Assessment of the Surgical Oncology Case Volume Within the Public Sector in Tanzania.

PURPOSE: Surgery provides vital services to diagnose, treat, and palliate patients suffering from malignancies. However, despite its importance, there is little information on the delivery of surgical oncology services in Tanzania. METHODS: Operative logbooks were reviewed at all national referral hospitals that offer surgery, all zonal referral hospitals in Mainland Tanganyika and Zanzibar, and a convenience sampling of regional referral hospitals in 2022. Cancer cases were identified by postoperative diagnosis and deidentified data were abstracted for each cancer surgery. The proportion of the procedures conducted for patients with cancer and the total number of cancer surgeries done within the public sector were calculated and compared with a previously published estimate of the surgical oncology need for the country. RESULTS: In total, 69,195 operations were reviewed at 10 hospitals, including two national referral hospitals, five zonal referral hospitals, and three regional referral hospitals. Of the cases reviewed, 4,248 (6.1%) were for the treatment of cancer. We estimate that 4,938 cancer surgeries occurred in the public sector in Tanzania accounting for operations conducted at hospitals not included in our study. Prostate, breast, head and neck, esophageal, and bladder cancers were the five most common diagnoses. Although 387 (83%) of all breast cancer procedures were done with curative intent, 506 (87%) of patients with prostate and 273 (81%) of patients with esophageal cancer underwent palliative surgery. CONCLUSION: In this comprehensive assessment of surgical oncology service delivery in Tanzania, we identified 4,248 cancer surgeries and estimate that 4,938 likely occurred in 2022. This represents only 25% of the estimated 19,726 cancer surgeries that are annually needed in Tanzania. These results highlight the need to identify strategies for increasing surgical oncology capacity in the country.

Novel dual action PARP and microtubule polymerization inhibitor AMXI-5001 powerfully inhibits growth of esophageal carcinoma both alone and in combination with radiotherapy.

Esophageal cancer is one of the leading causes of cancer deaths globally with an incidence that is concentrated in specific hot spots in Eastern Asia, the Middle East, Eastern Africa, and South America. 10-year overall survival for patients treated with standard of care chemoradiation followed by surgical resection is below 40% highlighting the need for novel therapeutics to treat this disease. We assessed the effect of AMXI-5001, a novel small molecule poly ADP-Ribose polymerase (PARP) inhibitor and microtubule polymerization inhibitor on tumor growth inhibition in both in-vitro and in-vivo murine models. We found that AMXI-5001 was the most potent growth inhibitor of 8 out of 9 different esophageal carcinoma cell lines compared to other clinically available PARP inhibitors, Olaparib, Niraparib, Rucaparib, and Talazoparib. We then confirmed the previously described mechanism of action of AMXI-5001 as a PARP-inhibitor and microtubule polymerization inhibitor using both a PARP trapping assay and immunofluorescence. To further assess AMXI-5001's potential as a therapeutic for esophageal carcinoma we evaluated the effect of AMXI-5001 in combination with standard chemotherapy agents, Cisplatin and 5 Fluorouracil. We showed that AMXI-5001 synergistically inhibits growth in KYSE-70, a squamous esophageal cell line in combination with these drugs. In addition, we found that AMXI-5001 was an effective radiosensitizer, and squamous esophageal carcinoma cell lines treated 24 hours prior to external beam radiation showed significantly more growth inhibition compared to controls. Finally, we assessed the effect of AMXI-5001 monotherapy and in combination with radiotherapy in a xenograft mouse model implanted with subcutaneous KYSE-70 cells. Compared to vehicle control, and those treated with either AMXI-5001 alone or radiation alone, mice treated with both AMXI-5001 and radiation had significant tumor response. In conclusion, AMXI-5001 is an orally bioavailable dual-action PARP and microtubule polymerization inhibitor that holds promise in the treatment of esophageal carcinoma.

IFNL4 Genotypes and Risk of Childhood Burkitt Lymphoma in East Africa.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele (IFNL4-dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4-dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4-dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations.

Exploring the complexity and spectrum of racial/ethnic disparities in colon cancer management.

BACKGROUND: Colorectal cancer is a leading cause of morbidity and mortality across U.S. racial/ethnic groups. Existing studies often focus on a particular race/ethnicity or single domain within the care continuum. Granular exploration of disparities among different racial/ethnic groups across the entire colon cancer care continuum is needed. We aimed to characterize differences in colon cancer outcomes by race/ethnicity across each stage of the care continuum. METHODS: We used the 2010-2017 National Cancer Database to examine differences in outcomes by race/ethnicity across six domains: clinical stage at presentation; timing of surgery; access to minimally invasive surgery; post-operative outcomes; utilization of chemotherapy; and cumulative incidence of death. Analysis was via multivariable logistic or median regression, with select demographics, hospital factors, and treatment details as covariates. RESULTS: 326,003 patients (49.6% female, 24.0% non-White, including 12.7% Black, 6.1% Hispanic/Spanish, 1.3% East Asian, 0.9% Southeast Asian, 0.4% South Asian, 0.3% AIAE, and 0.2% NHOPI) met inclusion criteria. Relative to non-Hispanic White patients: Southeast Asian (OR 1.39, p < 0.01), Hispanic/Spanish (OR 1.11 p < 0.01), and Black (OR 1.09, p < 0.01) patients had increased odds of presenting with advanced clinical stage. Southeast Asian (OR 1.37, p < 0.01), East Asian (OR 1.27, p = 0.05), Hispanic/Spanish (OR 1.05 p = 0.02), and Black (OR 1.05, p < 0.01) patients had increased odds of advanced pathologic stage. Black patients had increased odds of experiencing a surgical delay (OR 1.33, p < 0.01); receiving non-robotic surgery (OR 1.12, p < 0.01); having post-surgical complications (OR 1.29, p < 0.01); initiating chemotherapy more than 90 days post-surgery (OR 1.24, p < 0.01); and omitting chemotherapy altogether (OR 1.12, p = 0.05). Black patients had significantly higher cumulative incidence of death at every pathologic stage relative to non-Hispanic White patients when adjusting for non-modifiable patient factors (p < 0.05, all stages), but these differences were no longer statistically significant when also adjusting for modifiable factors such as insurance status and income. CONCLUSIONS: Non-White patients disproportionately experience advanced stage at presentation. Disparities for Black patients are seen across the entire colon cancer care continuum. Targeted interventions may be appropriate for some groups; however, major system-level transformation is needed to address disparities experienced by Black patients.

Comparative genomics between matched solid and lepidic portions of semi-solid lung adenocarcinomas.

BACKGROUND: Genetic changes that drive the transition from lepidic to invasive cancer development within a radiographic ground glass or semi-solid lung lesion (SSL) are not well understood. Biomarkers to predict the transition to solid, invasive cancer within SSL are needed. METHODS: Patients with surgically resected SSL were identified retrospectively from a surgical database. Clinical characteristics and survival were compared between stage I SSL (n = 65) and solid adenocarcinomas (n = 120) resected during the same time period. Areas of normal lung, in situ lepidic, and invasive solid tumor were microdissected from within the same SSL specimens and next generation sequencing (NGS) and Affymetrix microarray of gene expression were performed. RESULTS: There were more never smokers, Asian patients, and sub-lobar resections among SSL but no difference in 5-year survival between SSL and solid adenocarcinoma. Driver mutations found in both lepidic and solid invasive portion were EGFR (43%), KRAS (21%), and DNMT3A (5%). CEACAM5 was the most upregulated gene found in solid, invasive portions of SSL. Lepidic and invasive solid areas had many similarities in gene expression, however there were some significant differences with the gene SPP1 being a unique biomarker for the invasive component of a SSL. CONCLUSIONS: Common lung cancer driver mutations are present in in situ lepidic as well as invasive solid portions of a SSL, suggesting early development of driver mutations. CEACAM5 and SPP1 emerged as promising biomarkers of invasive potential in semi-solid lesions. Other studies have shown both genes to correlate with poor prognosis in lung cancer and their role in evolution of semi-solid lung lesions warrants further study.

Interventions Addressing Barriers to Delayed Cancer Diagnosis in Low- and Middle-Income Countries: A Systematic Review.

BACKGROUND: Delays to cancer diagnosis exist, resulting in worse survival outcomes for many cancers. Interventions targeting delays and barriers to cancer diagnosis and treatment have been investigated, but mostly in high-income countries. We conducted a systematic literature review to identify and characterize the interventions studied across cancers, within low- and middle-income countries (LMICs). METHODS: This systematic review forms part two of a wider study examining solutions to delays and barriers in cancer early diagnosis in LMICs. A comprehensive literature search was conducted on November 27, 2017, encompassing published studies from the preceding 15 years. We extracted study design, population, and intervention, and reported outcome measures from each study. Results were presented by target of interventions (general vs. health care professionals). A narrative synthesis was used to summarize intervention efficacy. RESULTS: Of 10,193 abstracts returned, 25 were included, consisting of studies across World Health Organization geographical regions, examining breast, cervix, childhood, prostate, head and neck, and gastric cancers. Altogether, 11 intervention studies targeted the general population, 12 targeted health care professionals, and 2 targeted both. The majority (17/25) of studies reported interventions focusing on patient and diagnosis-related barriers early in the cancer care pathway. Most studies reported knowledge score as primary outcome measure (17/25); few (6/25) reported on clinically relevant measures such as reducing disease stage at presentation or diagnostic time interval. Effectiveness of interventions was demonstrated for some cancers only. CONCLUSION: More interventions reporting clinically relevant measures and using standardized methods and outcomes are required to improve our ability to effectively improve cancer early diagnosis in LMICs. IMPLICATIONS FOR PRACTICE: Prior to this study, the extent of intervention literature in cancer early diagnosis in low- and middle-income countries had not been characterized. This study aimed to outline and characterize interventions across all cancer types and across all countries. This systematic review demonstrated that interventions have been investigated targeting both the general population and health care professionals. Furthermore, this review demonstrates that the majority of studies report knowledge as an outcome measure, rather than clinically significant measures that improve cancer-related outcomes, such as delay intervals or downstaging of disease. Future interventions should address clinically relevant measures to better assess efficacy of interventions.

Delays and Barriers to Cancer Care in Low- and Middle-Income Countries: A Systematic Review.

BACKGROUND: Advanced stage presentation of patients with is common in low- and middle-income countries (LMICs). A comprehensive analysis of existing delays and barriers in LMICs has not been previously reported. We conducted a systematic literature review to comprehensively outline delays and barriers to identify targets for future interventions and provide recommendations for future research in this field. MATERIALS AND METHODS: Multiple electronic databases were searched using a standardized search strategy. Eligible articles were of any language, from LMICs, and published between January 1, 2002, and November 27, 2017. Included studies reported cancer care intervals or barriers encountered. Intervals and associated barriers were summarized by cancer type and geographical region. RESULTS: This review included 316 study populations from 57 LMICs: 142 (44.9%) studies addressed time intervals, whereas 214 (67.7%) studies described barriers to cancer diagnosis. The median intervals were similar in the following three stages of early diagnosis: (a) access (1.2 months), (b) diagnostic (0.9 months), and (c) treatment (0.8 months). Studies from low-income countries had significantly longer access intervals (median, 6.5 months) compared with other country income groups. Patients with breast cancer had longer delay intervals than patients with childhood cancer. No significant variation existed between geographic regions. Low health literacy was reported most frequently in studies describing barriers to cancer diagnosis and was associated with lower education level, no formal employment, lower income, and rural residence. CONCLUSION: Early diagnosis strategies should address barriers during all three intervals contributing to late presentation in LMICs. Standardization in studying and reporting delay intervals in LMICs is needed to monitor progress and facilitate comparisons across settings. IMPLICATIONS FOR PRACTICE: This review draws the attention of cancer implementation scientists globally. The findings highlight the significant delays that occur throughout the cancer care continuum in low- and middle-income countries and describe common barriers that cause them. This review will help shape the global research agenda by proposing metrics and implementation studies. By demonstrating the importance of standardized reporting metrics, this report sets forth additional research and evidence needed to inform cancer control policies.

Knowledge Summaries for Comprehensive Breast Cancer Control: Feedback From Target Audiences in Kenya.

PURPOSE: Comprehensive breast cancer control programs are needed to decrease breast cancer mortality, but few tools exist to assist stakeholders in limited-resource settings. The Knowledge Summaries for Comprehensive Breast Cancer Control (KSBCs) are a series of evidence-based publications intended to support cancer control planning at various resource levels. The goals of this evaluation research study were to learn about the extent to which the KSBCs could be useful to policymakers, health care providers, and breast cancer advocates in Kenya, and whether introducing the KSBCs led to their uptake, and if so, how they were used. METHODS: This study used one-on-one interviews, focus groups, and self-administered online surveys. Policymakers were recruited from the Ministry of Health. Providers were recruited from four hospitals in two cities, Nairobi and Eldoret, and one rural municipality, Kijabe. Advocates were recruited from cancer advocacy organizations. RESULTS: Twenty individuals participated in the research. They found the KSBCs to be educational reference tools that create a shared planning-related knowledge base among diverse stakeholders. The KSBCs were seen to be applicable to a variety of contexts and stakeholders. CONCLUSION: This study found that the KSBCs can be useful as both an educational tool and a convening tool for multistakeholder engagement in breast cancer prevention and control in a variety of settings. Additional engagement with users of the KSBCs can provide more knowledge about how the KSBCs are used and how they contribute to building collaborations across stakeholder groups to strengthen breast cancer prevention and control in low-resource settings.

Sentinel Lymph Node Biopsy Pathology and 2-Year Postsurgical Recurrence of Breast Cancer in Kenyan Women.

PURPOSE: The goal of this study was to describe the pathologic findings and early follow-up experience of patients who underwent a sentinel lymph node biopsy (SLNB) at Aga Khan University Hospital (AKUH) between 2008 and 2017. PATIENTS AND METHODS: We performed a retrospective analysis of women with breast cancer who underwent an SLNB at AKUH between 2008 and 2017. The SLNB was performed on patients with stage I and stage II breast cancer, and identification of the sentinel lymph node was made by radioactive tracer, blue dye, or both, per availability and surgeon preference. Demographic, surgical, and pathologic data, including immunohistochemistry of the surgical sample for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, were abstracted from the patient records. Follow-up data were available for a subset of patients. RESULTS: Between 2008 and 2017, six surgeons performed SLNBs on 138 women, 129 of whom had complete records and were included in the study. Thirty-one of 129 (24%) had a positive SLNB, including 10 of 73 (14%) with stage I and 21 of 56 (38%) with stage II disease. Seventy-eight patients (60%) received systemic adjuvant chemotherapy and 79 (62%) received radiation therapy, and of the 102 patients who were estrogen receptor positive, 86 (85%) received endocrine therapy. Seventy-nine patients were observed for > 2 years, and, of these, four (5.1%) had a regional recurrence. CONCLUSION: The SLNB positivity rates were similar to those of high-income country (HIC) cohorts. However, preliminary data suggest that recurrence rates are elevated at AKUH as compared with those of HIC cohorts, perhaps because of a lower use of radiotherapy and chemotherapy at AKUH compared with HIC cohorts or because of differences in the characteristics of the primary tumor in patients at AKUH as compared with those in HICs.

Histology and Cytopathology Capacity in the Public Health Sector in Kenya.

PURPOSE: Histology and cytopathology services are necessary for cancer diagnosis and treatment. However, the current capacity of Kenya's pathology laboratories is unknown. A national survey was conducted among public sector pathology laboratories to assess their capacity to perform histology, fine-needle aspiration, and bone marrow aspiration. METHODS: Between April and June 2017, we identified all public hospitals that provide pathology services in Kenya. In total, two national and 13 county referral hospitals met the inclusion criteria and were sent a standardized, pretested, self-administered questionnaire. RESULTS: A total of 11 hospitals (73%) completed the survey. The reported total caseload of histology, fine-needle aspiration, and bone marrow aspiration for 2016 was 26,472. All of the facilities staffed a pathologist and were providing cancer-related diagnostic services. Nine (82%) of the hospitals maintain a register of diagnosed cancer cases, but only one (11%) of those uses an electronic system. Six (55%) of the surveyed hospitals were able to perform histology with a median turnaround time of 14 days. Six (55%) laboratories regularly referred some specimens elsewhere for interpretation, but three of these centers relied on patients for transportation of the specimen to the referral institution. No laboratories were accredited by an external organization; however, 10 (91%) of the laboratories were working toward achieving accreditation, but only for clinical pathology services. CONCLUSION: This study describes the current status of histology and cytopathology capacity in Kenya's public sector hospitals. It provides useful baseline information needed by the Ministry of Health to develop necessary capacity building and referral-strengthening interventions. A high proportion of hospitals are working to achieve accreditation points toward their commitment to providing quality services to the Kenyan public.

Differing Causes of Lactic Acidosis and Deep Breathing in Cerebral Malaria and Severe Malarial Anemia May Explain Differences in Acidosis-Related Mortality.

Lactic acidosis (LA) is a marker for mortality in severe malaria, but the mechanisms that lead to LA in the different types of severe malaria and the extent to which LA-associated mortality differs by type of severe malaria are not well described. We assessed the frequency of LA in children admitted to Mulago Hospital, Kampala, Uganda with cerebral malaria (CM, n = 193) or severe malarial anemia (SMA, n = 216). LA was compared to mortality and measures of parasite biomass and sequestration (P. falciparum histidine-rich protein-2 (PfHRP2) concentration, platelet count), and to a measure of systemic tissue oxygen delivery (hemoglobin level). LA was more frequent in children with SMA than CM (SMA, 47.7%, CM, 34.2%, P = 0.006), but mortality was higher in children with CM (13.0%) than SMA (0.5%, P<0.0001). In CM, LA was associated with increased PfHRP2 concentration and decreased platelet count but was not associated with hemoglobin level. In contrast, in SMA, LA was associated with a decreased hemoglobin level, but was not associated with PfHRP2 concentration or platelet count. LA was related to mortality only in CM. In multivariable regression analysis of the effect PfHRP2 and hemoglobin levels on LA and DB, only PfHRP2 level increased risk of LA and DB in CM, while in SMA, elevated hemoglobin strongly decreased risk of LA and DB, and PfHRP2 level modestly increased risk of LA. The study findings suggest that LA in CM is due primarily to parasite sequestration, which currently has no effective adjunctive therapy, while LA in SMA is due primarily to anemia, which is rapidly corrected with blood transfusion. Differing etiologies of LA in CM and SMA may explain why LA is associated with mortality in CM but not SMA.