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.

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.

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.

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.

Fallo de la interposición de colon tras esofagogastrectomía: ¿cuál es el siguiente paso? / Failed colonic interposition after esophagogastrectomy: What's the next step?

No disponible

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.

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.

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

Introducción La reconstrucción esofágica en un segundo tiempo es una intervención quirúrgica compleja que, en algunos casos, requiere asociar técnicas microvasculares para aumentar el flujo vascular a la plastia (supercharged). La ileocoloplastia supercharged permite crear una plastia larga que hace posible sustituir la totalidad del esófago. Describimos nuestra experiencia inicial con esta técnica para la reconstrucción de todo el esófago. Material y métodos La revisión retrospectiva del periodo octubre de 2007 a diciembre de 2009 identificó a 4 pacientes a los que se les realizó una reconstrucción esofágica diferida con una ileocoloplastia supercharged. Se evaluaron las indicaciones de esta técnica, la morbilidad y mortalidad, así como, los resultados funcionales durante el seguimiento. Resultados Las indicaciones de esta técnica fueron: fracaso previo de una interposición de colon izquierdo (1), desconexión esofágica por fístula gastropleural (1), esofagogastrectomía total (1) y esofagogastrectomía parcial (1) por ingesta de cáusticos, respectivamente. Las complicaciones digestivas fueron las más frecuentes. Se diagnosticaron dos fístulas cervicales que se resolvieron con dieta absoluta, antibioticoterapia y nutrición enteral. No hubo mortalidad. Tras una mediana de seguimiento de 14,7 meses, dos pacientes se nutrían exclusivamente por vía oral, uno por vía mixta (oral-enteral) y otro exclusivamente por vía enteral debido a una estenosis esofágica a 11 centímetros de arcada dentaria; este paciente ha precisado dilataciones y está pendiente de un injerto de yeyuno. Conclusiones La ileocoloplastia supercharged es una opción técnica compleja para reconstruir todo el esófago cuando no se dispone de otras alternativas. La morbilidad postoperatoria es significativa pero los resultados funcionales son buenos (AU)

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 (AU)