Spontaneous Reossification Following Craniectomy in a Pediatric Patient.

Spontaneous reossification following a cranial defect is described by only a few case reports. A 6-month-old male with epidural hematoma underwent decompressive craniotomy, subsequently complicated by scalp abscess requiring removal of the bone flap. On serial outpatient follow-up, the patient demonstrated near-complete resolution of cranial defect over the course of 18 months, thus deferring the need for future cranioplasty. Prior articles have identified this occurrence in children and young adults; however, the present case is the first to report of this phenomenon in an infant less than 1 year of age. A brief review of the literature is provided with the proposed physiologic underpinning for the spontaneous reossification observed. While prior studies propose that recranialization is mediated by contact with the dura mater and pericranium, new investigations suggest that calvarial bone repair is also mediated by stem cells from the suture mesenchyme.

NCCN Guidelines® Insights: Distress Management, Version 2.2023.

These NCCN Guidelines for Distress Management discuss the identification and treatment of psychosocial problems in patients with cancer. All patients experience some level of distress associated with a cancer diagnosis and the effects of the disease and its treatment regardless of the stage of disease. Clinically significant levels of distress occur in a subset of patients, and identification and treatment of distress are of utmost importance. The NCCN Distress Management Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights describe updates to the NCCN Distress Thermometer (DT) and Problem List, and to the treatment algorithms for patients with trauma- and stressor-related disorders.

Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with preserved or increased ejection fraction in the absence of secondary causes. Mutations in the sarcomeric protein-encoding genes predominantly cause HCM. However, relatively little is known about the genetic impact of signalling proteins on HCM. METHODS AND RESULTS: Here, using exome and targeted sequencing methods, we analysed two independent cohorts comprising 401 Indian patients with HCM and 3521 Indian controls. We identified novel variants in ribosomal protein S6 kinase beta-1 (RPS6KB1 or S6K1) gene in two unrelated Indian families as a potential candidate gene for HCM. The two unrelated HCM families had the same heterozygous missense S6K1 variant (p.G47W). In a replication association study, we identified two S6K1 heterozygotes variants (p.Q49K and p.Y62H) in the UK Biobank cardiomyopathy cohort (n=190) compared with matched controls (n=16 479). These variants are neither detected in region-specific controls nor in the human population genome data. Additionally, we observed an S6K1 variant (p.P445S) in an Arab patient with HCM. Functional consequences were evaluated using representative S6K1 mutated proteins compared with wild type in cellular models. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6 and ERK1/2 signalling cascades, suggesting a gain-of-function effect. CONCLUSIONS: Our study demonstrates for the first time that the variants in the S6K1 gene are associated with HCM, and early detection of the S6K1 variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of S6K1 gene variants.

Blood Pressure Challenge Reduces Hematomas in Gender-Affirming Mastectomy: A Retrospective Chart Review of 92 Consecutive Patients.

BACKGROUND: Gender-affirming mastectomy is a common surgery for the treatment of gender incongruence and gender dysphoria and improves quality of life. Hematoma rates for gender-affirming double incision mastectomies are between 2.8% and 8.1%. This study aims to investigate the utility of a blood pressure challenge, whereby the patient's blood pressure is medically increased intraoperatively to reveal bleeding vessels that can be addressed with additional hemostasis before skin closure, to reduce postoperative hematoma. METHODS: A retrospective chart review of patients who underwent gender-affirming double incision mastectomies over a 6-year period by a single surgeon was conducted. Surgeries were separated into a blood pressure challenge experimental group and a non-blood pressure challenge control group. Demographics, surgical characteristics, and postoperative complications were compared between the 2 cohorts using Pearson χ2, Fisher exact, t tests, univariate logistic regression, and multivariable logistical regression. Significance was established at P < 0.05. RESULTS: A total of 92 patients (184 breasts) were included with 32 patients (64 breasts) in the control group and 60 (120 breasts) in the blood pressure challenge group. In the control group, there were 5 hematomas (7.81%) compared with 1 (0.83%) in the blood pressure challenge group (P = 0.02). On univariate logistical regression analysis, blood pressure challenge was the only variable significantly associated with hematoma (odds ratio, 0.1; 95% confidence interval, 0.01-0.63; P = 0.04). On multivariable logistical regression, after controlling for age, body mass index, smoking status, and mass of excised breast tissue, patients who underwent blood pressure challenge demonstrated lower hematoma rates (odds ratio, 0.08; 95% CI, 0.004-0.59; P = 0.04). CONCLUSIONS: Using an intraoperative blood pressure challenge was associated with reduced hematoma rates. Guidelines for blood pressure challenge goals should be established to standardize care and reduce complications in gender-affirming mastectomies.

A Systematic Review and Meta-Analysis Comparing the Clinical Outcomes of Profunda Artery Perforator Versus Gracilis Thigh Flap as a Second Choice for Autologous Breast Reconstruction.

PURPOSE: Autologous breast reconstruction remains a versatile option to produce a natural appearing breast after mastectomy. The deep inferior epigastric perforator remains the most commonly used flap choice, but when this donor site is unsuitable or unavailable, the transverse upper gracilis (TUG) or profunda artery perforator (PAP) flaps are popular secondary alternatives. We conduct a meta-analysis to better understand patient outcomes and adverse events in secondary flap selection in breast reconstruction. METHODS: A systematic search was conducted on MEDLINE and Embase for all articles published on TUG and/or PAP flaps for oncological breast reconstruction in postmastectomy patients. A proportional meta-analysis was conducted to statistically compare outcomes between PAP and TUG flaps. RESULTS: The TUG and PAP flaps were noted to have similar reported rates of success and incidences of hematoma, flap loss, and flap healing (P > 0.05). The TUG flap was noted to have significantly more vascular complications (venous thrombosis, venous congestion, and arterial thrombosis) than the PAP flap (5.0% vs 0.6%, P < 0.01) and significantly greater rates of unplanned reoperations in the acute postoperative period (4.4% vs 1.8%, P = 0.04). Infection, seroma, fat necrosis, donor healing complications, and rates of additional procedures all exhibited high degree of heterogeneity precluding mathematical synthesis of outcomes across studies. CONCLUSIONS: Compared with TUG flaps, PAP flaps have fewer vascular complications and fewer unplanned reoperations in the acute postoperative period. There is need for greater homogeneity in reported outcomes between studies to enable for synthesis of other variables important in determining flap success.

The Impact of Venous Reconstruction on Finger Replantation Success Rates Based on Level of Injury.

PURPOSE: The requirement for anatomic venous reconstruction in digit replantation is an ongoing area of research. In this study, we evaluated our institutional experience to study whether replantation success is affected by the presence or absence of vein repair, stratified by the level of injury. METHODS: A retrospective review was performed at an urban, level-1 trauma center of all single-digit replantations performed in adults from 2012 to 2021. Patient demographics, injury mechanism, level of injury, whether a vein was repaired, and replant survival were recorded. RESULTS: Sixty-seven single replanted digits were included. Patients were, on average, 38 years old, and 94% were men. The most common mechanism of injury was a sharp laceration (81%). The overall survival rates for all replantations were 68.7% (46/67) and 60% (12/20) for distal finger replantation. Patients with digital replantations at Tamai zone III or more proximal exhibited a 1.8 times increase in survival rates when one vein was repaired versus zero veins (84.4% vs 46.7%). Patients with digital replantations at Tamai zones I and II exhibited similar survival rates. CONCLUSIONS: Replantations at or proximal to the middle phalanx should be repaired with at least one artery and vein to maximize the chance for success. However, for distal finger replantations, artery-only replantation is a viable option when vein anastomosis is not achievable. TYPO OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Phosphorylation of Tet3 by cdk5 is critical for robust activation of BRN2 during neuronal differentiation.

Tet3 regulates the dynamic balance between 5-methylcyotsine (5mC) and 5-hydroxymethylcytosine (5hmC) in DNA during brain development and homeostasis. However, it remains unclear how its functions are modulated in a context-dependent manner during neuronal differentiation. Here, we show that cyclin-dependent kinase 5 (cdk5) phosphorylates Tet3 at the highly conserved serine 1310 and 1379 residues within its catalytic domain, changing its in vitro dioxygenase activity. Interestingly, when stably expressed in Tet1, 2, 3 triple-knockout mouse embryonic stem cells (ESCs), wild-type Tet3 induces higher level of 5hmC and concomitant expression of genes associated with neurogenesis whereas phosphor-mutant (S1310A/S1379A) Tet3 causes elevated 5hmC and expression of genes that are linked to metabolic processes. Consistent with this observation, Tet3-knockout mouse ESCs rescued with wild-type Tet3 have higher level of 5hmC at the promoter of neuron-specific gene BRN2 when compared to cells that expressed phosphor-mutant Tet3. Wild-type and phosphor-mutant Tet3 also exhibit differential binding affinity to histone variant H2A.Z. The differential 5hmC enrichment and H2A.Z occupancy at BRN2 promoter is correlated with higher gene expression and more efficient neuronal differentiation of ESCs that expressed wild-type Tet3. Taken together, our results suggest that cdk5-mediated phosphorylation of Tet3 is required for robust activation of neuronal differentiation program.

Rethinking the Need for Nail Plate Removal: A Comparison of the Risks Between Standard Nail Bed Repair and Nonoperative Management.

PURPOSE: Nail bed injuries are commonly treated with nail plate removal and repair due to concern for future nail deformity. There is controversy whether this is necessary. We compared the outcomes for adult patients with simple nail bed lacerations who underwent either formal nail bed repair or nonoperative management. METHODS: A retrospective cohort study was performed of adult patients with nail bed lacerations from 2012 to 2019. Nail bed lacerations were diagnosed in patients with fingertip injuries resulting in subungual hematoma greater than 50% or in any subungual hematoma in the setting of a distal phalanx fracture. All patients included had an intact nail plate. Patients were treated with nail bed laceration repair or nonoperatively without nail plate removal. The primary outcome was the development of a nail deformity. Secondary outcomes included infection, fracture nonunion, and patient-reported functional outcomes using the quick Disabilities of the Arm, Shoulder and Hand score. RESULTS: Thirty-eight patients with nail bed lacerations were treated nonoperatively, and 40 patients were treated with nail bed repair. The average follow-up time was 4.5 weeks in the office. In addition, 1-year evaluation of patients was performed through telephone interview. The patients in the nonoperative group exhibited no statistically significant difference in the calculated risk for nail deformities compared with the nail bed repair group (13% vs 23%, relative risk = 0.58, P = 0.40, 95% confidence interval = 0.42-1.25). There were no significant differences in secondary outcomes or quick Disabilities of the Arm, Shoulder and Hand scores between groups. CONCLUSIONS: The authors observed no meaningful difference in the rate of nail deformities in adult patients who underwent nail bed repair compared with those managed nonoperatively.

The Economic Impact of Extensor Tendon Lacerations of the Hand in the United States.

PURPOSE: Extensor tendon lacerations (ETLs) are a common and debilitating injury for thousands of Americans annually. No study has attempted to estimate their economic impact. The objective of this study was to estimate the economic impact of ETLs in America. METHODS: The cost of ETLs to society was estimated using a validated prevalence-based cost of illness model. The primary cohort was defined as all patients with complete ETLs in the United States undergoing surgical repair and, secondarily, the imputed number of patients requiring reoperation within 1 year. For these groups, both direct and indirect costs (lost income, missed workdays, and disability payments) were measured. RESULTS: The total annual direct medical costs amounted to $14,095.28 per injury and 100,000 population. The total annual indirect labor costs were found to range between $80,842.90 and $150,136.82 per injury and 100,000 population. Hence, the estimated total costs of ETLs are $307 million per year in the United States alone and could be as high as $531 million annually depending on the effects of worker absenteeism on the core production-based industries. CONCLUSIONS: Extensor tendon lacerations incur a significant economic burden to our health care system and are more costly when compared with many other common hand conditions. Specifically, indirect costs are the major contributor toward the total cost these injuries incur on society, accounting for an upward of 91% of the total cost. These results suggest efforts be focused on improving rehabilitation protocols and treatments. LEVEL OF EVIDENCE: Level II-economic and decision analyses.

Evaluating the Inaccuracy of the National Surgical Quality Improvement Project Surgical Risk Calculator in Plastic Surgery: A Meta-analysis of Short-Term Predicted Complications.

BACKGROUND: Preoperative surgical risk assessment is a major component of clinical decision making. The ability to provide accurate, individualized risk estimates has become critical because of growing emphasis on quality metrics benchmarks. The American College of Surgeons National Surgical Quality Improvement Project (NSQIP) Surgical Risk Calculator (SRC) was designed to quantify patient-specific risk across various surgeries. Its applicability to plastic surgery is unclear, however, with multiple studies reporting inaccuracies among certain patient populations. This study uses meta-analysis to evaluate the NSQIP SRC's ability to predict complications among patients having plastic surgery. METHODS: OVID MEDLINE and PubMed were searched for all studies evaluating the predictive accuracy of the NSQIP SRC in plastic surgery, including oncologic reconstruction, ventral hernia repair, and body contouring. Only studies directly comparing SCR predicted to observed complication rates were included. The primary measure of SRC prediction accuracy, area under the curve (AUC), was assessed for each complication via DerSimonian and Laird random-effects analytic model. The I2 statistic, indicating heterogeneity, was judged low (I2 < 50%) or borderline/unacceptably high (I2 > 50%). All analyses were conducted in StataSE 16.1 (StataCorp LP, College Station, Tex). RESULTS: Ten of the 296 studies screened met criteria for inclusion (2416 patients). Studies were classified as follows: (head and neck: n = 5, breast: n = 1, extremity: n = 1), open ventral hernia repair (n = 2), and panniculectomy (n = 1). Predictive accuracy was poor for medical and surgical complications (medical: pulmonary AUC = 0.67 [0.48-0.87], cardiac AUC = 0.66 [0.20-0.99], venous thromboembolism AUC = 0.55 [0.47-0.63]), (surgical: surgical site infection AUC = 0.55 [0.46-0.63], reoperation AUC = 0.54 [0.49-0.58], serious complication AUC = 0.58 [0.43-0.73], and any complication AUC = 0.60 [0.57-0.64]). Although mortality was accurately predicted in 2 studies (AUC = 0.87 [0.54-0.99]), heterogeneity was high with I2 = 68%. Otherwise, heterogeneity was minimal (I2 = 0%) or acceptably low (I2 < 50%) for all other outcomes. CONCLUSIONS: The NSQIP Universal SRC, aimed at offering individualized quantifiable risk estimates for surgical complications, consistently demonstrated poor risk discrimination in this plastic surgery-focused meta-analysis. The limitations of the SRC are perhaps most pronounced where complex, multidisciplinary reconstructions are needed. Future efforts should identify targets for improving SRC reliability to better counsel patients in the perioperative setting and guide appropriate healthcare resource allocation.

Post-traumatic hydrocephalus may be associated with autologous cranioplasty failure, independent of ventriculoperitoneal shunt placement: a retrospective analysis.

PURPOSE: Decompressive craniectomy (DC) is a common procedure used for the treatment of intracranial hypertension. Once brain swelling has subsided, a cranioplasty is performed to restore cosmesis and protection to the brain. While using the patient's autologous bone flap is often the first choice in cranioplasty, this procedure is frequently complicated by bone flap resorption and infection. This study seeks to identify predictors of autologous cranioplasty failure. METHODS: A retrospective analysis was conducted on patients who underwent decompressive craniectomy and autologous cranioplasty. Patient demographics and factors related to both surgeries and failure rates were recorded from patient records. Logistic regressions were conducted to determine which factors were implicated in autologous cranioplasty failure. RESULTS: In our cohort, 127 patients underwent autologous cranioplasty. Overall, 18 (14.2%) patients experienced autologous cranioplasty failure. Regression analysis identified development of post-traumatic hydrocephalus (PTH) following DC (OR: 3.26, p = 0.043), presence of neurological deficits following DC (OR: 4.88, p = 0.025), and reoperation prior to CP (OR 3.0, p = 0.049) as significant predictors of autologous cranioplasty failure. Of the 16 patients who developed PTH following DC, 9 received a VP shunt. The rate of flap failure was similar across the 9 PTH patients who received a shunt and the 7 PTH patients who did not receive a shunt (33% vs. 57% failure rate, respectively, p = 0.341). CONCLUSION: Autologous cranioplasty is a reasonably successful procedure with a flap failure rate of 14.2%. We identified PTH, persistent neurological deficits, and reoperation prior to cranioplasty as significant predictors of autologous cranioplasty failure. Interestingly, the presence of VP shunt did not impact the odds of flap failure.

Re-evaluating the need for orthopantomography in the management of mandibular trauma: is computed tomography enough?

BACKGROUND: Mandibular fractures are frequent indications for computed tomography (CT) and orthopantomography (OPG) scans in emergency rooms. Numerous studies found CT to have higher sensitivity and enhanced accuracy compared to OPG in diagnosing mandible fractures. Controversy exists regarding additional need for OPG when evaluating dental trauma. This study investigates whether OPG adds diagnostic value to CT in mandibular trauma and whether additional OPG significantly alters management. METHODS: A retrospective chart review identified 100 patients ≥ 18 years of age with known mandibular trauma who received CT and OPG in the emergency department between May 2015 and January 2020. All patients demonstrated a fracture in at least one study. CT and OPG studies were anonymized and randomized. A single attending surgeon evaluated mandible fracture and dental trauma characteristics and subsequently compared findings. RESULTS: One hundred patient CT and OPG scans were reviewed. CT detected mandible fractures in all patients and OPG detected fractures in 93% (p = 0.01). Twenty-eight patients had different findings between scans. CT demonstrated 1 or more additional fracture(s) than OPG in 20 patients and dental trauma not seen on OPG in 4. OPG detected 1 fracture and no dental trauma that was not seen on CT. CT drove treatment-determining differences in 17 cases and OPG in 0 cases. CONCLUSIONS: CT appears efficacious in detecting clinically significant mandible fractures and dental trauma with little additional benefit from OPG in emergency settings. Helical CT may be the only imaging necessary in evaluating patients with such trauma.

Comparing diagnosis of midfacial fractures by radiologists and plastic surgeons.

BACKGROUND: Clinicians who manage facial fractures often rely on radiologist interpretations to help with assessment and management. Among treating physicians, facial fractures are categorized into clinically relevant patterns of injury. On the other hand, while radiologists are unsurpassed at identifying individual breaks in the bone, larger fracture patterns are not always conveyed in radiology reports. PURPOSE: This study aims to assess the frequency with which the terminology describing midfacial fracture patterns is concordant among radiologists and treating clinicians. METHODS: The authors identified patients with different patterns of midfacial injury including Le Fort I, Le Fort II, Le Fort III, naso-orbito-ethmoid (NOE), and zygomaticomaxillary complex (ZMC) fractures. Plastic surgery consult notes and radiological imaging reports were reviewed for concordance in documentation of injury patterns. Identification of individual fractures consistent with the diagnosed fracture pattern was also recorded. RESULTS: Radiologists were noted to be highly successful in describing individual fractures of the facial bones, identifying at least two defining components of a fracture pattern in 96% of Le Fort, 88% of NOE, and 94% of ZMC injuries. However, when injury patterns were considered, only 32% of Le Fort, 28% of ZMC, and 6% of NOE fractures were explicitly identified in radiology reports. CONCLUSIONS: Radiologists are highly skilled in discerning individual fractures in facial trauma cases. However, less reliability was seen in the identification of fracture patterns in midfacial injury, with particular weaknesses in descriptions of NOE and ZMC fractures. This data suggests that greater focus on patterns of midfacial injury would improve the clinical applicability of radiological reports.

Subgaleal drains may be associated with decreased infection following autologous cranioplasty: a retrospective analysis.

BACKGROUND: Autologous bone is often the first choice in cranioplasty following a decompressive craniectomy. However, infection is a common complication, with reported rates up to 25%. While the incidence and management of infection are well documented, the risk factors associated with infection remain less clear. The current study aims to identify predictors of infection risk following autologous cranioplasty. METHODS: A retrospective analysis was conducted on patients who underwent decompressive craniectomy and cranioplasty using cryopreserved autologous bone flaps between 2010 and 2020. Patient demographics and factors related to both surgeries and infection rates were recorded from patient records. Logistic regressions were conducted to determine which factors were implicated in the development of infection. RESULTS: In our cohort, 126 patients underwent autologous cranioplasty. A total of 10 patients (7.9%) developed an infection following reconstruction, with half resulting in implant failure. We did not identify any significant risk factors for infection. Regression analysis identified placement of subgaleal drain following cranioplasty as a protective factor against the development of infection (OR: 0.16, p = 0.007). On average, drains remained in for 3 days, with no difference between the length of drains for those with infection vs. those without (p = 0.757). CONCLUSIONS: The current study demonstrates an infection rate of 7.9% in patients who receive an autologous cranioplasty following decompressive craniectomy, which is consistent with previous data. Half (4%) of patients who experienced an infection ultimately required removal of the implant. While it is common practice for neurosurgeons to use drains to prevent hematomas and fluid collections, we found that subgaleal drain placement following cranioplasty was associated with decreased infection, thus demonstrating another benefit of a commonly used tool.

Postnatal Sagittal Craniosynostosis: A Novel Presentation and Considerations in Diagnosis and Management.

ABSTRACT: Sagittal craniosynostosis results in scaphocephaly from abnormal fusion of the sagittal suture. Traditionally, craniosynostosis presents at birth and is diagnosed within the first year of life. The authors report a patient with development of sagittal craniosynostosis after birth, which we term postnatal sagittal craniosynostosis. This is a rare occurrence in which management considerations are critical but are not well discussed. A 3-year-old boy presented with concerns of a metopic ridge. Workup revealed metopic ridging and an open sagittal suture. The patient later developed signs of increased intracranial pressure and repeat computed tomography scan 14 months later identified a newly fused sagittal suture. The patient underwent open posterior cranial vault expansion, resulting in resolution of symptoms. Postnatal sagittal craniosynostosis is a rare condition and should be considered in otherwise unexplained increases in increased intracranial pressure among pediatric patients. Open posterior cranial vault expansion represents a safe and effective method to treat this condition.

Metamorphosis of Twin Screw Extruder-Based Granulation Technology: Applications Focusing on Its Impact on Conventional Granulation Technology.

In order to be at pace with the market requirements of solid dosage forms and regulatory standards, a transformation towards systematic processing using continuous manufacturing (CM) and automated model-based control is being thought through for its fundamental advantages over conventional batch manufacturing. CM eliminates the key gaps through the integration of various processes while preserving quality attributes via the use of process analytical technology (PAT). The twin screw extruder (TSE) is one such equipment adopted by the pharmaceutical industry as a substitute for the traditional batch granulation process. Various types of granulation techniques using twin screw extrusion technology have been explored in the article. Furthermore, individual components of a TSE and their conjugation with PAT tools and the advancements and applications in the field of nutraceuticals and nanotechnology have also been discussed. Thus, the future of granulation lies on the shoulders of continuous TSE, where it can be coupled with computational mathematical studies to mitigate its complications.

Unraveling the role of aurora A beyond centrosomes and spindle assembly: implications in muscle differentiation.

Aurora kinases are critical mitotic serine/threonine kinases and are often implicated in tumorigenesis. Recent studies of the interphase functions for aurora kinase (Aurk)A have considerably expanded our understanding of its role beyond mitosis. To identify the unknown targets of AurkA, we used peptide array-based screening and found E2F4 to be a novel substrate. Phosphorylation of E2F4 by AurkA at Ser75 regulates its DNA binding and subcellular localization. Because E2F4 plays an important role in skeletal muscle differentiation, we attempted to gain insight into E2F4 phosphorylation in this context. We observed that a block in E2F4 phosphorylation retained it better within the nucleus and inhibited muscle differentiation. RNA sequencing analysis revealed a perturbation of the gene network involved in the process of muscle differentiation and mitochondrial biogenesis. Collectively, our findings establish a novel role of AurkA in the process of skeletal muscle differentiation.-Dhanasekaran, K., Bose, A., Rao, V. J., Boopathi, R., Shankar, S. R., Rao, V. K., Swaminathan, A., Vasudevan, M., Taneja, R., Kundu, T. K. Unravelling the role of aurora A beyond centrosomes and spindle assembly: implications in muscle differentiation.

Clinical and dosimetric evaluation of recurrent breast cancer patients treated with hyperthermia and radiation.

Background: Treatment for locally recurrent breast cancer poses a significant challenge because the benefits in local control must be weighed against the increased risk of side effects of the treatment. Frequently, patients have been heavily pre-treated with radiation and several types of chemotherapy. Moreover, they often present with large volumes of bulky disease, further complicating management. Hyperthermia can be used to improve the efficacy of radiation, particularly in the setting of recurrent disease. Methods: We reviewed our clinical and dosimetric experience of breast cancer patients who received hyperthermia and radiation for recurrent breast cancer from 2011 to 2017. Thirty-six patients were treated with hyperthermia and radiation. Median follow-up was 11 months. Thirty patients (83.3%) received prior radiotherapy. The most commonly used radiation fraction scheme was 32 Gy in 8 fractions. The median radiation dose at the time of recurrence was 35.5 Gy (range 20-64 Gy). Mild temperature hyperthermia was delivered two times per week. Results: The median repeat radiation volume was 574 cc (range 11-3620 cc). Electrons, conventional photons, and IMRT radiation techniques were used. IMRT was used for large and complex treatment volumes and showed acceptable doses to organs at risk. The overall response rate was 61.1%. Complete response was observed in 17 patients (47.2%), partial response in 5 patients (13.9%), stable disease in 11 patients (30.6%), and progressive disease in 3 patients (8.3%). Twenty-six patients experienced acute grade 1 and 2 toxicities, primarily pain and erythema; and 26 experienced long-term grade 1 and 2 toxicities, mainly hyperpigmentation and lymphedema. Three patients developed new ulcerations that healed with conservative management. One patient developed pulmonary fibrosis resulting in mild dyspnea on exertion. Conclusion: Hyperthermia and radiation provide good local control with a favorable side effect profile. Thermoradiotherapy may be offered to patients with recurrent breast cancer, including those with extensive volumes of disease.

G9a promotes proliferation and inhibits cell cycle exit during myogenic differentiation.

Differentiation of skeletal muscle cells, like most other cell types, requires a permanent exit from the cell cycle. The epigenetic programming underlying these distinct cellular states is not fully understood. In this study, we provide evidence that the lysine methyltransferase G9a functions as a central axis to regulate proliferation and differentiation of skeletal muscle cells. Transcriptome analysis of G9a knockdown cells revealed deregulation of many cell cycle regulatory genes. We demonstrate that G9a enhances cellular proliferation by two distinct mechanisms. G9a blocks cell cycle exit via methylation-dependent transcriptional repression of the MyoD target genes p21(Cip/Waf1) and Rb1. In addition, it activates E2F1-target genes in a methyltransferase activity-independent manner. We show that G9a is present in the E2F1/PCAF complex, and enhances PCAF occupancy and histone acetylation marks at E2F1-target promoters. Interestingly, G9a preferentially associates with E2F1 at the G1/S phase and with MyoD at the G2/M phase. Our results provide evidence that G9a functions both as a co-activator and a co-repressor to enhance cellular proliferation and inhibit myogenic differentiation.

Reoperation for left atrioventricular valve failure in repaired atrioventricular septal defect: Can more valves be preserved in the current era?

OBJECTIVE: Left atrio-ventricular valve (LAVV) regurgitation after repair of an atrio-ventricular septal defect (AVSD) may necessitate further surgery. However, redo-LAVV repair remains challenging. We sought to determine if more LAVV valves are preserved in the current era, and analyze early and longer-term results. PATIENTS: All consecutive patients with repaired AVSD who underwent redo-LAVV surgery from January 2004 to April 2017 were included. Patients with single ventricles, atrial isomerism, and complex associated anomalies were excluded. METHODS: This was a single-center study using retrospective chart review and an institutional database for follow-up information. Data analyzed included number and year of primary AVSD and redo-LAVV operation, presence of trisomy 21, morphology of AVSD, mortality, and reoperation. Univariate analysis included repair and replacement rates and early and long-term survival. RESULTS: During the study period 36 redo-LAVV operations were performed, with repair in 28 and replacement in eight. The number of redo-operations increased from 13 in the first part to 23 in the second part of the study. The rate of LAVV preservation significantly increased over time (54% vs 91%, P < 0.01), and was not affected by morphology of AVSD or trisomy 21. There was one in-hospital death at Day 42 and overall estimated survival was 94.5% at 5 years. Freedom from reoperation after redo-LAVV repair was 87% at 5 years with no significant difference between repair and replacement groups. CONCLUSION: In the current era, more LAVVs can be preserved at the time of redo-operation with excellent early and long-term survival and acceptable reoperation rates. LAVV morphology and presence of trisomy 21 did not affect outcome.