Duplex echography as an adjuvant tool to clinical examination to detect early postoperative free flap vascular compromise.

BACKGROUND: Clinical examination remains the cornerstone for postoperative monitoring of free flaps but is highly dependent on the surgeon's ability and experience. Duplex echography provides a noninvasive objective evaluation of tissue perfusion. The authors hypothesized that duplex echography may be a more sensitive and specific monitoring method for early detection of postoperative flap compromise compared to clinical examination alone. The goal was to evaluate any differences between combined duplex echography and clinical examination flap monitoring versus isolated clinical evaluation. METHODS: A total of 730 free flaps in 700 patients were included in the study. We conducted an intra-subject prospective study of a cohort of patients who underwent free flap reconstruction in our unit to compare clinical examination with duplex echography for postoperative monitoring. An inter-subject study was also undertaken comparing the prospective cohort with a historical control group of patients in whom free flap monitoring was made using clinical examination alone. The patency flow and velocities through the artery and vein of the flap were measured at the donor and recipient vessels of every anastomosis by duplex scanning, by the same plastic surgeon every 4 hr, during the first 18 hr after surgery. RESULTS: Duplex echography and clinical evaluation were used in 175 patients. The historical cohort included a total of 525 flaps. Every patient with suspicion of vascular compromise based on duplex echography was taken back for surgical re-exploration. There were no cases of overdiagnosis using duplex echography (Sensitivity 100%, Specificity 100%). Clinical evaluation detected issues with the vascularan astomoses in 23/175 flaps. However, it failed to detect 12/22 cases which presented with vascular complications and gave a false indication of possible complications in 13 flaps (Sensitivity 45%, Specificity 92%). CONCLUSION: In our practice, duplex echography is considered a useful adjunct monitoring tool for early detection of postoperative flap compromise, which compliments clinical evaluation. It provides anatomic and hemodynamic information of the vascular status and may therefore increase survival of flaps by allowing earlier detection of vascular compromise, compared to clinical examination alone, in postoperative monitoring of free flaps.

Endoscopic Delayed Breast Reconstruction With Expanders and Implants via the Axillary Incision Made for Sentinel Lymph Node Biopsy or Lymphadenectomy.

BACKGROUND: Classic techniques of delayed prosthetic breast reconstruction use the mastectomy scar as an access route. As a result, the filling of the expander must be postponed until the wounds have healed. This creates an asymmetry between the breasts with the volume changes caused by the filling of the expander, which may occur over several weeks and cause considerable discomfort. METHODS: Delayed breast reconstruction was performed via the axillary incision made for sentinel lymph node biopsy or lymphadenectomy with endoscopic assistance and detachment of the pectoralis major muscle. The filling of the expander and symmetrization with the contralateral breast was performed in the first stage.The expander was replaced with the definitive prosthesis 3 months later, after endoscopic capsulotomy. Fat grafting was performed to create a lipobed around the implant and to improve tissue quality. RESULTS: Sixty-two patients underwent surgery. Mean follow-up was 19 months. There were no major complications in the reconstructed breast. One case of hematoma in a contralateral breast reduction and an oil cystic mass secondary to fat grafting were recorded. In all cases, the filling of the expander with the definitive volume was possible during the first stage. CONCLUSIONS: Endoscopic delayed breast reconstruction with insertion of implants through the axillary incision for sentinel node biopsy or lymphadenectomy is safe and feasible. It achieves complete intraoperative expansion, symmetry between the volumes of the breasts during the first stage, and avoids problems with the scar and the risk of extrusion, as the scar is placed remotely in the axilla.

Outcomes of Gastro-omental Free Flap Reconstruction for Salvage Laryngopharyngectomy for Pharyngeal and Laryngeal Cancer After Concurrent Chemoradiotherapy.

BACKGROUND: In the case of salvage laryngopharyngectomy, replacement of the pharyngoesophageal segment is mostly performed with fasciocutaneous or jejunal flaps. However, these options do not represent the best surgical technique of reconstruction in some occasions. Thus, the gastro-omental free flap could serve as an alternative procedure. METHODS: A retrospective review was conducted on patients who underwent pharyngoesophageal reconstruction using gastro-omental free flap after salvage laryngopharyngectomy for recurrent pharyngeal or laryngeal carcinoma between 1992 and 2012 at Bellvitge Universitary Hospital. The perioperative morbidity, mortality, functional outcomes, and oncological outcomes were evaluated. RESULTS: Twenty-six patients were included and followed up at our hospital for a mean of 43.4 months (range, 12-184 months). Survival rate was 94% after 1-year follow-up and 89% after 3 years. Abdominal evisceration was observed in 2 cases, whereas no abdominal complications occurred to the other patients. Total flap necrosis was observed in 3 (11.5%) patients. Postoperative course was uneventful in 20 patients. Moreover, esophageal continuity without fistula was confirmed by barium swallow test. CONCLUSIONS: The gastro-omental flap represents a useful method for reconstruction of the pharyngoesophageal segment in a surgical field compromised by previous multimodal therapy. Despite being useful, the complication rate is relevant.

Merkel cell carcinoma: differences between sun-exposed and non-sun-exposed variants--a clinical analysis of 36 cases.

BACKGROUND: There are few studies focusing on the clinical characteristics of Merkel cell carcinoma (MCC). OBJECTIVE: To retrospectively analyze the clinical features of our patients and their relationship with sun exposure. METHODS: Thirty-six patients diagnosed with MCC (20 men and 16 women, mean age 72.08 years) were included in the study. RESULTS: 21 patients developed MCC in sun-exposed skin and 15 patients in non-sun-exposed areas. MCC was >2 cm in 19 cases. Six of the 7 patients who died as a result of MCC had non-sun-exposed tumors. Only tumor size >2 cm significantly influenced survival (p = 0.033). CONCLUSION: Sun-exposed lesions tended to be <2 cm in diameter and were more common in men, while non-sun-exposed tumors were larger, usually occurring in women and carrying a greater likelihood of death by MCC. Non-sun-exposed tumors usually present as fast-growing, multilobar nodular lesions with a smooth shiny surface.

[Supercharged ileocoloplasty: an option for complex oesophageal reconstructions]. / Ileocoloplastia supercharged: una opción para reconstrucciones esofágicas complejas.

INTRODUCTION: Oesophageal reconstruction in a second time is a complex surgical operation which, in some cases, requires combining microvascular techniques to increase vascular flow to the conduit. "Supercharged" ileocoloplasty allows creation of a longer conduit that makes it possible to replace the entire oesophagus. We describe our initial experience with this technique for the total reconstruction of the oesophagus. MATERIAL AND METHODS: A retrospective review of the period from October 2007 to December 2009 identified 4 patients on whom a deferred oesophageal reconstruction was performed with a "supercharged" ileocoloplasty. The indications of this technique, morbidity and mortality, as well as functional results during follow up were evaluated. RESULTS: The indications of this technique were: previous failure of a left colon interposition (1), oesophageal disconnection due to a gastro-pleural fistula (1), total oesophagogastrectomy (1) and partial oesophagogastrectomy (1) due to the ingestion of caustic substances, respectively. Gastrointestinal complications were the most frequent. Two cervical fistulas were diagnosed which were resolved with an absolute diet, antibiotic therapy and enteral nutrition. There was no mortality. After a median follow up of 14.7 months, two patients were nourished exclusively by mouth, one by a mixed route (oral-enteral) and another exclusively by the enteral route due to an oesophageal stenosis 11 centimetres from the dental arch; this patient required dilations and is awaiting a jejunal graft. CONCLUSIONS: "Supercharged" ileocoloplasty is a complex treatment option for the total reconstruction of the oesophagus when no other alternatives are available. Postoperative morbidity is significant but the functional results are good.

FGFR Inhibition Overcomes Resistance to EGFR-targeted Therapy in Epithelial-like Cutaneous Carcinoma.

PURPOSE: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy. EXPERIMENTAL DESIGN: We generated primary cell cultures and patient cSCC-derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance. RESULTS: cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors. CONCLUSIONS: EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.

PDGFR-induced autocrine SDF-1 signaling in cancer cells promotes metastasis in advanced skin carcinoma.

Advanced and undifferentiated skin squamous cell carcinomas (SCCs) exhibit aggressive growth and enhanced metastasis capability, which is associated in mice with an expansion of the cancer stem-like cell (CSC) population and with changes in the regulatory mechanisms that control the proliferation and invasion of these cells. Indeed, autocrine activation of PDGFRα induces CSC invasion and promotes distant metastasis in advanced SCCs. However, the mechanisms involved in this process were unclear. Here, we show that CSCs of mouse advanced SCCs (L-CSCs) express CXCR4 and CXCR7, both receptors of SDF-1. PDGFRα signaling induces SDF-1 expression and secretion, and the autocrine activation of this pathway in L-CSCs. Autocrine SDF-1/CXCR4 signaling induces L-CSC proliferation and survival, and mediates PDGFRα-induced invasion, promoting in vivo lung metastasis. Validation of these findings in patient samples of skin SCCs shows a strong correlation between the expression of SDF1, PDGFRA, and PDGFRB, which is upregulated, along CXCR4 in tumor cells of advanced SCCs. Furthermore, PDGFR regulates SDF-1 expression and inhibition of SDF-1/CXCR4 and PDGFR pathways blocks distant metastasis of human PD/S-SCCs. Our results indicate that functional crosstalk between PDGFR/SDF-1 signaling regulates tumor cell invasion and metastasis in human and mouse advanced SCCs, and suggest that CXCR4 and/or PDGFR inhibitors could be used to block metastasis of these aggressive tumors.

Salvage surgery after head and neck squamous cell carcinoma treated with bioradiotherapy.

BACKGROUND: The purpose of this study was to describe the results and complications of primary site salvage surgery after head and neck squamous cell carcinoma (HNSCC) treated with bioradiotherapy. METHODS: We conducted a retrospective chart review of 268 patients treated with bioradiotherapy between March 2006 and December 2013 at the Hospital Universitari de Bellvitge-ICO. RESULTS: Fifty-nine patients developed local recurrence or had residual disease with a 1-year and 3-year overall survival of 47% and 15.4%, respectively. Salvage surgery was feasible in 22 patients (37.3%). There were 16 complications in these 22 patients (72.7%), 11 (50%) of which were major. Bilateral neck dissection was identified as a risk factor for complications. CONCLUSION: Salvage surgery after bioradiotherapy is associated with a high rate of complications. Neck dissection seems to be related to an increased rate of complications with no survival improvement. © 2016 Wiley Periodicals, Inc. Head Neck 39: 116-121, 2017.

Clinical practice guidelines for the diagnosis and treatment of patients with soft tissue sarcoma by the Spanish group for research in sarcomas (GEIS).

Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours, which require a complex and specialized multidisciplinary management. The diagnostic approach should include imaging studies and core needle biopsy performed prior to undertaking surgery. Wide excision is the mainstay of treatment for localized sarcoma, and associated preoperative or postoperative radiotherapy should be administered in high-risk patients. Adjuvant chemotherapy was associated with a modest improvement in survival in a meta-analysis and constitutes a standard option in selected patients with high-risk STS. In metastatic patients, surgery must be evaluated in selected cases. In the rest of patients, chemotherapy and, in some subtypes, targeted therapy often used in a sequential strategy constitutes the treatment of election. Despite important advances in the understanding of the pathophysiology of the disease, the advances achieved in therapeutic results may be deemed still insufficient. Moreover, due to the rarity and complexity of the disease, the results in clinical practice are not always optimal. For this reason, the Spanish Group for Research on Sarcoma (GEIS) has developed a multidisciplinary clinical practice guidelines document, with the aim of facilitating the diagnosis and treatment of these patients in Spain. In the document, each practical recommendation is accompanied by level of evidence and grade of recommendation on the basis of the available data.

Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression.

Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. ß-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC.

Late toxicity after radical treatment for locally advanced head and neck cancer.

BACKGROUND: Multimodal treatment for locally advanced head and neck carcinomas (LAHNC) has been reported to improve survival. However, it is less clear to what extent this survival gain is given at the expense of an impact on the quality of life of our patients. Our aim is to analyze the ongoing late toxic effects among long survivors, to determine how much these impairments affect their QoL, and if there is any factor that clearly impacts on this toxicity. METHODS: 152 Patients diagnosed with LAHNC were treated radically in our clinical practice, either with concomitant chemoradiotherapy or bioradiotherapy, with or without induction chemotherapy. We prospectively assessed these patients' treatment-related late toxicities according to the Radiation Therapy Oncology Group scoring system, and patients answered a QoL question to subjectively evaluate the degree of impact caused by these sequelae in their daily life. Multivariate logistic regressions were performed to detect factors that could influence in toxicity. RESULTS: 21.9% Patients experienced grade 3-4 toxicity. Concomitant chemoradiation with cisplatin was found to be a risk factor of moderate and severe late toxicity compared to concomitant cetuximab in the adjusted analysis by RT fractionation. OR for moderate toxicity 0.292 (CI: 0.125-0.680, p=0.004); OR for severe toxicity: 0.299 (CI: 0.0909-0.999, p=0.05). Induction chemotherapy was found to be a protective factor for moderate late toxicity compared to concomitant treatment alone. CONCLUSION: Patients treated with concomitant chemoradiation with cisplatin have significantly more late toxicity compared to bioradiotherapy, whereas induction chemotherapy prevents from developing moderate late toxicity.

Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine.

Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. We present the generation and characterization of five distinct MPNST orthoxenograft models for preclinical testing and personalized medicine. Four of the models are patient-derived tumor xenografts (PDTX), two independent MPNSTs from the same NF1 patient and two from different sporadic patients. The fifth model is an orthoxenograft derived from an NF1-related MPNST cell line. All MPNST orthoxenografts were generated by tumor implantation, or cell line injection, next to the sciatic nerve of nude mice, and were perpetuated by 7-10 mouse-to-mouse passages. The models reliably recapitulate the histopathological properties of their parental primary tumors. They also mimic distal dissemination properties in mice. Human stroma was rapidly lost after MPNST engraftment and replaced by murine stroma, which facilitated genomic tumor characterization. Compatible with an origin in a catastrophic event and subsequent genome stabilization, MPNST contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Mutational frequency and type of somatic point mutations were highly variable among the different MPNSTs modeled, but very consistent when comparing primary tumors with matched orthoxenografts generated. Unsupervised cluster analysis and principal component analysis (PCA) using an MPNST expression signature of ~1,000 genes grouped together all primary tumor-orthoxenograft pairs. Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines. Following standardization and extensive characterization and validation, the orthoxenograft models were used for initial preclinical drug testing. Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth. The development of genomically well-characterized preclinical models for MPNST allowed the evaluation of novel therapeutic strategies for personalized medicine.

Arsenic immobilization as alunite-type phases: the arsenate substitution in alunite and hydronium alunite.

AsO4-for-SO4 substitution in alunite (KAl3(SO4)2(OH)6) and hydronium alunite ((H3O)Al3(SO4)2(OH)6) has been investigated by hydrothermal precipitation at 200°C. Arsenical alunite presented a good precipitation yield and a significant AsO4 substitution (up to 15% molar). The degree of arsenate substitution depends on the solution composition. It increased as (AsO4/(AsO4+SO4))alunite ≅ 0.5 (AsO4/(AsO4+SO4))L. For (AsO4/(AsO4+SO4))L<0.26, arsenical alunite was the unique phase and, above this ratio, mansfieldite (AlAsO4·2H2O) co-precipitated. The a unit cell parameter is practically independent of the AsO4 substitution, but the c unit cell parameter increased consistently with the differences between the AsO1 and SO1 distances in tetrahedral sites of the structure. The maximum stability of arsenical alunite in short-term tests is between pH 5 and 8, with an As-solubilization of 0.01-0.03 mg/L in 24h. Long-term tests were performed at some synthesized samples at its natural pH. Arsenical alunite was stabilized at 0.3mg/L released As in 2.5 weeks. These values were similar to those obtained in pure and largely crystalline natural scorodite (0.4 mg/L released As), but lower than the obtained for synthetic scorodite (1.3mg/L released As). Thus, arsenical alunite could be effective for arsenic immobilization, especially for effluents or wastes containing large SO4/AsO4 ratio. Hydronium alunite presents a low precipitation yield and a very low arsenate incorporation (up to 1% molar). This may be related by the difficulty of substituting protonated H2O-for-OH(-) groups, due to the location of the H-bridges of the H3O in the structure. These characteristics make hydronium alunite unsuitable for arsenic immobilization.

[Soft tissue sarcomas: clinical practice guidelines]. / Guía de práctica clínica en los sarcomas de partes blandas.

Soft tissue sarcomas (STS) constitute a rare heterogeneous group of tumours that include a wide variety of histological subtypes, which require a multidisciplinary and, frequently specialized and complex management. Despite advances in our understanding of the pathophysiology of the disease, there are no consensus multidisciplinary recommendations about its diagnosis and treatment in our country. The objective of these guidelines is to provide practical therapeutic recommendations that may contribute to improve the therapeutic results of this disease in our environment. With this purpose, the Spanish Group for Research in Sarcomas (GEIS) held a meeting with a multidisciplinary group of experts for the study and management of sarcomas. The results of this meeting are compiled in this document, in which recommendations on diagnosis, treatment and monitoring of soft tissue sarcomas are included. In summary, these guidelines aim to facilitate the identification and management of STS for clinical practice in Spain.