Personalized Medicine in Oncology in the Developing World: Barriers and Concepts to Improve Status Quo.

Personalized medicine (PM) has revolutionized oncology management in high human development indexed countries. By interrogating both disease and host factors through a variety of tools, oncologists have been able to better target an individual's cancer, leading to improved outcomes. But both the tools used to define these variables, such as next generation sequencing, large immunohistochemical and fluorescence in situ hybridization (FISH) panels, and the weapons employed against each target are extremely expensive. The expenses have to be measured as not only the direct cost to the patient but also the cost to the system to develop and deploy the necessary infrastructure to optimally use them. However, the concepts of predictive, timely prevention and PM have demonstrated improvement in patient's satisfaction and cost effectiveness. In this paper we will summarize the relevant barriers and challenges that limit the implementation of PM in the developing world with an emphasis on the challenges in Nigeria and Nepal.

Impact of margin status on survival after radical nephrectomy for renal cell carcinoma.

BACKGROUND: Data about the impact of surgical margin positivity on patient outcomes following radical nephrectomy (RN) for renal cell carcinoma (RCC) is limited. We evaluate the effect of positive surgical margins (PSMs) on relapse-free survival (RFS) and overall survival (OS.) METHODS: Clinicopathologic data of patients who underwent RN for RCC was analyzed based on margin status. χ2 and Student t test were used to compare groups. Cox regression analysis was used for the analysis. Kaplan-Meier method was used for survival curves. RESULTS: A total of 485 patients who underwent RN for RCC were analyzed. Most patients with T1/T2 stage had NSM. Most patients with T4 had PSM. T3 patients were split between the two groups. Analysis of the T3 group showed shorter RFS in the PSM group at 3 years (hazard ratio [HR]: 4.3, p = .01), and 5 years (HR: 4.3, p = .01.) OS analysis showed worse OS in PSM but not statistically significant. There was a significant association between PSM and laterality (p = .023) and histologic type (p = .025.) CONCLUSIONS: PSM was associated with shorter RFS after RN in T3 RCC patients. There was a trend towards worse OS in the PSM group, but it did not reach statistical significance. Laterality and histologic type were associated with surgical margin status.

Association Between Pesticide Use and Incidence of Diffuse Large B-Cell Lymphoma.

BACKGROUND/AIM: Exposure to pesticides has been reportedly associated with several types of cancer. MATERIALS AND METHODS: In this study, we used data from The United States Geological Survey (USGS), United States Census, and the Surveillance, Epidemiology, and End Results (SEER) database to analyze the association between the area density of specific agricultural pesticides and the county level annual incidence of diffuse large B-cell lymphoma (DLBCL). RESULTS: Incidence of DLBCL was significantly associated with an area density of 14 of the pesticides reported by USGS. CONCLUSION: This highlights the need for further investigation into the safety of the use of these pesticides. The importance of this study comes not only from the significant association it shows between pesticides and the incidence of cancer, but also from the fact that it included all compounds reported to USGS as being used in agriculture. This helps in prioritizing pesticides for further evaluation.

Distribution of Breast Cancer Subtypes Among Nigerian Women and Correlation to the Risk Factors and Clinicopathological Characteristics.

BACKGROUND: Breast cancer in African women differs from the Caucasian. Understanding the profile of Nigerian women with breast cancer will help with preventive measures and treatment. This study focused on the clinico-pathological characteristics, with risk factors of breast cancer patients in Nigeria. METHODS: Newly diagnosed female patients with breast cancer were assessed over 12 months. Patients were reviewed using a predesigned proforma which focused on socio-demographic information, clinical information, risk factors and tumor biology. RESULTS: A total of 251 women were identified; their mean age was 46 years. More than half (62.5%) are premenopausal at presentation, 37.8% with Eastern Cooperative Oncology Group (ECOG) score of 0 and right side (50.2%) as the most common primary site of disease. Less than half of them (43.0%) are estrogen receptor (ER) positive, 27.9% are progesterone receptor (PR) positive, 43.8% and 47.4% are hormone receptor positive and triple negative, respectively. Most patients presented at the latter stage of the disease, stage III (66.9%) and stage IV (18.3%). Only 15.9% are well differentiated and almost all (92.8%) had invasive ductal histological type. Obesity (66.2%) and physical inactivity (41.9%) are the most common risk factors for the disease. A significant relationship was found between immunohistochemistry status and family history of breast cancer, tumor site, previous breast surgery, previous lump and alcohol intake. CONCLUSION: Findings from this study showed that Nigerian breast cancer patients differ from their counterparts in the high human development index (H-HDI) countries in terms of the patients and disease characteristics. In view of this, prevention and treatment options should consider this uniqueness to ensure better outcome.

Tumor Mutational Burden Is Site Specific in Non-Small-Cell Lung Cancer and Is Highest in Lung Adenocarcinoma Brain Metastases.

PURPOSE: Tumor mutational burden (TMB) is a developing biomarker in non-small-cell lung cancer (NSCLC). Little is known regarding differences between TMB and sample location, histology, or other biomarkers. METHODS: A total of 3,424 unmatched NSCLC samples, including 2,351 lung adenocarcinomas (LUADs) and 1,073 lung squamous cell carcinomas (LUSCs), underwent profiling, including next-generation sequencing of 592 cancer-related genes, programmed death ligand 1 immunohistochemistry, and TMB. The rate TMB of 10 mutations per megabase (Mb) or greater was compared between primary and metastatic LUAD and LUSC. Molecular alteration frequency was compared at a cutoff of 10 mutations/Mb. RESULTS: LUAD metastases were more likely to have a TMB of 10 mutations/Mb or greater compared with primary LUADs (38% v 25%; P < .001), and this difference was most pronounced with brain metastases (61% v 35% for other metastases; P < .001). The median TMB for LUAD brain metastases was 13 mutations/Mb compared with six mutations/Mb for primary LUADs. Variability existed for other LUAD metastasis sites, with adrenal metastases most likely to meet the cutoff of 10 mutations/Mb (51%) and bone metastases least likely to meet the cutoff (19%). TMB was more commonly 10 mutations/Mb or greater for LUSC primary tumors than for LUAD primary tumors (35% v 25%, respectively; P < .001). LUSC metastases were more likely to have a TMB of 10 mutations/Mb or greater than LUSC primary tumors. Poorly differentiated disease was more likely have a TMB of 10 mutations/Mb or greater when stratified by histology and primary tumor or metastasis. Site-specific molecular differences existed at this TMB cutoff including programmed death ligand 1 positivity and STK11 and KRAS mutation rate. CONCLUSION: TMB is a site-specific biomarker in NSCLC with important spatial and histologic differences. TMB is more frequently 10 mutations/Mb or greater in LUAD and LUSC metastases and highest in LUAD brain metastases. Along this TMB cutoff, clinically informative distinctions exist in other tumor profiling characteristics. Further investigation is needed to expand on these findings.

Molecular Alterations Associated with DNA Repair in Pancreatic Adenocarcinoma Are Associated with Sites of Recurrence.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with a rising incidence. Mutational analysis of PDAC has provided valuable information but has not yet dramatically changed the therapeutic landscape due to the number of variations detected in any one individual. The pattern of molecular alterations-gene mutations, variations in copy number, and changes in gene expression-has been described in the literature. The purpose of this study is to further investigate the molecular alterations in recurrent or metastatic PDAC based on the site of disease. METHODS: Molecular alterations in patients with recurrent or metastatic PDAC from 2007 to 2015 were analyzed. The most common molecular alterations found in PDAC tumors from the pancreas were compared to metastatic PDAC specimens from the liver, lung, peritoneum, and other locations. Means were compared with a two-tailed Student's t test or ANOVA as appropriate. Rates of molecular alterations among the different groups were compared with Pearson's χ2. RESULTS: Two thousand five hundred fifty-two patients with PDAC were identified in a retrospective database, and the 15 most common molecular alterations were utilized for analysis. The most common alterations among all patients were mutations in KRAS and PTEN (59 and 62%, respectively), with differences in prevalence by site of metastasis (p = 0.042 and p = 0.037, respectively). KRAS mutations were more commonly found in metastasis in the lung (72%) than in other sites (59%, p = 0.042). Low expression of ERCC1 was found in 49% of lung metastases from PDAC but only 15% in PDAC in the pancreas (p < 0.001). Five of the 8 molecular alterations significantly associated with site of metastatic disease were involved in DNA maintenance, repair, replication, or transcription (each p < 0.001). CONCLUSIONS: Aberrant expression or mutation in genes involved in DNA maintenance is found in association with specific sites of metastatic PDAC. Personalizing therapy for metastatic PDAC based on site of disease and their associated molecular alterations warrants further investigation.

Impact of Provider Volume on Outcomes of Patients With Hodgkin Lymphoma.

BACKGROUND: While the provider volume-outcome relationship has been established for many complex surgeries and invasive procedures, the provider volume impact on outcomes for Hodgkin lymphoma (HL) is less certain. We hypothesized that high-volume providers (HVPs) may have superior outcomes compared with low-volume providers (LVPs). METHODS: We performed a chart-based, retrospective review of all patients receiving adriamycin, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for HL at the West Cancer Center from January 2010 to June 2015. Patients were divided into HVP (> 3 inpatient chemotherapy (CT)/month (m)) versus LVP (< 3 CT per m) groups. Of 95 patients identified, 93 received at least one dose of ABVD, 21 treated by HVP and 72 by LVP. Patient characteristics were well balanced between groups. RESULTS: HVPs were less likely to prescribe dose delays (odds ratio (OR): 0.32; confidence interval (CI): 0.16 - 0.65; P = 0.0007) and to hold doses for afebrile neutropenia (OR: 0.05; CI: 0.00 - 0.85; P = 0.0006). HVP delivered significantly fewer prophylactic growth factors (0% of doses vs. 42%, OR: 0.00; CI < 0.00 - 0.06; P < 0.0001). Both event-free survival (EFS) (HR: 6.68; CI: 1.10 - 7.63; P = 0.0321) and overall survival (OS) (HR: 3.68; CI: 1.11 - 12.22; P = 0.032) were significantly inferior in the patients treated by LVP. CONCLUSIONS: In this study, patients with HL treated by LVP had inferior outcomes compared with those treated by HVP. HVPs were less likely to prescribe dose delays, hold doses for afebrile neutropenia or administer growth factor prophylaxis. These observations need to be confirmed in alternative datasets.

Cutaneous Mucormycosis Following a Bullous Pemphigoid Flare in a Chronic Lymphocytic Leukemia Patient on Ibrutinib.

While the recent development of novel therapeutics in oncology, such as small molecule kinase inhibitors (SMKIs), has enabled our ability to target disease-specific molecular pathways, the prolonged impact of these agents on the immune system and infectious risk remains to be seen. We present a 68-year-old male with refractory chronic lymphocytic leukemia (CLL) on ibrutinib monotherapy for 3 years who developed extensive cutaneous mucormycosis following a severe bullous pemphigoid (BP) flare. He received amphotericin B for 4 weeks and was continued on posaconazole with resolution of his mucormycosis infection. Consistent with a growing evidence of literature identifying opportunistic fungal infections in patients on ibrutinib therapy, providers should be cognizant of medical comorbidities that may predispose to such infections and explore methods of prevention before starting ibrutinib and other SMKIs.

Recurrent Cytogenetic Abnormalities in Intravascular Large B-Cell Lymphoma.

OBJECTIVES: Data characterizing the cytogenetic landscape of intravascular large B-cell lymphoma (ILBCL) are limited. Here, we developed a comprehensive karyotypic data set to identify recurrent cytogenetic abnormalities in ILBCL. METHODS: Cases of ILBCL with complete cytogenetic analysis were identified from an institutional database and the literature. The combined data were systematically reviewed for the presence of recurrent abnormalities. RESULTS: Four new cases were identified and combined with 25 karyotypes previously published in the literature. Karyotypes were uniformly complex with a median of 10 aberrations. In total, 72.4% had abnormalities involving chromosome 1, with 31.0% involving rearrangements of 1p13 or 1q21; 58.6% had abnormalities involving chromosome 6, which in almost all cases involved 6q; 34.5% had abnormalities involving chromosome 14, with 27.6% involving rearrangements of 14q32; and 55.2% had abnormalities of chromosome 18, with 37.9% harboring trisomy 18. CONCLUSIONS: Recurrent cytogenetic abnormalities involving chromosomes 1, 6q, and 18 are present in greater than 50% of ILBCL.

Multi-Database Description of Primary Splenic Diffuse Large B-Cell Lymphoma.

BACKGROUND/AIM: Stage I splenic diffuse large B-cell lymphoma (DLBCL) is rare and there are few data to guide management. We sought to further define prognosis and outcomes. MATERIALS AND METHODS: We utilized the Surveillance, Epidemiology, and End Results registry to identify patients with stage I splenic DLBCL diagnosed 1973-2013. Patients were divided into two cohorts based on the year of diagnosis (1983-2005; 2006-2013) as rituximab was approved by the U.S. Food and Drug Administration in 2006 for first-line treatment of DLBCL. RESULTS: Utilization of splenectomy decreased after the approval of rituximab (82% pre- versus 72% rituximab-era). Disease-specific and overall survival were greater with splenectomy [hazard ratio (HR)=0.57, p=0.04; and HR=0.66, p=0.03, respectively], but this benefit was only seen in the pre-rituximab cohort, not in the rituximab-era cohort. There was a trend toward improved overall survival with the introduction of rituximab (HR=0.75, p=0.054). CONCLUSION: Utilization of splenectomy for stage I splenic DLBCL has decreased with the introduction of rituximab without compromising outcomes.

Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain with next-generation sequencing.

While conventional organization of EGFR mutations in non-small cell lung cancer (NSCLC) includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to the tyrosine kinase domain (TKD) in exons 18-21, next-generation sequencing (NGS) raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. NSCLC patients at our institution who received tumor profiling with NGS from 2013 to 2015 were identified. EGFR mutations were arranged based upon their distribution relative to the TKD. In silico analysis was performed to predict non-synonymous single nucleotide polymorphism (nsSNP) pathogenicity. Of 247 patients, 43 EGFR variants were seen in 39 patients (16%). While 32 had TKD lesions demonstrable through standard testing, 7 had extra-TKD nsSNPs (7/43), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 1 carboxy-terminal (CT). Aside from known pathogenic ECD mutation G598V, 5/6 extra-TKD nsSNPs were predicted damaging with in silico analysis. Seven of 7 extra-TKD nsSNP+ patients smoked and were stage IV; 5/7 were adenocarcinoma. An adenocarcinoma patient with JM R675Q had erlotinib, 150 mg daily, added following progression of disease on carboplatin and paclitaxel and had a partial response for 4 months. No other extra-TKD nsSNP+ patient received EGFR-directed therapy. >2% NSCLC cases in our cohort had EGFR nsSNPs located outside of the TKD, representing >16% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets.

Addition of Rituximab to Chemotherapy Reduced the Rate of Surgery for Gastric-DLBCL Without Increasing Early Mortality.

BACKGROUND: We evaluated surgical trends for gastric diffuse large B-cell lymphoma (gDLBCL) before and after the approval of rituximab and whether an association of early mortality existed in patients treated after approval of rituximab. PATIENTS AND METHODS: We utilized the Surveillance Epidemiology and End Results (SEER) 18 database to extract data on patients with gDLBCL diagnosed between 1983-2012. Primary site-specific cancer-directed surgery using SEER site-specific surgical codes and annual trends were analyzed. Patients were analyzed before and after 2006, the year rituximab gained U.S. Food and Drug Administration approval. RESULTS: Joinpoint trend analysis showed the sharpest decline in surgical rates between 2000-2010. Adjusted surgical rates computed using poisson regression declined from 54.4% in 1983 to 6.9% in 2012, with an annual percentage change of -8.9% (95% confidence interval=-9.7% to -8.3%; p-value <0.01). No significant mortality increase at 30 and 60 days was found. CONCLUSION: While rituximab appears to have significantly changed how surgery is utilized for patients with gDLBCL, early mortality was unchanged.

Sweet's syndrome associated with clonal hematopoiesis of indeterminate potential responsive to 5-azacitidine.

Sweet's syndrome (SS) is a rare condition characterized by the abrupt appearance of painful skin lesions due to neutrophilic dermal infiltration. Hematologic neoplasms, particularly acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs), have been commonly reported in association with SS. Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging entity that is a precursor state to myeloid neoplasms. CHIP has not been previously associated with SS. We report the case of a 71-year-old man who presented with recurrent, painful edematous and erythematous papules and nodules for 18 months despite treatment with corticosteroids. He had normal blood counts, but a macrocytosis was noted (110 fl). Alternative causes of macrocytosis were ruled out. A skin biopsy confirmed a diagnosis of SS. Bone marrow biopsy specimen yielded a normal karyotype except for loss of the Y chromosome and equivocal morphologic findings. Polymerase chain reaction (PCR) and reverse transcription polymerase chain reaction (RT-PCR) of selected genes from the peripheral blood demonstrated a mixed lineage leukemia (MLL) partial tandem duplication (PTD) and sequence variant in CCAAT/enhancer binding protein alpha (CEBPA). These findings were consistent with a diagnosis of CHIP. The patient was treated with 5-azacitidine and achieved a complete remission of his skin lesions and was able to discontinue corticosteroids. To our knowledge, this is the first report of a patient with recurrent SS associated with CHIP. In addition to other myeloid neoplasms like AML and MDS, CHIP should be considered as a potential etiology in cases of recurrent SS. Treatment with a hypomethylating agents such as azacitidine could also serve as an alternative to systemic corticosteroid therapy.

Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of cytokine-driven immune activation. Cardinal features include fever, hemophagocytosis, hepatosplenomegaly, lymphocytic infiltration, and hypercytokinemia that result in multisystem organ dysfunction and failure. Familial HLH is genetically driven, whereas secondary HLH (SHL) is caused by drugs, autoimmune disease, infection, or cancer. SHL is associated with worse outcomes, with a median overall survival typically of less than 1 year. This reflects difficulty in both diagnostic accuracy and in establishing reliable treatments, especially in cases of malignancy-induced SHL, which have significantly worse outcomes. Malignancy-induced HLH is seen almost exclusively with hematologic malignancies, constituting 97% of cases in the literature over the past 2 years. In these situations, the native immune response driven by CD8 T cells produces an overabundance of T helper 1 cytokines, notably interferon-γ, tumor necrosis factor-α, and interleukin-6, which establish a positive feedback loop of inflammation, enhancing replication of hematologic malignancies while leaving the host immune system in disarray. In this paper, we present 2 case studies of secondary HLH driven by HM, followed by a review of the literature discussing the cytokines driving HLH, diagnostic criteria, and current treatments used or undergoing investigation.

Outcome of Adolescents and Young Adults Compared With Pediatric Patients With Acute Myeloid and Promyelocytic Leukemia.

BACKGROUND: Studies on the outcome of adolescents and young adults (AYAs) with acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) are limited. METHODS: We compared the outcome of AYA (19-30 years) patients with AML and PML and pediatric (0-18 years) patients with AML (pAMLs) and APL (pAPLs) utilizing the Surveillance Epidemiology and End Results-18 registry. Early mortality rate (EMR), defined as mortality within 1 month of diagnosis, was used as a surrogate for treatment-related mortality. Survival statistics were computed using the Kaplan-Meier method. Multivariate analysis was done using logistic regression and the Cox proportional hazard regression model. RESULTS: A total of 6343 patients with AML were identified; 44.7% were AYAs. pAMLs had lower EMR (6.2% vs. 9.2%; P < .01) and higher overall survival (OS) (1-year, 70.3% vs. 62.1%; 5-year, 48.2% vs. 36.4%; P < .01). Nine hundred twenty patients with APL were also identified; 59.5% were AYAs. No statistically significant difference was found between AYAs with APL and pAPLs in EMR (11.4% vs. 14.1%; P = .23) and OS (1-year, 83.8% vs. 81.2%; P = .31 and 5-year, 68.2% vs. 73.1%; P = .11]. Comparing all patients with AML and APL, AYAs with APL and pAPLs had higher EMR (11.4% and 14.1% vs. 6.2% and 9.2%; P ≤ .01) but better OS than AYAs with AML and pAMLs (5-year OS, 68.2% and 73.1% vs. 48.2% and 36.4%; P ≤ .01). CONCLUSION: Our analysis shows AYAs with AML have worse EMR and OS compared with pAMLs. AYAs with APL and pAPLs have similar outcomes. To our knowledge, this is the first study reporting outcomes of AYAs with APL and pAPLs using a large population-based registry and their comparison with same age patients with AML.

Non-Hodgkin lymphoma across the pediatric and adolescent and young adult age spectrum.

The non-Hodgkin lymphomas (NHLs) occurring in children and adolescents and young adults (AYA) are characterized by various age-related differences in tumor biology and survival. Children generally present with high-grade lymphomas, such as Burkitt lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and anaplastic large cell lymphoma, whereas low-grade histologic subtypes, such as follicular lymphoma, occur more frequently with increasing age. Treatment outcome for children with NHL is generally superior to that observed in adults. Factors contributing to this discrepancy include psychosocial factors, patient factors, and differences in tumor biology and therapy. These factors will be reviewed, with particular attention to the biological features of diffuse large B-cell lymphoma and anaplastic large cell lymphoma and corresponding therapeutic challenges. Novel targeting agents have been developed, which have been shown to be active in some patients. There is clearly a need for treatment protocols with eligibility criteria that cover the full span of the pediatric and AYA age range and that incorporate detailed molecular characterization of the tumors.