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.

Clinical significance of indeterminate pulmonary nodules in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this study was to determine whether indeterminate pulmonary nodules (IPNs) at staging are predictive of lung metastasis, primary lung carcinoma, or survival in patients with advanced head and neck squamous cell carcinoma (HNSCC). METHODS: One hundred ten patients with IPN at staging who had follow-up imaging and 100 patients without IPN were identified from an HNSCC database. The primary endpoints were lung progression-free survival (PFS) and overall survival (OS). RESULTS: Two-year lung PFS for the IPN and No-IPN cohorts were 66% versus 61% (p = .92) and the OS for these cohorts were 71% versus 68% (p = .77). Within the IPN cohort, level IV/V lymph node involvement (odds ratio = 4.34; p = .03), hypopharynx primary (odds ratio = 21.5; p = .005), and race (odds ratio = 9.29; p = .001) were independent predictors of developing lung malignancy. CONCLUSION: IPNs at staging in patients with HNSCC do not affect prognosis and should neither influence initial treatment planning nor the frequency of posttreatment surveillance.

Prognostic significance of bone invasion for oral cavity squamous cell carcinoma considered T1/T2 by American joint committee on cancer size criteria.

BACKGROUND: It is unclear whether bone invasion in small oral cavity squamous cell carcinomas (OCSCC) results in worse prognosis. METHODS: Two hundred fifty-four patients with OCSCC were identified and divided into 3 cohorts: (1) ≤4 cm with no bone invasion; (2) ≤4 cm with bone invasion; and (3) ≥4 cm or other factors (eg, skin invasion, deep muscle invasion) that would qualify for American Joint Committee on Cancer (AJCC) T4 classification aside from bone invasion. Depth of bone invasion (none, cortical, or medullary) was also recorded. RESULTS: Cohorts 1 and 2 had similar outcomes. Cohort 3 had lower rates of regional control (p = .04), disease-specific survival (DSS; p < .01), and overall survival (OS; p < .01). On multivariate analysis, margin status and medullary bone invasion were associated with worse outcomes. CONCLUSION: Bone invasion does not seem to significantly influence outcomes in patients with small primary tumors treated with surgery/radiation. Medullary bone invasion seems to result in reduced rates of control and survival.

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.

Patterns of care in older patients with squamous cell carcinoma of the head and neck: a surveillance, epidemiology, and end results-medicare analysis.

BACKGROUND: There is growing evidence in the literature that older patients may not benefit from more intensive therapy for head and neck squamous cell carcinoma (HNSCC). A growing number of patients with HNSCC are age 65 years or older; however, much of the evidence base informing treatment decisions is based on substantially younger and healthier clinical trial populations. The purpose of this study was to assess the patterns of care of older HNSCC patients to better understand how age is associated with treatment decisions. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (1992­2007), we identified patients with non-metastatic HNSCC (n = 10,867) and categorized them by treatment: surgery vs. non-surgery and chemoradiotherapy (CRT) vs. radiotherapy (RT). Multivariate logistic regression models were used to identify variables associated with the receipt of surgery and CRT. RESULTS: Increasing age was associated with decreased odds of receiving CRT (OR = 0.94; 95% CI 0.93­0.94) but not surgery (OR 1.00; 95% CI 0.99­1.00). Co-morbidity and race were not associated with receipt of either surgery or CRT. Utilization of CRT increased while surgery decreased between 1992 and 2007. CONCLUSION: Age may influence the receipt of CRT for older HNSCC patients. There has been an increasing trend in the receipt of CRT and a decrease in primary surgery.

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.

Incidence of nodal disease after nonsurgical therapy in head and neck squamous cell carcinoma patients with bilateral neck disease: can a bilateral neck dissection be avoided?

BACKGROUND: We evaluated whether classifying 1 side of a patients' neck as "high risk" would help in deciding the extent of neck dissection in patients with bilateral nodal disease. METHODS: We conducted a retrospective review of 44 patients (88 heminecks) with head and neck squamous cell carcinoma who had bilateral nodal disease and received definitive chemoradiotherapy (CRT). For lateralized lesions (70%), the ipsilateral neck was designated as the "high-risk" neck. For midline lesions, pre-CRT and post-CRT computed tomography scans were used to stage each side of the neck (hemineck); the higher staged hemineck was designated as the "high-risk" neck. RESULTS: Twenty-seven patients had died at the time of analysis. Patients had a median follow-up of 27.8 months (range, 6 to 150 mo). Two-year neck control and overall survival were 83% and 56%, respectively. Sixty-two heminecks (71%) were dissected. A total of 6/22 (27%) "low-risk" necks were positive after CRT if the "high-risk" neck was positive versus 0/22 if the "high-risk" neck was negative (P=0.02). CONCLUSIONS: Identifying the more "high-risk" neck may be useful when deciding the extent of neck dissection after CRT. For patients with bilateral nodal disease treated with CRT, dissection of the "low-risk" hemineck may be omitted if the "high-risk" neck is pathologically negative.

Incidence of subclinical nodal disease at the time of salvage surgery for locally recurrent head and neck cancer initially treated with definitive radiation therapy.

OBJECTIVES/HYPOTHESIS: To estimate the incidence of subclinical nodal disease at the time of isolated local recurrence (LR) after chemoradiotherapy for an initially staged N0 head and neck squamous cell carcinoma. METHODS: We retrospectively reviewed 44 patients who underwent salvage surgery with or without elective neck dissection (END) for an isolated LR between 1997 and 2010. The incidence of subclinical nodal disease was determined from the pathology reports and from clinical neck failures. RESULTS: Thirty patients received END. The overall incidence of subclinical nodal disease in patients with dissected necks was 10% (3/30 patients). The rate of regional control for the 14 observed necks was 100%. Three-year local control and overall survival rates for the END and non-END cohorts were 71% versus 73% (P=0.80) and 55% versus 64%, respectively (P=0.40). CONCLUSIONS: The risk of subclinical nodal disease is low for patients with an isolated LR after chemoradiotherapy.

Patterns of local failure for sinonasal malignancies.

PURPOSE: To identify the patterns of local failure for sinonasal malignancies treated with radiation therapy (RT). METHODS AND MATERIALS: We retrospectively identified 79 patients with sinonasal malignancies treated between 2000 and 2011. The median follow-up was 34 months (7-137). Fifty patients (63%) had surgery and RT with or without chemotherapy, and 29 (37%) received definitive chemoradiation therapy. Twenty-six of 79 patients (33%) failed locally; 11 had persistent disease and 15 had local recurrence (LR). The patients with LR had at least a 3-month disease-free interval posttreatment. Imaging of the 15 LR was registered to the treatment planning computed tomography. Failures were categorized as in-field, marginal, or out-of-field if >95%, 20%-95%, or <20% of the LR was within the 95% prescription isodose line, respectively. RESULTS: Of the 15 patients with LR, 7 were in-field, 2 were marginal, and 6 were out-of-field. For 3 patients, treatment plans were not retrievable; however, it was apparent from clinical records that 2 had in-field LR and 1 had an out-of-field LR (untreated contralateral maxillary sinus). No patient with a marginal or out-of-field recurrence had more than 39% of their recurrent tumor volume within 95% of the prescribed dose. Coverage of the LR by 54 Gy and 45 Gy was suboptimal in 7/7 and 5/7 patients with LR, respectively. Marginal and out-of-field LR were predominantly above the pretreatment tumor location and at the level of or superior to the eyes. CONCLUSIONS: Sinonasal malignancies failed marginally or out-of-field in 53% (8/15) of LR and 31% (8/26) of all local failures. The anatomic location of these marginal and out-of field LR are predominately at, or superior to, the level of the eyes. This pattern of failure may be directly related to efforts to minimize RT to the optic structures and the degree of difficulty of skull base operations.

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.