Clinical Penetrance of Hereditary Hemochromatosis-Related End-Organ Damage of C282Y Homozygosity, A Newfoundland Experience.

INTRODUCTION: Hereditary hemochromatosis is an autosomal recessive disorder of iron absorption, leading to organ dysfunction. C282Y gene homozygosity is implicated in 80%-95% of cases of hereditary hemochromatosis. The clinical penetrance of this genotype remains unclear. The purpose of the study was to better describe the clinical penetrance and disease progression of C282Y homozygotes. METHODS: This is a retrospective study of all individuals in Newfoundland and Labrador, Canada, homozygous for the C282Y mutation from 1999 to 2009. Using electronic health records, laboratory values, phlebotomy status, radiologic reports, and clinic records were recorded up to November 2017. Iron overload status was classified via the HealthIron study. SPSS Version 19.0 (IBM Corporation) was used for descriptive statistics. Predictors of disease penetrance were assessed with logistic regression; a Student t test was used for continuous variables, and χ tests were used for categorical variables. RESULTS: Between 1999 and 2009, 360 individuals tested positive for C282Y/C282Y. The mean age of diagnosis was 49.1 years. Three hundred six individuals had adequate follow-up for analysis (mean 11.6 years). End-organ damage was observed in 18.3%, with 5.8% developing liver disease. End-organ damage was more frequently observed in men 24.3% vs 10.5% (P < 0.05). Clinical penetrance in postmenopausal women approached that of men 18.3%. DISCUSSION: This is the largest reported cohort of C282Y homozygotes, followed for an extended duration of time in North America. The findings reflect outcomes in routine clinical practice and suggest that C282Y homozygosity uncommonly causes end-organ damage and liver disease.

Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease.

BACKGROUND: Bacteroides thetaiotaomicron (Bt) is a prominent member of the human intestinal microbiota that, like all gram-negative bacteria, naturally generates nanosized outer membrane vesicles (OMVs) which bud off from the cell surface. Importantly, OMVs can cross the intestinal epithelial barrier to mediate microbe-host cell crosstalk involving both epithelial and immune cells to help maintain intestinal homeostasis. Here, we have examined the interaction between Bt OMVs and blood or colonic mucosa-derived dendritic cells (DC) from healthy individuals and patients with Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: In healthy individuals, Bt OMVs stimulated significant (p < 0.05) IL-10 expression by colonic DC, whereas in peripheral blood-derived DC they also stimulated significant (p < 0.001 and p < 0.01, respectively) expression of IL-6 and the activation marker CD80. Conversely, in UC Bt OMVs were unable to elicit IL-10 expression by colonic DC. There were also reduced numbers of CD103+ DC in the colon of both UC and CD patients compared to controls, supporting a loss of regulatory DC in both diseases. Furthermore, in CD and UC, Bt OMVs elicited a significantly lower proportion of DC which expressed IL-10 (p < 0.01 and p < 0.001, respectively) in blood compared to controls. These alterations in DC responses to Bt OMVs were seen in patients with inactive disease, and thus are indicative of intrinsic defects in immune responses to this commensal in inflammatory bowel disease (IBD). CONCLUSIONS: Overall, our findings suggest a key role for OMVs generated by the commensal gut bacterium Bt in directing a balanced immune response to constituents of the microbiota locally and systemically during health which is altered in IBD patients. Video Abstract.

Microneedles with Tunable Dissolution Rate.

Dissolvable microneedle (MN) patches have been widely investigated for transdermal drug delivery. The dissolution rate of MN controls the status of drug release from the MN, which in turn determines drug absorption through skin. However, no systematic approaches have been reported to tune the dissolution profile of dissolvable MN matrices. This is the first study to show polyvinylpyrrolidone (PVP)-based dissolvable MN patches with varying dissolution profiles when PVP is copolymerized with cellulose materials. The MN patches were fabricated through thermal curing and photolithography in tandem. The various grades of pharmaceutical cellulose, such as hydroxypropyl methylcellulose and methyl cellulose, have been investigated as dissolution modifier incorporated in the MN patches. The resultant MN patches had dissolution profiles ranging from 45 min to 48 h. The dissolution rates varied with the grades of cellulose materials. Besides dissolution examination, the MN patches were characterized for their mechanical strength, moisture absorption, and skin penetration efficiency. All of the MN patches were able to penetrate the human skin in vitro. Overall, the PVP MN patches have great potential for skin applications as drug carriers with tunable dissolution profiles.

Deficient Resident Memory T Cell and CD8 T Cell Response to Commensals in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The intestinal microbiota is closely associated with resident memory lymphocytes in mucosal tissue. We sought to understand how acquired cellular and humoral immunity to the microbiota differ in health versus inflammatory bowel disease [IBD]. METHODS: Resident memory T cells [Trm] in colonic biopsies and local antibody responses to intraepithelial microbes were analysed. Systemic antigen-specific immune T and B cell memory to a panel of commensal microbes was assessed. RESULTS: Systemically, healthy blood showed CD4 and occasional CD8 memory T cell responses to selected intestinal bacteria, but few memory B cell responses. In IBD, CD8 memory T cell responses decreased although B cell responses and circulating plasmablasts increased. Possibly secondary to loss of systemic CD8 T cell responses in IBD, dramatically reduced numbers of mucosal CD8+ Trm and γδ T cells were observed. IgA responses to intraepithelial bacteria were increased. Colonic Trm expressed CD39 and CD73 ectonucleotidases, characteristic of regulatory T cells. Cytokines/factors required for Trm differentiation were identified, and in vitro-generated Trm expressed regulatory T cell function via CD39. Cognate interaction between T cells and dendritic cells induced T-bet expression in dendritic cells, a key mechanism in regulating cell-mediated mucosal responses. CONCLUSIONS: A previously unrecognised imbalance exists between cellular and humoral immunity to the microbiota in IBD, with loss of mucosal T cell-mediated barrier immunity and uncontrolled antibody responses. Regulatory function of Trm may explain their association with intestinal health. Promoting Trm and their interaction with dendritic cells, rather than immunosuppression, may reinforce tissue immunity, improve barrier function, and prevent B cell dysfunction in microbiota-associated disease and IBD aetiology.

Laparoscopic and endoscopic cooperative surgery (LECS) to overcome the limitations of endoscopic resection for colorectal tumors.

Background and study aims We developed a laparoscopy endoscopy cooperative surgery (LECS) to overcome the limitations of endoscopic resection for colorectal tumors. The aim of this study was to evaluate the feasibility of LECS, which combines endoscopic submucosal dissection (ESD) and laparoscopic partial colectomy. Patients and methods We performed LECS for 17 colorectal tumors in 17 patients (male:female 10:7; mean age, 66.5 years). The clinicopathological outcomes of these 17 cases and the feasibility of LECS were evaluated retrospectively. Indications for LECS were as follows: 1) intramucosal cancer and adenoma accompanied by wide and severe fibrosis; 2) intramucosal cancer and adenoma involving the diverticulum or appendix; and 3) submucosal tumors. Results We successfully performed LECS procedures in 17 cases (intramucosal cancer [n = 6], adenoma [n = 9], schwannoma [n = 1], and gastro-intestinal stromal tumour [GIST] [n = 1]. Mean tumor diameter was 22.4 mm (range, 8 - 41 mm). LECS was successfully performed in all 17 cases without conversion to open surgery; the R0 rate was 100 %. LECS was applied to the following situations: involving the appendix (n = 6), tumor accompanied by severe fibrosis (n = 5), involving the diverticulum (n = 3), submucosal tumor (n = 2), and poor endoscopic operability (n = 1). We experienced no adverse events (e. g., leakage or anastomotic stricture) and the median hospital stay was 6.4 dayus (range, 4 to 12). All 17 patients who were followed for ≥ 3 months (median, 30.8 months; range, 3 - 72 months) showed no residual/local recurrence. Conclusion LECS was a safe, feasible, minimally invasive procedure that achieved full-thickness resection of colorectal tumors and showed excellent clinical outcomes.

Eosinophilic gastrointestinal disorder in coeliac disease: a case report and review.

Eosinophilic gastrointestinal disorder is a rare disorder characterised by eosinophilic infiltration of the gastrointestinal tract. There are various gastrointestinal manifestations with eosinophilic ascites being the most unusual and rare presentation. Diagnosis requires high index of suspicion and exclusion of various disorders associated with peripheral eosinophilia. There are no previous case reports to suggest an association between eosinophilic gastrointestinal disorder and coeliac disease in adults. We report a case of eosinophilic ascites and gastroenteritis in a 30-year-old woman with a known history of coeliac disease who responded dramatically to a course of steroids.

Oncogenic pathway combinations predict clinical prognosis in gastric cancer.

Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.

Recurrent giant fibrovascular polyp of the esophagus.

Giant fibrovascular polyps of the esophagus and hypopharynx are rare benign esophageal tumors. They arise most commonly in the upper esophagus and may, rarely, originate in the hypopharynx. They can vary significantly in size. Even though they are benign, they may be lethal due to either bleeding or, rarely, asphyxiation if a large polyp is regurgitated. Patients commonly present with dysphagia or hematemesis. The polyps may not be well visualized on endoscopy and imaging plays a vital role in aiding diagnosis as well as providing important information for pre-operative planning, such as the location of the pedicle, the vascularity of the polyp and the tissue elements of the mass. They can also be recurrent in rare cases, especially if the resection margins of the base are involved. We review the recent literature and report a case of a 61-year-old man with a recurrent giant esophageal fibrovascular polyp with illustrative contrast barium swallow, CT and intra-operative images, who required several surgeries via a combination of endoscopic, trans-oral, trans-cervical, trans-thoracic and trans-abdominal approaches.

Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma.

Chromosomal amplifications of the 11q13 genomic region are frequent in head and neck squamous cell carcinoma (HNSCC). To identify novel 11q13 amplification targets, we integrated high-resolution array-based comparative genomic hybridization and Affymetrix gene-expression profiling of eight HNSCC cell lines. We found that PPFIA1 was the highest upregulated gene in the 11q13 amplicon of HNSCC cell lines when compared with HNSCC lines without 11q13 amplification and confirmed the upregulation of PPFIA1 in primary HNSCCs by real-time PCR. Using siRNA knockdown, we investigated PPFIA1 function in three HNSCC lines using both in vitro invasion assays and wound-healing assays. Surprisingly, we found that cancer cells become more invasive when the PPFIA1 protein levels were reduced, suggesting that PPFIA1 may act as an invasion inhibitor in HNSCC. This unexpected result suggests that the 11q13 amplicon may comprise both positive and negative regulators involved in HNSCC. Our study is the first to evaluate the role of PPFIA1 in head and neck carcinogenesis and suggests a potential link between PPFIA1 activity and cell-extracellular matrix interactions. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Clinical validation of a customized multiple signature microarray for breast cancer.

PURPOSE: Current histopathologic systems for classifying breast tumors require evaluation of multiple variables and are often associated with significant interobserver variability. Recent studies suggest that gene expression profiles may represent a promising alternative for clinical cancer classification. Here, we investigated the use of a customized microarray as a potential tool for clinical practice. EXPERIMENTAL DESIGN: We fabricated custom 188-gene microarrays containing expression signatures for three breast cancer molecular subtypes [luminal/estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2), and "basaloid"], the Nottingham prognostic index (NPI-ES), and low histologic grade (TuM1). The reliability of these multiple-signature arrays (MSA) was tested in a prospective cohort of 165 patients with primary breast cancer. RESULTS: The MSA-ER signature exhibited a high concordance of 90% with ER immunohistochemistry reported on diagnosis (P < 0.001). This remained unchanged at 89% (P < 0.001) when the immunohistochemistry was repeated using current laboratory standards. Expression of the HER2 signature showed a good correlation of 76% with HER2 fluorescence in situ hybridization (FISH; ratio > or =2.2; P < 0.001), which further improved to 89% when the ratio cutoff was raised to > or =5. A proportion of low-level FISH-amplified samples (ratio, 2.2-5) behaved comparably to FISH-negative samples by HER2 signature expression, HER2 quantitative reverse transcription-PCR, and HER2 immunohistochemistry. Luminal/ER+ tumors with high NPI-ES expression were associated with high NPI scores (P = 0.001), and luminal/ER+ TuM1-expressing tumors were significantly correlated with low histologic grade (P = 0.002) and improved survival outcome in an interim analysis (hazard ratio, 0.2; P = 0.019). CONCLUSION: The consistency of the MSA platform in an independent patient population suggests that custom microarrays could potentially function as an adjunct to standard immunohistochemistry and FISH in clinical practice.

Significance of tumour volume measurements in tongue cancer: a novel role in staging.

BACKGROUND: Tongue cancers are staged by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer TNM staging systems. Cancer, however, evolves in a 3-D plane. Hence, using the largest tumour diameter will not reflect total cancer volume. We aim to evaluate the use of tongue cancer tumour volume (Tv) as a prognostic predictor of disease recurrence and survival. METHODS: The study is a retrospective analysis of patients in Singapore General Hospital who underwent complete resection for histologically proven tongue carcinoma from 2000 to 2002. The Tv was measured on staging T(2)-weighted magnetic resonance imaging datasets by semiautomated methods. RESULTS: Seventeen patients with a median follow-up duration of 57.9 months were studied. A wide range of volumes was noted in each T stage. The median time to relapse was 8.6 months for those with Tv > or = 13 cc but was not achieved for those with Tv < 13 cc. The hazard ratio comparing Tv > or = 13 cc versus <13 cc is 9.02 (95% confidence interval (CI) 1.70-47.94, P = 0.014). Of the seven deaths reported, five patients had Tv > or = 13 cc. The median overall survival was 15.8 months for those with Tv > or = 13 cc but was not achieved for those with Tv < 13 cc. The hazards of death for Tv > or = 13 cc was 3.91 times that of Tv < 13 cc (95% CI 0.86-17.86, P = 0.078). CONCLUSION: Tongue cancer Tv measurement allows a more refined and accurate assessment of tumour status. This can be a possible prognostic indicator and be used in a novel staging method for the future.

Extracranial non-vestibular head and neck schwannomas: a ten-year experience.

INTRODUCTION: We present a series of head and neck extracranial non-vestibular schwannomas treated during a ten-year period, assessing epidemiology, presenting signs and symptoms, location, nerve of origin, diagnostic modalities, treatment and clinical outcome. MATERIALS AND METHODS: Clinical records of all patients with head and neck schwannomas treated at our department from April 1995 to July 2005 were retrospectively reviewed. RESULTS: There was female predominance (67%). The mean age at diagnosis was 48 years. Sixteen (76%) presented with a unilateral neck mass. Eleven schwannomas (52%) were in the parapharyngeal space. The most common nerves of origin were the vagus and the cervical sympathetic chain. The tumour may masquerade as a cervical lymph node and other myriad conditions. Treatment for all but 2 cases was complete excision with nerve preservation. Two cases of facial schwannoma required sacrifice of the affected nerve portion with nerve reconstruction. All facial schwannoma patients suffered postoperative facial palsy with only partial resolution (mean final House-Brackman grade, 3.25/6). Among non-facial schwannoma patients, postoperative neural deficit occurred in 12 with partial to complete resolution in 7. The median follow-up period was 24 months. No schwannoma was malignant and none recurred. CONCLUSION: Non-vestibular extracranial head and neck schwannomas most frequently present as an innocuous longstanding unilateral parapharyngeal neck mass. Preoperative diagnosis may be aided by fine-needle cytology and magnetic resonance imaging or computed tomographic imaging. The mainstay of treatment is complete intracapsular excision preserving the nerve of origin, but for extensive tumour or facial schwannomas, subtotal resection or nerve sacrifice with reconstruction and rehabilitation are considerations. Surgery on intraparotid facial schwannomas carries considerable morbidity and conservative management has a place in treatment. Early recognition of facial schwannomas is key to optimal treatment.

An isothermal method for whole genome amplification of fresh and degraded DNA for comparative genomic hybridization, genotyping and mutation detection.

Molecular genotyping has important biomedical and forensic applications. However, limiting amounts of human biological material often yield genomic DNA (gDNA) in insufficient quantity and of poor quality for a reliable analysis. This motivated the development of an efficient whole genome amplification method with quantitatively unbiased representation usable on fresh and degraded gDNA. Amplification of fresh frozen, formalin-fixed paraffin-embedded (FFPE) and DNase-degraded DNA using degenerate oligonucleotide-primed PCR or primer extension amplification using a short primer sequence bioinformatically optimized for coverage of the human genome was compared with amplification using current primers by chromosome-based and BAC-array comparative genomic hybridization (CGH), genotyping at short tandem repeats (STRs) and single base mutation detection. Compared with current primers, genome amplification using the bioinformatically optimized primer was significantly less biased on CGH in self-self hybridizations, and replicated tumour genome copy number aberrations, even from FFPE tissue. STR genotyping could be performed on degraded gDNA amplified using our technique but failed with multiple displacement amplification. Of the 18 different single base mutations 16 (89.5%) were correctly identified by sequencing gDNA amplified from clinical samples using our technique. This simple and efficient isothermal method should be helpful for genetic research and clinical and forensic applications.

Non-neoplastic cystic and cystic-like lesions of the pancreas: may mimic pancreatic cystic neoplasms.

BACKGROUND: Cystic lesions of the pancreas consist of a broad range of pathological entities. With the exception of the pancreatic pseudocyst, these are usually caused by pancreatic cystic neoplasms. Non-neoplastic pancreatic cystic and cystic-like lesions are extremely rare. In the present article, the surgical experience with these unusual entities over a 14-year period is reported. METHODS: Between 1991 and 2004, all patients who underwent surgical exploration for a cystic lesion of the pancreas were retrospectively reviewed. Patients with a pancreatic pseudocyst were excluded. There were 106 patients of whom 8 (7.5%) had a final pathological diagnosis consistent with a non-neoplastic pancreatic cystic or cystic-like lesion, including 3 patients with a benign epithelial cyst, 2 with a pancreatic abscess (one tuberculous and one foreign body), 2 with mucous retention cysts and 1 with a mucinous non-neoplastic cyst. These eight patients are the focus of this study. RESULTS: There were six female and two male patients with a median age of 61.5 years (range, 41-71 years). All the patients were of Asian origin including seven Chinese and one Indian. Four of the patients were asymptomatic and their pancreatic cysts were discovered incidentally on radiological imaging for other indications. All the patients underwent preoperative radiological investigations, including ultrasonography, computed tomography or magnetic resonance imaging, which showed a cystic lesion of the pancreas. Three patients, all of whom were symptomatic, were diagnosed preoperatively with a malignant cystic neoplasm on the basis of radiological imaging. Two patients were eventually found to have a pancreatic abscess, one tuberculous and the other, secondary to foreign body perforation. The third patient was found on final histology to have chronic pancreatitis with retention cysts. The remaining five patients had a preoperative diagnosis of an indeterminate cyst; on pathological examination, they were found to have a benign epithelial (congenital) cyst (n = 3), retention cyst (n = 1) and mucinous non-neoplastic cyst (n = 1). At a median follow up of 20 months (range, 3-34 months), none of the patients had any evidence of recurrent disease. CONCLUSION: Non-neoplastic cystic and cystic-like lesions of the pancreas are rare causes of pancreatic cystic lesions that are generally benign and do not require surgery when asymptomatic. However, despite advances in diagnostic investigations such as endoscopic ultrasound with fluid aspirate and magnetic resonance imaging, the preoperative diagnosis remains unreliable. Hence, the challenge for all clinicians is to recognize these lesions preoperatively and to avoid 'unnecessary' surgery.

An isothermal primer extension method for whole genome amplification of fresh and degraded DNA: applications in comparative genomic hybridization, genotyping and mutation screening.

We describe a protocol that uses a bioinformatically optimized primer in an isothermal whole genome amplification (WGA) reaction. Overnight incubation at 37 degrees C efficiently generates several hundred- to several thousand-fold increases in input DNA. The amplified product retains reasonably faithful quantitative representation of unamplified whole genomic DNA (gDNA). We provide protocols for applying this isothermal primer extension WGA protocol in three different techniques of genomic analysis: comparative genomic hybridization (CGH), genotyping at simple tandem repeat (STR) loci and screening for single base mutations in a common monogenic disorder, beta-thalassemia. gDNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues can also be amplified with this protocol.

Intrahepatic biliary cystadenoma presenting with obstructive jaundice.

Biliary cystadenoma (BCA) is a rare neoplasm of the bile duct with malignant potential. We report a case of intrahepatic BCA with an unusual presentation of obstructive jaundice. Computed tomography scan of the abdomen revealed a dilated common bile duct and intrahepatic ducts with internal septa. Endoscopic retrograde cholangiography showed an oval filling defect in the bile duct causing the obstruction. At laparotomy, this proved to be a multiloculated mucinous polyp in the common bile duct, with its origin in the left intrahepatic duct, detected using intraoperative choledochoscopy. A left hemihepatectomy was performed, and histology confirmed intrahepatic mucinous BCA with mesenchymal stroma. The imaging process and surgical options for BCA are discussed.

A combined comparative genomic hybridization and expression microarray analysis of gastric cancer reveals novel molecular subtypes.

Comparative genomic hybridization (CGH), microsatellite instability (MSI) assays, and expression microarrays were used to molecularly subclassify a common set of gastric tumor samples. We identified a number of novel genomic aberrations associated with gastric cancer and discovered that gastric tumors could be grouped by their expression profiles into three broad classes: "tumorigenic," "reactive," and "gastric-like." Patients with gastric-like tumors exhibited a significantly better overall survival than patients belonging to the other two classes (P < 0.05). A novel supervised learning methodology for multiclass prediction was used to identify optimal predictor gene sets that accurately predicted the class of an unknown tumor sample. These predictor sets may prove useful in the development of new diagnostic applications for gastric cancer staging and prognostication.

Squamous cell carcinoma of the head and neck (HNSCC)--multi-modality treatment and impact on survival.

INTRODUCTION: Head and neck cancers remain one of the top twenty cancers in Singapore for the past decade. Squamous cell carcinoma (SCC) is the commonest histology. Our aim was to obtain local figures on treatment modalities and survival outcomes. METHODS: This is a ten-year retrospective study of all head and neck SCC (HNSCC) cases operated from 1988-1998 at the Department of General Surgery, Singapore General Hospital. RESULTS: We treated 242 patients with HNSCC. Median follow-up time was 31 months. Seventy percent of these patients presented with Stage III/IV disease. The 3 most commonly occurring sites of HNSCC are 79 (33%) tongue, 68 (28%) rest of oral cavity and 36 (15%) larynx. The majority of the patients underwent surgical resection with reconstruction and adjuvant radiotherapy. The recurrence-free survival at 2 and 5 years are 60% (95% CI) and 52% (95% CI). The overall survival at 2 and 5 years are 70% (95% CI) and 55% (95% CI). The overall survival for Stages I-IV at 2 years' follow-up were 97%, 83%, 66% and 60% respectively and at 5 years' follow-up, were 83%, 71%, 59% and 38% respectively. CONCLUSIONS: HNSCC treated in this department over the last decade have resulted in survival rates that are comparable with those reported from international cancer centres and an improvement over previous local experience.

Unusual recurrence after chemoirradiation and surgery for squamous cell carcinoma of the tongue.

Locally advanced squamous cell carcinoma of the tongue represents a significant therapeutic challenge. Novel methods using systemic chemotherapy with concurrent radiotherapy have been used to improve loco-regional response in patients who historically have poor prognosis. The simultaneous use of both modalities enhances planned local treatment by radiosensitization and potentially eradicates micrometastatic disease. With good local control, the appearance of distant metastasis or second primary tumors becomes a problem we need to address. Here, we describe a patient who completed concurrent chemoirradiation with good local response but only to relapse with unusual sites of metastases involving the scalp, gluteus muscle and right kidney. This represents a particularly aggressive form of disease with very poor prognosis.