranked in a priority list. Shape of the lower pole and upper pole and breast height are primary factors of female breast aesthetics. These should be prioritized in any aesthetic breast surgery. Vertical dimensional factors seem to be more determinative than horizontal factors.

Rifampin combination therapy in staphylococcal prosthetic joint infections: a randomized controlled trial.

BACKGROUND: The evidence supporting rifampin combination therapy in prosthetic joint infections (PJI) is limited due to the lack of controlled studies. The aim of this study is to evaluate the effect of adding rifampin to conventional antimicrobial therapy in early staphylococcal PJIs treated with debridement and retention of the implant (DAIR). METHODS: In this multicenter randomized controlled trial, 99 patients with PJI after hip and knee arthroplasties were enrolled. They were randomly assigned to receive rifampin or not in addition to standard antimicrobial treatment with cloxacillin or vancomycin in case of methicillin resistance. The primary endpoint was no signs of infection after 2 years of follow-up. RESULTS: Forty-eight patients were included in the final analyses. There were no differences in patient characteristics or comorbidities between the two groups. There was no significant difference in remission rate between the rifampin combination group (17 of 23 (74%)) and the monotherapy group (18 of 25 (72%), relative risk 1.03, 95% confidence interval 0.73 to 1.45, p = 0.88). CONCLUSION: This trial has not proven a statistically significant advantage by adding rifampin to standard antibiotic treatment in acute staphylococcal PJIs. TRIAL REGISTRATION: The Regional Ethics Committee and the Norwegian Medicines Agency approved the study (EudraCT 2005-005494-29), and the study was registered at ClinicalTrials.gov at Jan 18, 2007 ( NCT00423982 ).

Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability.

Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Molecular Profiling Using Breast Cancer Subtype to Plan for Breast Reconstruction.

BACKGROUND: Molecular profiling using breast cancer subtype has an increasing role in the multidisciplinary care of the breast cancer patient. The authors sought to determine the role of breast cancer subtyping in breast reconstruction and specifically whether breast cancer subtyping can determine the need for postmastectomy radiation therapy and predict recurrence-free survival to plan for the timing and technique of breast reconstruction. METHODS: The authors reviewed prospectively collected data from 1931 reconstructed breasts in breast cancer patients who underwent mastectomy between November of 1999 and December of 2012. Reconstructed breasts were grouped by breast cancer subtype and examined for covariates predictive of recurrence-free survival and need for postmastectomy radiation therapy. RESULTS: Of the reconstructed breasts, 753 (39 percent) were luminal A, 538 (27.9 percent) were luminal B, 224 (11.6 percent) were luminal HER2, 143 (7.4 percent) were HER2-enriched, and 267 (13.8 percent) were triple-negative breast cancer. Postmastectomy radiation therapy was delivered in 69 HER2-enriched patients (48.3 percent), 94 luminal HER2 patients (42 percent), 200 luminal B patients (37.2 percent), 99 triple-negative breast cancer patients (37.1 percent), and 222 luminal A patients (29.5 percent) (p < 0.0001). Luminal A cases had better recurrence-free survival than HER2-enriched cases, and triple-negative breast cancer cases had worse recurrence-free survival than HER2-enriched cases. Luminal B and luminal HER2 cases had recurrence-free survival similar to that for HER2-enriched cases. Luminal A subtype was associated with the best recurrence-free survival. Subtyping may have improved the breast surgery planning for 33.1 percent of delayed reconstructions that did not require postmastectomy radiation therapy and 37 percent of immediate reconstructions that did require postmastectomy radiation therapy. CONCLUSION: This study is the first publication in the literature to evaluate breast cancer subtype to stratify risk for decision making in breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

The Plastic Surgery Compass: Navigating the Reconstructive Ladder in the Personalized Health Care Era.

The reconstructive ladder and the reconstructive elevator have withstood the test of time as didactic tools for resident education. Over time, many alternative models have been suggested to incorporate the technological advances in plastic surgery, but none of them have focused on the patient. Changes in practice and the trend toward personalized health care demand a 360-degree evaluation and solution of surgical problems incorporating patient-specific characteristics. We, therefore, suggest the concept of the plastic surgery compass to navigate the ladder.

Prediction of Drug Penetration in Tuberculosis Lesions.

The penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous and drug-specific, but the factors underlying such differential partitioning are unknown. We hypothesized that drug binding to macromolecules in necrotic foci (or caseum) prevents passive drug diffusion through avascular caseum, a critical site of infection. Using a caseum binding assay and MALDI mass spectrometry imaging of tuberculosis drugs, we showed that binding to caseum inversely correlates with passive diffusion into the necrotic core. We developed a high-throughput assay relying on rapid equilibrium dialysis and a caseum surrogate designed to mimic the composition of native caseum. A set of 279 compounds was profiled in this assay to generate a large data set and explore the physicochemical drivers of free diffusion into caseum. Principle component analysis and modeling of the data set delivered an in silico signature predictive of caseum binding, combining 69 molecular descriptors. Among the major positive drivers of binding were high lipophilicity and poor solubility. Determinants of molecular shape such as the number of rings, particularly aromatic rings, number of sp(2) carbon counts, and volume-to-surface ratio negatively correlated with the free fraction, indicating that low-molecular-weight nonflat compounds are more likely to exhibit low caseum binding properties and diffuse effectively through caseum. To provide simple guidance in the property-based design of new compounds, a rule of thumb was derived whereby the sum of the hydrophobicity (clogP) and aromatic ring count is proportional to caseum binding. These tools can be used to ensure desirable lesion partitioning and guide the selection of optimal regimens against tuberculosis.

Extensive Abdominal Wall Incisional Heterotopic Ossification Reconstructed with Component Separation and Strattice Inlay.

Symptomatic heterotopic ossification of abdominal surgical incisions is a rare occurrence. We present a 67-year-old man with severe discomfort caused by heterotopic ossification extending from the xiphoid to the umbilicus. The patient underwent an abdominal aortic aneurysm repair 3 years before our treatment. A 13 × 3.5 cm ossified lesion was excised. The resulting midline defect was closed using component separation and inlay Strattice. Tension-free midline adaptation of the recti muscles was achieved. A computed tomography scan of the abdomen 6 months after the surgery showed no recurrence or hernias. Heterotopic ossification in symptomatic patients has previously been treated with excision and primary closure. We believe that tension-free repair is important to prevent recurrence. Acellular dermal matrix may add to this effect and also compartmentalize the process.

Predicting hydration free energies with chemical accuracy: the SAMPL4 challenge.

An implicit solvent model described by a non-simple dielectric medium is used for the prediction of hydration free energies on the dataset of 47 molecules in the SAMPL4 challenge. The solute is represented by a minimal parameter set model based on a new all atom force-field, named the liquid simulation force-field. The importance of a first solvation shell correction to the hydration free energy prediction is discussed and two different approaches are introduced to address it: either with an empirical correction to a few functional groups (alcohol, ether, ester, amines and aromatic nitrogen), or an ab initio correction based on the formation of a solute/explicit water complex. Both approaches give equally good predictions with an average unsigned error <1 kcal/mol. Chemical accuracy is obtained.

Impact of adjuvant chemotherapy on abdominal wall hernias and bulges after muscle-sparing free TRAM flaps for breast reconstruction.

BACKGROUND: Free tissue transfer from an abdominal donor site has become a popular method for postmastectomy breast reconstruction. The detrimental effects of adjuvant chemotherapy on healing and the resulting clinical impact on patient outcome remains somewhat unclear for abdominal bulges and hernias resulting after free tissue transfer from the abdominal donor site. METHODS: An institutional review board-approved retrospective review of 155 free muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps performed for breast reconstruction was undertaken to evaluate the effect of adjuvant chemotherapy on abdominal donor-site morbidity. The primary outcome studied was the development of hernias and bulges. Statistical analysis was performed using univariate and multivariate classification and regression tree (CART) analysis. RESULTS: Of the 155 patients, 51 underwent bilateral MS-TRAM flaps and 104 underwent unilateral MS-TRAM flap reconstruction. Thirty-nine patients underwent adjuvant chemotherapy. A statistically significant association was seen between chemotherapy treatment and the incidence of hernias alone (P < 0.05; odds ratio, 6.42; 95% confidence interval, 0.88-73.58). Multivariable CART analyses corroborated these findings and revealed that presence of diabetes mellitus (DM), bilaterality, and receiving chemotherapy treatment were related to increased incidence of hernias (P = 0.011, 0.005, and 0.017, respectively) after controlling for clinical variables such as smoking status, chronic obstructive pulmonary disease, and type of closure. Univariate analyses also revealed a statistically significant association between bilaterality in conjunction with chemotherapy treatment and the incidence of hernias alone (P = 0.0002; odds ratio, 37.56; 95% confidence interval, 4.56-476.35). This highly significant finding is further augmented by multivariable CART analyses, which found that patients who were bilateral and underwent chemotherapy treatment or those with DM were significantly more likely to develop hernias (P < 0.001 and P = 0.016, respectively). CONCLUSIONS: To date, our study is the single largest series of abdominal donor-site complications in patients receiving chemotherapy and free MS-TRAM breast reconstruction. We have demonstrated an increase in the incidence of abdominal donor-site complications, specifically abdominal bulges and hernias, in patients undergoing chemotherapy for advanced stages of breast cancer. This increased complication rate is most pronounced in patients requiring chemotherapy who undergo bilateral reconstruction, and is also a significant risk for patients receiving chemotherapy who have preexisting DM.

Identification of novel NaV1.7 antagonists using high throughput screening platforms.

Congenital Insensitivity to Pain (CIP) is a loss of function mutation resulting in a truncated NaV1.7 protein, suggesting a pivotal role in pain signaling and rendering it an important pharmaceutical target for multiple pain conditions. The structural homology in the NaV-channel family makes it challenging to design effective analgesic compounds without inducing for example cardiotoxicity or seizure liabilities. An additional approach to structural isoform selectivity is to identify compounds with use- or state-dependent profiles, i.e. inhibition efficacy based on the gating of the ion channel. In general nerve cells in damaged or inflamed tissue are more depolarized and electrically active compared to healthy nerve cells in for instance the heart. This observation has led to the design of two types of screening protocols emulating the voltage condition of peripheral neurons or cardiac tissue. The two voltage protocols have been developed to identify both use- and state-dependent antagonists. In this paper we describe an attempt to merge the two different protocols into one to increase screening efficacy, while retaining relevant state- and use-dependent pharmacology. The new protocol is constructed of two stimulation pulses and a slow voltage ramp for simultaneous assessment of resting and state-dependent block. By comparing all protocols we show that the new protocol indeed filter compounds for state-dependence and increase the prediction power of selecting use-dependent compounds.

Phenethyl nicotinamides, a novel class of Na(V)1.7 channel blockers: structure and activity relationship.

The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.

Structure and activity relationship in the (S)-N-chroman-3-ylcarboxamide series of voltage-gated sodium channel blockers.

Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model.

3-Oxoisoindoline-1-carboxamides: potent, state-dependent blockers of voltage-gated sodium channel Na(V)1.7 with efficacy in rat pain models.

The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure-activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.