The role of endoscopy after upper gastrointestinal bleeding in sub-Saharan Africa: A prospective observational cohort study.

Background: Upper gastrointestinal (UGI) bleed is a common surgical disease in sub-Saharan Africa where there is often a lack of diagnostic and interventional adjuncts such as endoscopy. This study sought to characterize the role of endoscopy in management of acute UGI bleeding. Materials and Methods: This is a prospective observational analysis of adults presenting with an UGI bleed to a tertiary center in Lilongwe, Malawi, over two years. Patients were classified as having no endoscopy, diagnostic endoscopy, or endoscopy with variceal banding. Bivariate, survival analysis, and logistic regression analyses were used to compare intervention cohorts. Results: 293 patients were included with 49 patients (16.7%) receiving endoscopy with banding, 65 (22.2%) patients receiving diagnostic endoscopy only, and 179 (61.1%) receiving no endoscopy. Upon survival analysis comparing to the no endoscopy group, cox hazard modelling showed an adjusted hazard ratio over 30 days of 0.12 (95% CI 0.02, 0.88, p=0.038) for the endoscopic banding group and a hazard ratio of 0.39 (95% CI 0.13, 1.16, p=0.090) for the diagnostic endoscopy only group. Physical exam findings consistent with cirrhosis and decreasing age were independent predictors of an endoscopic diagnosis of variceal bleeding. Conclusion: Esophagogastric varices are a common cause of UGI bleeding in sub-Saharan Africa and can be predicted with age and physical exam findings. Endoscopy with variceal banding has a survival benefit for patients presenting with acute UGI bleed even with relatively low utilization. Appropriately triaging patients with likely variceal bleeding and improving endoscopy capacity would likely have a significant impact on mortality.

Correction: Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes.

[This corrects the article DOI: 10.1371/journal.pone.0056823.].

Risk factors for common cancers among patients at Kamuzu Central Hospital in Lilongwe, Malawi: A retrospective cohort study.

BACKGROUND: Little is known about risk factors for different cancers in Malawi. This study aimed to assess risk factors for and epidemiologic patterns of common cancers among patients treated at Kamuzu Central Hospital (KCH) in Lilongwe, and to determine the prevalence of Human Immunodeficiency Virus (HIV) infection in the same population. METHODS: We analysed data from the hospital-based KCH cancer registry, from June 2009 to September 2012, including data from a nested substudy on coinfections among cancer patients. Demographics and behavioural variables, including smoking and alcohol use, were collected through personal interviews with patients. We assessed HIV prevalence across cancer types. The distribution of cancer types was reported overall and by gender. Logistic regression was used to assess risk factors associated with common cancer types. RESULTS: Data from 504 registered cancer patients were included-300 (59.5%) were female and 204 (40.5%) were male. Mean age was 49 years (standard deviation, SD = 16). There were 343 HIV-negative patients (71.2%), and 139 (28.8%) were HIV-positive. The commonest cancers were oesophageal (n = 172; 34.5%), cervical (n = 109; 21.9%), and Kaposi's sarcoma (KS) (n = 52; 10.4%). Only 18% of cancer cases were histologically confirmed. Patients with oesophageal cancer were likely to be older than 50 years (odds ratio, OR = 2.22), male (OR = 1.47), and smokers (OR = 2.02). Kaposi's sarcoma patients had the highest odds (OR = 54.4) of being HIV-positive and were also more likely to be male (OR = 6.02) and smokers. Cervical cancer patients were more likely to be HIV-positive (OR = 2.2) and less than 50 years of age. CONCLUSIONS: Age, smoking, and HIV are important risk factors for the 3 commonest cancer types (oesophageal, KS, and cervical) at this teaching hospital in Malawi. HIV is the single most important risk factor for Kaposi's sarcoma and cervical cancer.

Human papillomavirus in head and neck squamous cell carcinoma: A descriptive study of histologically confirmed cases at Kamuzu Central Hospital in Lilongwe, Malawi.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is common in sub-Saharan Africa, but the aetiologic contribution of human papillomavirus (HPV) is not well established. METHODS: We assessed HNSCC cases for HPV using p16 immunohistochemistry (IHC) in Malawi. Associations between p16 IHC and tumour site, behavioural risk factors, demographic characteristics, and HIV status were examined. RESULTS: From 2010 to 2014, 77 HNSCC cases were identified. Mean age was 52 years, 50 cases (65%) were male, and 48 (62%) were in the oropharynx (OP) or oral cavity (OC). HIV status was known for 35 patients (45%), with 5 (14%) HIV-infected. Substance use was known for 40 patients (52%), with 38% reporting any tobacco and 31% any alcohol. Forty-two cases (55%) had adequate tissue for p16 IHC, of which seven (17%) were positive, including 22% of OP/OC tumours. CONCLUSIONS: Despite high cervical cancer burden, HPV-associated HNSCC is not very common in Malawi.

Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis.

Esophageal squamous cell carcinoma (ESCC) is endemic in regions of sub-Saharan Africa (SSA), where it is the third most common cancer. Here, we describe whole-exome tumor/normal sequencing and RNA transcriptomic analysis of 59 patients with ESCC in Malawi. We observed similar genetic aberrations as reported in Asian and North American cohorts, including mutations of TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1, and FBXW7. Analyses for nonhuman sequences did not reveal evidence for infection with HPV or other occult pathogens. Mutational signature analysis revealed common signatures associated with aging, cytidine deaminase activity (APOBEC), and a third signature of unknown origin, but signatures of inhaled tobacco use, aflatoxin and mismatch repair were notably absent. Based on RNA expression analysis, ESCC could be divided into 3 distinct subtypes, which were distinguished by their expression of cell cycle and neural transcripts. This study demonstrates discrete subtypes of ESCC in SSA, and suggests that the endemic nature of this disease reflects exposure to a carcinogen other than tobacco and oncogenic viruses.

A preliminary study of the use of ultrasound in defining nasal fractures: criteria for a confident diagnosis.

Nasal fractures are usually diagnosed by clinical examination, with or without the support of imaging studies. While plain-film radiography lacks sensitivity and specificity for diagnosing nasal fractures, and computed tomography (CT) is not always practical or cost-effective, ultrasonography (US) may be useful in this regard. The criteria by which adult nasal fractures are reliably identified on US must be clear. We conducted a preliminary prospective, controlled, observational study to define the appearance of nasal fractures on US. We used US to image 12 patients with a clinical or radiologic (CT or x-ray) diagnosis of nasal fracture. All patients presented within 2 weeks of their injury. For comparison purposes, we also obtained US images from 12 control subjects who had no history of nasal trauma or surgery. We found that we could confidently diagnose nasal fractures on lateral-view US on the basis of a disruption of bone continuity and/or displacement of fracture segments. However, our findings were not as consistent with dorsal-view US, and we do not believe it is adequate for diagnosis. We conclude that lateral US can be used to detect nasal fractures in adults, but further studies are needed to assess its sensitivity, specificity, cost-effectiveness, and practicality.

Cancer Treatment in Malawi: A Disease of Palliation.

BACKGROUND: Worldwide, new cancer cases will nearly double in the next 20 years while disproportionately affecting low and middle income countries (LMICs). Cancer outcomes in LMICs also remain bleaker than other regions of the world. Despite this, little is known about cancer epidemiology and surgical treatment in LMICs. To address this we sought to describe the characteristics of cancer patients presenting to the Surgery Department at Kamuzu Central Hospital in Lilongwe, Malawi. METHODS: We conducted a retrospective review of adult (18 years or older) surgical oncology services at Kamuzu Central Hospital in Lilongwe, Malawi from 2007 - 2010. Data obtained from the operating theatre logs included patient demographics, indication for operative procedure, procedure performed, and operative procedures (curative, palliative, or staging). RESULTS: Of all the general surgery procedures performed during this time period (7,076 in total), 16% (406 cases) involved cancer therapy. The mean age of male and female patients in this study population was 52 years and 47 years, respectively. Breast cancer, colorectal cancer, gastric cancer, and melanoma were the most common cancers among women, whereas prostate, colorectal, pancreatic, and, gastric were the most common cancers in men. Although more than 50% of breast cancer operations were performed with curative intent, most procedures were palliative including prostate cancer (98%), colorectal cancer (69%), gastric cancer (71%), and pancreatic cancer (94%). Patients with colorectal, gastric, esophageal, pancreatic, and breast cancer presented at surprisingly young ages. CONCLUSION: The paucity of procedures with curative intent and young age at presentation reveals that many Malawians miss opportunities for cure and many potential years of life are lost. Though KCH now has pathology services, a cancer registry and a surgical training program, the focus of surgical care remains palliative. Further research should address other methods of increasing early cancer detection and treatment in such populations.

Early experience after developing a pathology laboratory in Malawi, with emphasis on cancer diagnoses.

BACKGROUND: Despite increasing cancer burden in Malawi, pathology services are limited. We describe operations during the first 20 months of a new pathology laboratory in Lilongwe, with emphasis on cancer diagnoses. METHODS AND FINDINGS: We performed a cross-sectional study of specimens from the Kamuzu Central Hospital pathology laboratory between July 1, 2011 and February 28, 2013. Patient and specimen characteristics, and final diagnoses are summarized. Diagnoses were categorized as malignant, premalignant, infectious, other pathology, normal or benign, or nondiagnostic. Patient characteristics associated with premalignancy and malignancy were assessed using logistic regression. Of 2772 specimens, 2758 (99%) with a recorded final diagnosis were included, drawn from 2639 unique patients. Mean age was 38 years and 63% were female. Of those with documented HIV status, 51% had unknown status, and 36% with known status were infected. Histologic specimens comprised 91% of cases, and cytologic specimens 9%. Malignant diagnoses were most common overall (n = 861, 31%). Among cancers, cervical cancer was most common (n = 117, 14%), followed by lymphoma (n = 91, 11%), esophageal cancer (n = 86, 10%), sarcoma excluding Kaposi sarcoma (n = 75, 9%), and breast cancer (n = 61, 7%). HIV status was known for 95 (11%) of malignancies, with HIV prevalence ranging from 9% for breast cancer to 81% for cervical cancer. Increasing age was consistently associated with malignancy [bivariable odds ratio 1.24 per decade increase (95% CI 1.19-1.29) among 2685 patients with known age; multivariable odds ratio 1.33 per decade increase (95% CI 1.14-1.56) among 317 patients with known age, gender, and HIV status], while HIV infection and gender were not. CONCLUSIONS: Despite selection and referral bias inherent in these data, a new pathology laboratory in Lilongwe has created a robust platform for cancer care and research. Strategies to effectively capture clinical information for pathologically confirmed cancers can allow these data to complement population-based registration.

ERCC1 protein expression is associated with differential survival in oropharyngeal head and neck squamous cell carcinoma.

OBJECTIVE: To investigate ERCC1 protein expression and its relationship to clinical factors and treatment outcomes in patients with head and neck squamous cell carcinoma (HNSCC). DESIGN: Case series. SETTING: Tertiary care academic center. SUBJECTS: One hundred and seventy-six patients diagnosed with HNSCC and treated with intent to cure between 2002 and 2008 were analyzed with respect to clinical data and tumor pathology. MAIN OUTCOME MEASURES: Tissue microarrays were constructed from tumor blocks and immunohistochemical staining for ERCC1 performed. ERCC1 expression status was dichotomized into high and low using the Allred score. Clinical characteristics of patients with high versus low ERCC1 expression were compared. Distributions of overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. RESULTS: Of 176 patients, ERCC1 showed baseline nuclear staining in 148 patients (84.1%). Lower staining intensity ERCC1 expression was prominent in parabasal cells in the lower half of the epithelium, while at high staining intensity, ERCC1 expression was present throughout the epithelium. The median H-score was 50. No significant differences in age, gender, smoking status, tumor site, or stage were seen between the high and low ERCC1 expression groups. Expression of ERCC1 stratified by tumor site correlates with OS. Patients with oropharyngeal HNSCC and high ERCC1 expression (H-score > 120) were more likely to survive (P < .01) and remain disease free when compared to non-oropharyngeal squamous cell carcinoma (SCCa) patients with high ERCC1 expression despite treatment modality and human papillomavirus virus (HPV) status. CONCLUSION: Patients with oropharyngeal SCCa and high ERCC1 expression may have better outcomes despite HPV status.

Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes.

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

Prevalence of HIV and Disease Outcomes on the Medical and Surgical Wards at Kamuzu Central Hospital, Lilongwe, Malawi.

INTRODUCTION: The World Health Organization (WHO) recommends HIV Counseling and Testing (HCT) in a range of clinical settings. We describe the characteristics of patients diagnosed with HIV on the medical and surgical wards at a tertiary care hospital in Malawi. METHODS: Under the universal opt-out HCT protocol we characterized the number of new HIV/AIDS infections and associated clinical features among hospitalized surgical and medical patients diagnosed during the course of admission. RESULTS: All 2985 and 3959 medical and surgical patients, respectively, admitted between April 2012 and January 2013 were screened for HCT. 62% and 89% of medical and surgical patients, respectively, had an unknown status on admission and qualified for testing. Of the patients with an unknown status, a new HIV diagnosis was made in 20% and 7% of medical and surgical patients, respectively. Of the newly diagnosed patients with a CD4 count recorded, 91% and 67% of medical and surgical patients, respectively, had a count less than 350, qualifying for ART by Malawi ART guidelines. Newly HIV-diagnosed medical and surgical patients had an inpatient mortality of 20% and 2%, respectively. DISCUSSION: While newly diagnosed HIV-positive medical patients had high inpatient mortality and higher rates of WHO stage 3 or 4 conditions, surgical patients presented with less advanced HIV, though still meeting ART initiation guidelines. The medical inpatient wards are an obvious choice for implementing voluntary counseling and testing (VCT), but surgical patients present with less advanced disease and starting treatment in this group could result in more years of life gained.

Addressing Malawi's surgical workforce crisis: a sustainable paradigm for training and collaboration in Africa.

BACKGROUND: The exodus of health professionals including surgeons from sub-Saharan Africa has been well documented, but few effective, long-term solutions have been described. There is an increasing burden of surgical diseases in Africa attributable to trauma (road traffic injuries), burns, and other noncommunicable diseases such as cancer, increasing the need for surgeons. METHODS: We conducted a Descriptive analysis of surgical academic partnership between Kamuzu Central Hospital (KCH) Malawi, the University of Malawi-College of Medicine, the University of North Carolina in the United States, and Haukeland University Hospital, Norway, to locally train Malawian surgical residents in a College of Surgeons of East, Central and Southern Africa (COSECSA) approved program. RESULTS: The KCH Surgery Residency program began in 2009 with 3 residents, adding 3 general surgery and 2 orthopedic residents in 2010. The intention is to enroll ≥ 3 residents per year to fill the 5-year program and the training has been fully accredited by COSECSA. International partners have provided near-continuous presence of attending surgeons for direct training and support of the local staff surgeons, while providing monetary support in addition to the Malawi Ministry of Health salary. CONCLUSION: This collaborative, academic model of local surgery training is designed to limit brain drain by keeping future surgeons in their country of origin as they establish themselves professionally and personally, with ongoing collaboration with international colleagues.

Liver function tests: inadequate screening modality for detection of liver metastasis in head and neck carcinoma.

OBJECTIVE: Report the prevalence and risk factors of liver metastasis in head and neck squamous cell carcinoma (HNSCC) while evaluating the utility of liver function tests (LFTs) in detection of such metastases. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Of 745 patients with newly diagnosed HNSCC (oral cavity, oropharynx, hypopharynx, larynx) treated at University of North Carolina hospitals from 1989 to 2005, 655 had sufficient data for analysis. RESULTS: Prevalence of liver metastasis was 3% (20/655) with 7 patients demonstrating early metastasis and 12 with late metastasis. Oropharyngeal and hypopharyngeal lesions constituted 65% of identified liver metastasis but only 39% of the study population. Patients with oropharyngeal lesions were most likely to develop liver metastasis (P = .047). Abnormal LFTs were seen in 26% of all patients. Overall sensitivity and specificity were 45% and 75%. Seventy-five percent of patients with liver metastasis had stage IV disease at diagnosis and were more likely to have abnormal LFTs than other stages (P = .048). In these patients, 2.2% (8/365) had liver metastases and abnormal LFTs, whereas 1.9% (7/365) had liver metastases and normal LFTs. Sensitivity for alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase 0%, 10%, 20%, and 30%, respectively. Specificities ranged from 88.0% to 94.3%. Positive predictive values were poor, with the highest being 10.5%. CONCLUSIONS: Liver metastases are rare in HNSCC and often delayed in presentation. This study clearly reveals that LFTs do not reliably identify patients with liver metastasis and do not provide physicians with an adequate screening modality in this population.

An Observational Study of the Etiology, clinical presentation and outcomes associated with peritonitis in Lilongwe, Malawi.

INTRODUCTION: Peritonitis is a life-threatening condition with a multitude of etiologies that can vary with geographic location. The aims of this study were to elucidate the etiology, clinical presentation and outcomes associated with peritonitis in Lilongwe, Malawi. METHODS: All patients admitted to Kamuzu Central Hospital (KCH) who underwent an operation for treatment of peritonitis during the calendar year 2008 were eligible. Peritonitis was defined as abdominal rigidity, rebound tenderness, and/or guarding in one or more abdominal quadrants. Subjects were identified from a review of the medical records for all patients admitted to the adult general surgical ward and the operative log book. Those who met the definition of peritonitis and underwent celiotomy were included. RESULTS: 190 subjects were identified. The most common etiologies were appendicitis (22%), intestinal volvulus (17%), perforated peptic ulcer (11%) and small bowel perforation (11%). The overall mortality rate associated with peritonitis was 15%, with the highest mortality rates observed in solid organ rupture (35%), perforated peptic ulcer (33%), primary/idiopathic peritonitis (27%), tubo-ovarian abscess (20%) and small bowel perforation (15%). Factors associated with death included abdominal rigidity, generalized (versus localized) peritonitis, hypotension, tachycardia and anemia (p < 0.05). Age, gender, symptoms (obstipation, vomiting) and symptom duration, tachypnea, abnormal temperature, leukocytosis, hemoconcentration, thrombocytopenia and thrombocytosis were not associated with mortality (p = NS). CONCLUSIONS: There are several signs and laboratory findings predictive of poor outcome in Malawian patients with peritonitis. Tachycardia, hypotension, anemia, abdominal rigidity and generalized peritonitis are the most predictive of death (P < 0.05 for each). Similar to studies from other African countries, in our population the most common cause of peritonitis was appendicitis, and the overall mortality rate among all patients with peritonitis was 15%. Identified geographical differences included intestinal volvulus, rare in the US but the 2nd most common cause of peritonitis in Malawi and gallbladder disease, common in Ethiopia but not observed in Malawi. Future research should investigate whether correction of factors associated with mortality might improve outcomes.

High XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma.

PURPOSE: We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome. EXPERIMENTAL DESIGN: XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1). RESULTS: Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44-8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16(INK4a)-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52-4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06-0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36-15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08-0.92, respectively; P = 0.037). CONCLUSIONS: In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment.

STT3A, C1orf24, TFF3: putative markers for characterization of follicular thyroid neoplasms from fine-needle aspirates.

OBJECTIVES/HYPOTHESIS: The goals of this study were to characterize gene expression using fine-needle aspirates (FNAs) from follicular neoplasms to distinguish follicular adenomas (FAs) from follicular thyroid carcinomas (FTCs) and follicular variant of papillary thyroid carcinomas (FVPTCs); and to use FNA material to distinguish benign from malignant follicular neoplasms. STUDY DESIGN: Retrospective expression analysis of diagnosed follicular neoplasms (level of evidence 2b); prospective cohort of FNA from the operating room after thyroid lobectomy (level of evidence 1b). METHODS: Gene expression analysis via reverse-transcription polymerase chain reaction (rt-PCR) of nine genes previously noted to be differentially expressed in follicular neoplasms was performed on formalin-fixed, paraffin-embedded archived normal thyroid tissue (n = 63) and follicular neoplasms as diagnosed on preoperative FNA: FA (n = 16), FTC (n = 13), FVPTC (n = 24), and papillary thyroid carcinomas (PTCs) (n = 10). All cases were originally read as follicular neoplasms on preoperative FNA. To determine if these results could be translated into fresh tissue, ex vivo FNA was performed on follicular neoplasms (n = 17) in the operating room after thyroidectomy. RESULTS: Quantitative gene analysis detected differential TFF3 expression in FA versus FTC, FVPTC, and PTC (P = .02). Rt-PCR of FNA samples demonstrated that malignant nodules overexpress STT3A as compared with benign disease (P = .046). The combination of STT3A overexpression/Clorf24 underexpression identified malignant disease (P = .03) on FNA samples. CONCLUSIONS: Gene-expression data suggest a difference in expression between STT3A, Clorf24, and TFF3 in FAs versus carcinomas that may be detected from an FNA sample. Findings must be validated from preoperative FNAs in larger numbers.

Antitumor activity of enzastaurin as radiation sensitizer in head and neck squamous cell carcinoma.

BACKGROUND: The antitumor effect of enzastaurin, a specific protein kinase C beta (PKC-ß) inhibitor, was tested on head and neck squamous cell carcinoma (HNSCC) cell lines, as well as HNSCC xenograft model. METHODS: HNSCC cell lines and xenograft were treated with enzastaurin alone or in combination with radiation to evaluate its antitumor effect. Annexin V-FITC staining and Western blot were done to analyze enzastaurin-induced changes in apoptosis and the PIK3/AKTAKT signal transduction pathway. RESULTS: Enzastaurin showed strong antitumor activity either alone or in combination with radiation both in HNSCC cell lines and in xenograft, with a corresponding reduction in the expression of key radioresponsive proteins. CONCLUSION: Enzastaurin can inhibit tumor growth and improve the efficacy of radiation for HNSCC both in vitro and in vivo. This suggests that enzastaurin may represent a better strategy for the treatment of HNSCC patients, either as a monotherapy or as a radiosensitizer.

Concomitant radiotherapy and chemotherapy for high-risk nonmelanoma skin carcinomas of the head and neck.

Background. To report on the use and feasibility of a multimodality approach using concomitant radiotherapy and chemotherapy in patients with high-risk nonmelanoma skin carcinoma (NMSC) of the head and neck. Methods. Records of patients with NMSC of the head and neck who received concomitant CRT at the University of North Carolina between 2001 and 2007 were reviewed. Results. Fifteen identified patients had at least one of the following high-risk factors: T4 disease (93%), unresectability (60%), regional nodal involvement (40%), and/or recurrence (47%). Ten patients were treated in the definitive setting and five in the postoperative setting. Platinum based chemotherapy was given in 14 (93%) patients. Ten of fifteen (67%) patients completed all planned chemotherapy treatments, and thirteen patients (87%) completed at least 80% of planned chemotherapy. Mild radiation dermatitis occurred in all patients and reached grade 3 in 13% of patients. No patients experienced grade 4 or 5 toxicity. With a median followup of 31 months in surviving patients, the 2-year actuarial locoregional control and relapse-free survival were 79% and 49%, respectively. Conclusions. Definitive or postoperative chemoradiotherapy for patients with locally advanced or regionally metastasized NMSC of the head and neck appears feasible with acceptable toxicities and favorable locoregional control.

BIIB021, a novel Hsp90 inhibitor, sensitizes head and neck squamous cell carcinoma to radiotherapy.

Heat shock protein 90 (Hsp90) is a molecular chaperone that promotes the conformational maturation of numerous client proteins, many of which play critical roles in tumor cell growth and survival. The ansamycin-based Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in Phase III clinical testing. However, 17-AAG is difficult to formulate and associated with dose-limited toxicity issues. A fully synthetic and bioavailable Hsp90 inhibitor, BIIB021, was evaluated for antitumor activity in a variety of head and neck squamous cell carcinoma (HNSCC) cell lines and HNSCC xenograft models, either as a single agent or in combination with fractionated radiation and the results were compared with that of 17-AAG. BIIB021 showed strong antitumor activity, comparable with, and in certain instances, superior to 17-AAG. BIIB021 enhanced the in vitro radiosensitivity of HNSCCA cell lines with a corresponding reduction in the expression of key radioresponsive proteins, increased apoptotic cells and enhance G2 arrest. In xenograft studies, BIIB021 exhibited a strong antitumor effect outperforming 17-AAG, either as a single agent and or in combination with radiation, thereby improved the efficacy of radiation. These results suggest that this synthetic and bioavailable Hsp90 inhibitor affects multiple pathways involved in tumor development and progression in the HNSCC setting and may represent a better strategy for the treatment of HNSCC patients, either as a monotherapy or a radiosensitizer. Furthermore, it also demonstrates the benefits of using preclinical models of chemosensitization to radiotherapy to explore clinically relevant radiation dosing schemes.