An up-to-date myopathologic characterisation of facioscapulohumeral muscular dystrophy type 1 muscle biopsies shows sarcolemmal complement membrane attack complex deposits and increased skeletal muscle regeneration.

The aim of this study was to identify key routinely used myopathologic biomarkers of FSHD1. Needle muscle biopsies were taken in 34 affected muscles (m. quadriceps femoris (QF), n = 20, m. tibialis anterior (TA), n = 13, m. biceps brachii, n = 1) from 22 patients (age, 53.5 (10) years; M = 12, F = 10). Eleven patients had more than one biopsy (2xQF, n = 1; QF+TA, n = 9; 2xQF+TA, n = 1). Histochemistry, immunoperoxidase, and immunofluorescence stainings were performed and compared to age and muscle type matched muscle specimens of 11 healthy controls. Myopathologic features observed in our FSHD1 cohort were internalized nuclei, type 1 fibre hypertrophy and NADH central clearances/cores. We observed a prominent inflammatory response with MAC deposits, MHC I expression, and muscle regeneration that correlated with the inflammatory score. Our up-to-date characterization of FSHD1 points towards MHC I, MAC, and embryonic Myosin Heavy Chain/muscle regeneration as useful myopathologic readouts of FSHD1.

MEK-inhibitors decrease Nfix in muscular dystrophy but induce unexpected calcifications, partially rescued with Cyanidin diet.

Muscular dystrophies (MDs) are incurable genetic myopathies characterized by progressive degeneration of skeletal muscles. Dystrophic mice lacking the transcription factor Nfix display morphological and functional improvements of the disease. Recently, we demonstrated that MAPK signaling pathway positively regulates Nfix in muscle development and that Cyanidin, a natural antioxidant molecule, strongly ameliorates the pathology. To explore a synergistic approach aimed at treating MDs, we administered Trametinib, a clinically approved MEK inhibitor, alone or combined with Cyanidin to adult Sgca null mice. We observed that chronic treatment with Trametinib and Cyanidin reduced Nfix in myogenic cells but, unexpectedly, caused ectopic calcifications exclusively in dystrophic muscles. The combined treatment with Cyanidin resulted in histological improvements by preventing Trametinib-induced calcifications in Diaphragm and Soleus. Collectively, this first pilot study revealed that Nfix is modulated by the MAPK pathway in MDs, and that Cyanidin partly rescued the unexpected ectopic calcifications caused by MEK inhibition.

Receptor interacting protein kinase-3 mediates both myopathy and cardiomyopathy in preclinical animal models of Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive muscle degenerative disorder, culminating in a complete loss of ambulation, hypertrophic cardiomyopathy and a fatal cardiorespiratory failure. Necroptosis is the form of necrosis that is dependent upon the receptor-interacting protein kinase (RIPK) 3; it is involved in several inflammatory and neurodegenerative conditions. We previously identified RIPK3 as a key player in the acute myonecrosis affecting the hindlimb muscles of the mdx dystrophic mouse model. Whether necroptosis also mediates respiratory and heart disorders in DMD is currently unknown. METHODS: Evidence of activation of the necroptotic axis was examined in dystrophic tissues from Golden retriever muscular dystrophy (GRMD) dogs and R-DMDdel52 rats. A functional assessment of the involvement of necroptosis in dystrophic animals was performed on mdx mice that were genetically depleted for RIPK3. Dystrophic mice aged from 12 to 18 months were analysed by histology and molecular biology to compare the phenotype of muscles from mdxRipk3+/+ and mdxRipk3-/- mice. Heart function was also examined by echocardiography in 40-week-old mice. RESULTS: RIPK3 expression in sartorius and biceps femoris muscles from GRMD dogs positively correlated to myonecrosis levels (r = 0.81; P = 0.0076). RIPK3 was also found elevated in the diaphragm (P ≤ 0.05). In the slow-progressing heart phenotype of GRMD dogs, the phosphorylated form of RIPK1 at the Serine 161 site was dramatically increased in cardiomyocytes. A similar p-RIPK1 upregulation characterized the cardiomyocytes of the severe DMDdel52 rat model, associated with a marked overexpression of Ripk1 (P = 0.007) and Ripk3 (P = 0.008), indicating primed activation of the necroptotic pathway in the dystrophic heart. MdxRipk3-/- mice displayed decreased compensatory hypertrophy of the heart (P = 0.014), and echocardiography showed a 19% increase in the relative wall thickness (P < 0.05) and 29% reduction in the left ventricle mass (P = 0.0144). Besides, mdxRipk3-/- mice presented no evidence of a regenerative default or sarcopenia in skeletal muscles, moreover around 50% less affected by fibrosis (P < 0.05). CONCLUSIONS: Our data highlight molecular and histological evidence that the necroptotic pathway is activated in degenerative tissues from dystrophic animal models, including the diaphragm and the heart. We also provide the genetic proof of concept that selective inhibition of necroptosis in dystrophic condition improves both histological features of muscles and cardiac function, suggesting that prevention of necroptosis is susceptible to providing multiorgan beneficial effects for DMD.

An early onset benign myopathy with glycogen storage caused by a de novo 1.4 Mb-deletion of chromosome 14.

Early onset myopathies are a clinically and histologically heterogeneous monogenic diseases linked to approximately 90 genes. Molecular diagnosis is challenging, especially in patients with a mild phenotype. We describe a 26-year-old man with neonatal hypotonia, motor delay and seizures during infancy, and non-progressive, mild muscular weakness in adulthood. Serum Creatine kinase level was normal. Whole-body muscle MRI showed thin muscles, and brain MRI was unremarkable. A deltoid muscle biopsy showed glycogen storage. WGS revealed a de novo 1.4 Mb-deletion of chromosome 14, confirmed by Array-CGH. This microdeletion causes the loss of ten genes including RALGAPA1, encoding for RalA, a regulator of glucose transporter 4 (GLUT4) expression at the membrane of myofibers. GLUT4 was overexpressed in patient's muscle. Here we highlight the importance to search for chromosomal alterations in the diagnostic workup of early onset myopathies.

Transnasal endoscopic surgery in selected nasal-ethmoidal cancer with suspected brain invasion: Indications, technique, and outcomes.

BACKGROUND: In nasal-ethmoidal malignancies, brain involvement is associated with dismal prognosis. METHOD: Patients undergoing endoscopic resection with transnasal craniectomy and subpial dissection (ERTC-SD) for brain-invading nasal-ethmoidal cancer between 2008 and 2016 were included. Complications were analyzed in all patients, whereas oncological outcomes only in patients with pathological brain invasion. The prognostic impact of previous treatments, brain edema, and histology was assessed. Hospitalization ratio was calculated. RESULTS: Nineteen patients received ERTC-SD and 11 had pathological-proven brain invasion. Histologies were 6 olfactory neuroblastomas (ONB), 3 neuroendocrine carcinomas, and 2 intestinal-type adenocarcinomas. Mean follow-up was 21.9 months. Three-year overall, local recurrence-free, and distance recurrence-free survivals were 65.5%, 81.8%, and 68.2%, respectively. Overall and distant recurrence-free survivals were significantly better in patients with ONB (P = 0.032 and P = 0.013, respectively). Hospitalization ratio was 4.1%. Complication rate was 10.5%. CONCLUSION: In selected nasal-ethmoidal tumors with brain invasion, ERTC-SD can provide good local control, satisfactory survival, and limited morbidity.

Fasciocutaneous free flaps for reconstruction of hypopharyngeal defects.

OBJECTIVES/HYPOTHESIS: Different reconstructive options are available for defects following total laryngectomy (TL) and circumferential (CH) or partial hypopharyngectomy (PH). We evaluated the flap success, pharyngocutaneous fistula, and pharyngoesophageal stenosis rates in two groups of patients treated by different policies. STUDY DESIGN: Comparison between two cohorts of patients treated by TL with PH/CH ± cervical esophagectomy and reconstructed according to different strategies. METHODS: Group A (historical) was composed of 89 patients reconstructed by pectoralis major myocutaneous (PMMC), radial forearm (RF), and anterolateral thigh (ALT) flaps. A salivary bypass stent (SBPS) was not routinely applied and left in place for a maximum of 14 days. Forty-four (49%) patients received preoperative radiotherapy/chemoradiotherapy (RT/CRT). Group B (prospective) included 105 patients reconstructed by RF or ALT with long-lasting SBPS left in place for a maximum of 45 days. Sixty-one (59%) received preoperative RT/CRT. RESULTS: In group A, flap failure occurred in four (4%) cases, and all were managed by PMMC. We encountered 22 (26%) fistulas and 14 (16%) stenoses. In group B, flap failure occurred in six (6%) cases and was managed by PMMC. We encountered seven (7%) fistulas and three (3%) stenoses. Comparing complications among the two groups, we encountered a statistically significant difference in favor of group B for both fistula (P < .001) and stenosis (P = .001). We did not evidence any significant difference in terms of flap success rate. CONCLUSIONS: First-line application of RF and ALT free flaps with long-lasting SBPS in reconstruction after PH/CH allows obtaining reduced incidences of both fistula and stenosis. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2731-2737, 2017.

Palato-maxillary reconstruction by the angular branch-based tip of scapula free flap.

The angular branch (AB)-based tip of scapula free flap is a valuable reconstructive option in palato-maxillary defects needing significant structural support. We herein retrospectively evaluate our surgical series with special focus on functional outcomes and postoperative morbidity. Ninety-seven consecutive palatomaxillary oncologic resections were performed at our institution between August 2008 and November 2015. The analysis focused on those reconstructed by an AB-based tip of scapula free flap (N = 18; 19 %). A prospective assessment of donor site morbidity was performed by the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire in 12 (67 %) patients. Among patients reconstructed by an AB-based tip of scapula free flap, 13 (72 %) had a Class II and 5 (28 %) a Class III defect according to Okay classification. Flap success rate was 94 %, with one failure requiring an anterolateral thigh flap. Eight (44 %) patients experienced recipient site complications, while donor site problems occurred in two only (11 %). Eleven (61 %) subjects were able to maintain a normal and 7 (39 %) a soft-to-firm diet. The mean DASH score was 10.5. Our results confirm that the AB-based tip of scapula free flap is a reliable choice in palatomaxillary reconstruction, with both satisfactory functional outcomes and negligible donor site morbidity.

Microvascular head and neck reconstruction in the elderly: The University of Brescia experience.

BACKGROUND: Microvascular reconstruction in head and neck surgery is increasing in the elderly because of prolonged life expectancy. The purpose of this study was to evaluate the impact of age on outcomes after microvascular reconstruction. METHODS: We retrospectively reviewed 453 microvascular reconstructions and stratified patients according to age (40.8% >65 years old). Medical and surgical complications and flap success rates were evaluated according to the American Society of Anesthesiologists (ASA) score for physical status and age. RESULTS: Overall flap success and perioperative mortality were 96.1% and 0.7%, respectively. Minor medical complications were higher in the elderly (28.1% vs 15.3%; p = .001). High ASA scores affected rates of major surgical (20% vs 9.2%; p = .001) and minor medical complications (27.2% vs 13.3%; p < .001). CONCLUSION: Microvascular reconstruction is reliable in the elderly. Age should not be considered a contraindication by itself; comorbidities play a stronger role in predicting adverse events. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1488-E1492, 2016.

Free flaps in head and neck reconstruction after oncologic surgery: expected outcomes in the elderly.

OBJECTIVE: To provide surgeons and clinicians with a critical review of microvascular reconstructive options and their expected outcomes after head and neck cancer resection in the elderly. DATA SOURCES: Medline, Isiweb, and Cochrane databases. REVIEW METHODS: A literature search was performed in May 2014 and included studies published between 2000 and 2014. Keywords were used for articles identification, and inclusion criteria were defined for consideration in the present review. CONCLUSIONS: Evaluation of the pertinent literature is hampered by a number of biases, such as a lack of general consensus of a definition of "elderly," differences among scales used to quantify comorbidities, and subjective evaluation of flap-related and systemic complications. However, our findings showed no differences in terms of free flap success, surgical complications, or mortality rate between older and younger patients. Moreover, recipient site complications do not seem to be affected by age. IMPLICATION FOR PRACTICE: Microvascular reconstruction in the elderly can be performed with high success rates, even though medical complications can occur more frequently compared to younger patients. Minor and major surgical complications in the elderly appear to be comparable to those in the younger population and do not affect final outcome or the perioperative mortality rate. Flap outcome does not seem to be significantly affected by age. Careful preoperative assessment and postoperative monitoring are mandatory to prevent adverse events, and prompt management is warranted whenever present.

Is it time to incorporate 'depth of infiltration' in the T staging of oral tongue and floor of mouth cancer?

PURPOSE OF REVIEW: To summarize recent acquisitions in three-dimensional tongue and floor of mouth anatomy that can help in better evaluation of the pathways of cancer progression within these oral subsites, thus giving some hints for refining of the current TNM staging system. RECENT FINDINGS: The Visual Human Project is an initiative aimed at establishing a three-dimensional dataset of anatomy of two cadavers made available free to the scientific community. Visual human data have been analyzed by specific software thus improving our three-dimensional understanding of the tongue myostructure. It is already known that there is limited prognostic utility in using the two-dimensional surface diameter alone as criterion for T1-T3 definition. Recently, also the T4a categorization for the infiltration of 'deep' or extrinsic tongue muscles has been criticized. This is largely because the descriptor 'deep' does not take into account the fact that considerable portions of these muscles lie in a very superficial plane. Different prognosticators have been proposed for inclusion into the TNM staging system of oral cancer but 'depth of tumor infiltration' seems to be the most robust, universally recognized, and reproducible in the preoperative, intraoperative, and postoperative settings. SUMMARY: Oral tongue and floor of mouth cancer needs to be classified according to a revised TNM staging system in which 'depth of infiltration' should be taken into account. An 'ideal cut off' for distinguishing 'low' (T1-T2) from 'high-risk' (T3-T4) categories has been proposed based on the literature review, but needs retrospective as well as large prospective trials before its validation.

End-to-end versus end-to-side venous microanastomoses in head and neck reconstruction.

Venous thrombosis (VT) is the primary reason for microvascular free flaps (MFFs) failure. Different series have addressed the influence of venous anastomosis, end-to-end (ETE) vs. end-to-side (ETS), on this issue in head and neck (HN) microsurgery, but a consensus about the optimal technique to be adopted is still lacking. The aim of this study is to prospectively compare the venous complication rates of ETE and ETS techniques in 422 homogeneously treated patients who underwent MFF for HN oncologic defects between 2000 and 2012 at our Institution. Patients were divided into two groups: Group A (n = 269 patients) receiving an ETE and Group B (n = 153) an ETS venous anastomosis. The choice between the type of venous anastomosis was based on the several variables: availability of adequate caliber recipient veins in the neck, length and caliber of the donor vein, geometry and orientation of the vascular pedicle, and possibility to create a tensionless anastomosis. An ETE anastomosis was always preferred when feasible, while an ETS (performed on the internal jugular vein) was reserved to cases in which the abovementioned considerations contraindicated an ETE. Overall, the MFF failure rate was 3%. Among the 13 failures, five had VT (1.1%): three had received an ETE, and two an ETS. Venous anastomosis re-exploration and failure rates of the two groups were compared by the Chi-squared test showing no statistically significant differences. In conclusion, our data show how ETS venous anastomosis is a safe alternative to ETE whenever the latter cannot be properly accomplished for the previously mentioned contraindications.

Evolution of complex palatomaxillary reconstructions: the scapular angle osteomuscular free flap.

PURPOSE OF REVIEW: This review summarizes the worldwide experience (105 patients) in primary and secondary reconstruction of palatomaxillary oncologic defects with the angular branch-based subscapular system of free flaps, comparing the advantages and disadvantages of the technique with those of other well known osseous donor sites such as the fibula and iliac crest. RECENT FINDINGS: The most recognized indications for angular branch-based osteomuscular free flaps are class II (especially in association with zygomaticomaxillary buttress and/or floor of the orbit removal) and class III defects according to the Okay classification. Defects involving clearance of the orbital content have also been reconstructed in this manner. One of the most important drawbacks of this technique (i.e., need for intraoperative patient repositioning) is no longer considered an issue, and evidence has been provided that harvesting of angular branch-based scapular flaps may be routinely performed in a supine position. Three-dimensional morphologic similarity of the tip of the scapula with the native hard palate and other maxillary structures makes flap fabrication easy and practical, with at least two (horizontal and vertical) most commonly used flap orientations applied to reconstruct different defects. SUMMARY: Angular branch-based osteomuscular scapular free flaps represent a major advance in palatomaxillary reconstruction: their versatility, long pedicle with large caliber donor vessels, morphologic similarity with maxillary bony structures, and limited donor-site morbidity compare favorably with those of other osteomuscular and osteomusculocutaneous free flaps described for such challenging reconstructive purposes.

Reconstructive options after total laryngectomy with subtotal or circumferential hypopharyngectomy and cervical esophagectomy.

PURPOSE OF REVIEW: The present review is focused on the main reconstructive options currently used after partial or circumferential resection of the hypopharynx and cervical esophagus. The advantages and disadvantages of pectoralis major myocutaneous (PMMC) pedicled flap, fasciocutaneous free flaps as radial forearm and anterolateral thigh (ALT), and visceral free grafts like jejunum and gastro-omental are overviewed. RECENT FINDINGS: For partial hypopharyngeal defects with limited extension to the cervical esophagus, no specific pedicled or free flap is deemed superior over others: the patient's body habitus and surgeon's preference remain the most important factors affecting the reconstructive choice. In contrast, after circumferential hypopharyngectomy, pharyngocutaneous fistula (PCF) and stricture rates of PMMC are higher than those obtained by free flaps. In the most recent series applying ALT and jejunum, PCF and stricture occurrence is comparable, whereas reduced mortality, overall complication rate, and donor-site morbidity of ALT and its better swallowing and speech outcomes have contributed to make this option progressively more popular. On the other hand, gastro-omental seems to offer an unparalleled amount of highly vascularized tissue to manage the difficult situation of salvage surgery after chemoradiation, even though complication rates remain not negligible and this technique has not been widely adopted. SUMMARY: The reconstructive armamentarium of head and neck surgeons involved in hypopharyngeal and cervical esophagus reconstruction should encompass every option described herein in order to appropriately deal with specific clinical needs and patient requirements. However, fasciocutaneous free flaps (especially ALT) seem to play an ever greater role in restoration of pharyngoesophageal continuity.

Deep inferior epigastric artery perforated rectus abdominis free flap for head and neck reconstruction.

The deep inferior epigastric artery perforated rectus abdominis (DIEAP-ra) free flap is a modification of the classic myocutaneous DIEA free flap in which only fasciocutaneous tissue is harvested based on the paraumbilical perforators of the medial row. The aim of this retrospective study is to describe our experience with this reconstructive technique in head and neck surgery. Between 2004 and 2009, 24 patients affected by oncologic maxillofacial, skull base, oral, and oropharyngeal defects were submitted to reconstruction with DIEAP-ra. After harvesting the DIEAP-ra, the longitudinally split muscular belly was sutured and the anterior rectus sheath closed with a nonabsorbable mattress suture without inlay mesh interposition. Surgical defects encompassed half of the hard palate in ten patients, orbit and part of the cranial vault in one, radical extended parotidectomy in four, subtotal glossectomy in seven, and total glossectomy in two cases. The only complete flap necrosis (4%) developed as a consequence of an orocutaneous fistula and required a second latissimus dorsi free flap. Another case (4%) developed a partial necrosis for oropharyngeal fistula after total glossectomy that healed after transposition of a pedicled myofascial pectoralis major. Two patients (8%) presented a minor salivary fistula that healed by medication alone. No major complication of the donor site was observed. DIEAP-ra is a valid alternative to the DIEA free flap when applied to complex maxillofacial or tongue major defects. Its greatest advantages are the reduced donor site morbidity and a more adjustable thickness of the skin paddle, particularly in females and obese patients.