Nodular lymphocyte-predominant Hodgkin lymphoma characteristics, management of primary and relapsed/refractory disease and outcome analysis: the first comprehensive report from the Middle East.

BACKGROUND: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon variant of Hodgkin lymphoma. There is limited data on treatment, management of refractory and relapsed disease, and long-term outcome. Many registries or country-wide data reports are unable to provide detailed primary and subsequent management. We are reporting our observation on patient's characteristics, management, and outcome. METHODS: This single-institution retrospective cohort analysis includes NLPHL patients seen from 1998 to July 2019. We used Fisher's exact test, chi-square, and Kaplan-Meier (KM) method for various analyses. RESULTS: Two hundred patients were identified, (6.34% of all the HL). Male:female was 3:1. The median age at diagnosis was 22 years (4-79 years). Stage I-II in 145 (72.5%) cases. One hundred patients (50%) received chemotherapy, 68 (34%) chemotherapy + radiation therapy (RT); 87% of all chemotherapy was ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Thirteen patients (6.5%) received RT alone and 16 (8%) had surgery alone. Complete response in 82%, partial response in 5.5% and progressive disease in 10.5%. The median follow is 60 months (5-246). Median 5 and 10 years overall survival (OS) is 94.8 and 92.4% (stages I-II, 97.7 and 97.7%, stage III-IV, 94.8 and 92.4%). Median event-free survival (EFS) is 62.3 and 54% respectively (stage I-II, 72 and 64%, stage III-IV, 36.4 and 18.2%). Stage I-II vs III-IV OS (p = < 0.001) and EFS (p = < 0.001) were significant. For stage I-II, 5 year EFS of chemotherapy + RT (83.3%) was superior to chemotherapy alone (60%, p = 0.008). Five year EFS for early favorable (80%), early unfavorable (60%), and advanced (36.4%) was significant (p = < 0.001). Eleven patients (5.5%) had high-grade transformation. Twenty-nine patients underwent HDC auto-SCT, all are alive (28 in remission). 25% of patients had pathologically proved nodal hyperplasia at some point in time. CONCLUSION: OS of NLPHL is excellent and independent of treatment type. EFS is better for chemotherapy + RT than chemotherapy alone. Stem cell transplant in refractory / multiple relapses resulted in excellent disease control. There is a need to identify optimal treatment strategies accordingly to the risk stratification.

Risk of hematological malignancies in the families of patients treated for nodular lymphocyte-predominant Hodgkin lymphoma.

BACKGROUND: Familial clustering of lymphoid and/or hematological malignancies (FHM) provides an opportunity to study the responsible genes. The data is limited in patients with lymphoid and hematological malignancies. METHODS: The lymphoma database was used to identify patients seen in our institution from 1998 to 2019 with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We studied FHM by collecting detailed history of any malignancy in the family (FM). RESULTS: Two hundred NLPHL patients were identified. Contacting was not possible in 30 patients due to no response to the phone calls (22) and death [1]. 170/200 patients were interviewed; represented 167 families (3 patients with a family member with NLPHL). These 170 patients provided information about 8225 family members. These 167 families had a total of 329 family members with 334 malignancies (including 167 NLPHL patients and 5 members with 2 malignancies each). Of these 167 patients, 77 (46.1%) had no FM while 90 (53.9%) patients had a positive FM; 162 family members with 167 malignancies. Among these 167 families, 31 families (18.6%) had members with FHM +/- solid cancers. These 31 families had 35 family members (25 males:10 females) with 16 lymphomas: diffuse large B cell lymphoma [2], follicular center cell lymphoma [3], chronic lymphocytic leukemia/small lymphocytic lymphoma [3], non-Hodgkin lymphoma [2], classical HL [2], and NLPHL [4]. Total of 8 leukemia: acute lymphoblastic leukemia [4], acute myeloid leukemia [3], and leukemia - no subtyping [5]. These 35 FHM members are 1st [6], 2nd (16), and 3rd [7] degree relatives of 31 NLPHL patients. There are 4 families with NLPHL in family members; all these 8 NLPHL patients are male and are alive. The median total number of 1st + 2nd +3rd degree members are 81. The decrease in the age of diagnosis from 1st generation to the 2nd generation (anticipation) was noted in 13/17 patients; 2nd generation median age at diagnosis was 29.7 years vs 1st generation age 53 years (developed malignancy 23.3 years earlier). CONCLUSION: FHM is frequent in NLPHL. This study provided us many important insights for planning future studies in terms of interviewing technique, time, and resource allocation and genetic testing.

Impact of the coronavirus disease 2019 (COVID-19) pandemic on pediatric oncology care in the Middle East, North Africa, and West Asia region: A report from the Pediatric Oncology East and Mediterranean (POEM) group.

BACKGROUND: Childhood cancer is a highly curable disease when timely diagnosis and appropriate therapy are provided. A negative impact of the coronavirus disease 2019 (COVID-19) pandemic on access to care for children with cancer is likely but has not been evaluated. METHODS: A 34-item survey focusing on barriers to pediatric oncology management during the COVID-19 pandemic was distributed to heads of pediatric oncology units within the Pediatric Oncology East and Mediterranean (POEM) collaborative group, from the Middle East, North Africa, and West Asia. Responses were collected on April 11 through 22, 2020. Corresponding rates of proven COVID-19 cases and deaths were retrieved from the World Health Organization database. RESULTS: In total, 34 centers from 19 countries participated. Almost all centers applied guidelines to optimize resource utilization and safety, including delaying off-treatment visits, rotating and reducing staff, and implementing social distancing, hand hygiene measures, and personal protective equipment use. Essential treatments, including chemotherapy, surgery, and radiation therapy, were delayed in 29% to 44% of centers, and 24% of centers restricted acceptance of new patients. Clinical care delivery was reported as negatively affected in 28% of centers. Greater than 70% of centers reported shortages in blood products, and 47% to 62% reported interruptions in surgery and radiation as well as medication shortages. However, bed availability was affected in <30% of centers, reflecting the low rates of COVID-19 hospitalizations in the corresponding countries at the time of the survey. CONCLUSIONS: Mechanisms to approach childhood cancer treatment delivery during crises need to be re-evaluated, because treatment interruptions and delays are expected to affect patient outcomes in this otherwise largely curable disease.

Excision of pediatric craniopharyngioma: pattern of recurrence in 35 patients at a tertiary care hospital in Saudi Arabia.

BACKGROUND AND PURPOSE: Craniopharyngiomas are benign tumors of central nervous system which are known to affect both adults and children. Despite their benign origin, the recurrence is still one of the main postoperative challenges. The aim of this study was to investigate in retrospect factors related to recurrence of craniopharyngioma in a tertiary center in Riyadh, Saudi Arabia. PATIENTS AND METHODS: We conducted a review of charts of all craniopharyngioma patients operated in neurosurgery department at King Faisal Specialist Hospital & Research Center in Riyadh (KFSH-RC). Age at surgery, gender, body mass index, symptoms at presentation, hormonal data, tumor characteristics and location, presence of hydrocephalus, previous treatments, neuroimaging features, surgical results, and recurrence were abstracted from the medical charts of the patients retrospectively. RESULTS: In all, 70.6% of patients had gross total resection (GTR). The recurrence after GTR in our series was 25% which considered low when compared to most surgical series. From all above studied variables, VP shunt insertion at presentation was constantly significant in both uni- and multi-variable analysis. CONCLUSION: In this study, we analyzed several factors to determine if they had any significant correlation with recurrence. Only VP shunt insertion was found significant. Further researches are needed to verify these factors and to discover others.

Incidence, clinical distribution, and patient characteristics of childhood cancer in Saudi Arabia: A population-based analysis.

PURPOSE: Information regarding the incidence and patterns of childhood malignancies is disproportionately overrepresented by high-income countries, representing mainly the Caucasian population. There is a need to evaluate and disseminate information for other ethnicities, particularly from the Middle East. METHODS: Data from the National Cancer Registry, Saudi Arabia (SA-NCR), for pediatric patients (age 0-14 years) diagnosed between 2005 and 2009 and for similar patients at our institution during the same period were analyzed. Population numbers reported in the 2007 national census were used to calculate the annual incidence of childhood cancer. RESULTS: Data from SA-NCR on 3885 patients were included in this analysis. The median age was 5.58 years, and 57.3% were males. The annual age-specific cancer incidence rate (ASR) for children in SA is 99.83 per million population; ASR per million for lymphoid leukemia is 25.75, 12.05 for brain tumors, and 9.82 for Hodgkin lymphoma. Of all childhood cancers in SA, 35% were treated at our institution. The five-year overall survival for these 1350 patients is 74.6% (median follow-up 7.52 years [95% confidence interval: 7.36-7.68]). Significant differences in the distribution of childhood malignancy subtypes were evident compared with other countries. CONCLUSION: We have reported differences in the cancer ASR and cancer subtype distribution for children in SA as compared with the worldwide incidence and with other populations. This paper provides a comprehensive epidemiological overview of childhood cancer in SA, which could be extrapolated to other regional Arab populations.

Risk-adapted stratification for optimally intensive treatment assignment of pediatric patients with non-Hodgkin lymphoma is an effective strategy in developing countries.

BACKGROUND: Pediatric patients with non-Hodgkin lymphoma (NHL) in developing countries (DCs) present with greater tumor load even at lower stages and with comorbidities that impact therapy delivery. This causes toxic mortality with "standard" intensive protocols or recurrences with "gentler" treatment. OBJECTIVES: We developed and evaluated a risk stratification schema that guides intensity of therapy. DESIGN/METHODS: Sixty-nine patients were prospectively assigned to five risk groups (A-E; n = 6, 15, 16, 15, and 17) following staging and treated with protocols of risk-stratified intensity. Risk stratification utilized St. Jude stage, disease bulk, and sites involved. RESULTS: Between 2006 and 2011, 69 patients with B-cell NHL were enrolled. Among these, 72.5% were boys with mean age of 6.9 years (±3.33 [SD]; range 2.4-14.2 years). Eighty-seven percent had Burkitt lymphoma, 82.6% had advanced stage (25 [36.2%] stage III; 32 [46.4%] stage IV), and 24.6% were central nervous system positive. Mean lactate dehydrogenase increased progressively across the risk strata. Among these, 0/6, 1/15, 3/16, 2/15, and 7/17 patients relapsed/progressed within each risk stratum. Fifteen patients died; three from treatment-related toxicity. At a median follow-up of 6.2 years, the overall and event-free survival (EFS) for all patients was 78.1 and 75.4%, respectively; EFS was related to risk assignment. The frequency of documented infectious and noninfectious toxicities increased with higher risk group assignment causing prolongation of admissions and potential treatment delays. CONCLUSIONS: Reduction in treatment intensity for an identified subset of patients with NHL is feasible, while high-intensity therapy is required for high-risk groups. This risk stratification system may be a first step toward improving the outcomes in some DCs.

Physicians' Knowledge, Attitudes, and Perception Toward Pediatric Palliative Care in Saudi Arabia: A National Exploratory Survey.

Background: Pediatric palliative care (PPC) helps maintain the quality of life for both children and their families. It has been identified as an important goal within the global health agenda. In Saudi Arabia, the discipline remains in its infancy, as illustrated by the absence of PPC programs in academic and health care institutions. Aim: The aim was to conduct a pilot study assessing physicians' knowledge, attitudes, and perceptions toward PPC. Method: Data were gathered through a self-administered questionnaire sent to physicians working in Saudi Arabia. Results: One hundred twelve completed the survey (male 54.2%, n = 50). A total of 40.8% (n = 42) had 20 years or more of experience, 42.9% (n = 48) were from the hematology-oncology specialty, and 68.5% (n = 74) received no training in PPC. Half suggested that children should be informed of their condition but mostly when reaching 12 or 15 years of age. Various physicians reported that the most appropriate time to discuss a transition to palliative care goals is when diagnosing an incurable condition or when despite all efforts, a condition continues to progress and death is expected. Conclusion: Multiple gaps were identified. PPC basic concepts should be included in the formal medical curriculum (e.g., pain management, communication, and ethical considerations at the end of life). There is also a significant need to develop further both primary and specialized palliative care.

Atypical Teratoid Rhabdoid Tumors (ATRT): King Faisal Specialist Hospital and Research Centre experience.

BACKGROUND: Atypical teratoid rhabdoid tumor is an uncommon aggressive central nervous system tumor. All retrospective series have shown a short mean overall survival rate. Considering the rarity of the disease, few prospective clinical trials addressed treatment recommendations for such aggressive tumors, and consequently no definitive treatment guidelines have been established. In this study, we are reviewing our experience in treating atypical teratoid rhabdoid tumor patients. METHODS: We reviewed the medical charts of 43 patients with atypical teratoid rhabdoid tumor who were treated in King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia, between 1996 and 2013. We evaluated the overall survival rate and the influence of different clinical features and treatment protocols on survival. RESULTS: The median overall survival time was 16.9 months (95% Confidence Interval, 5.2-32.9 months) with an estimated 2- and 5-year overall survival of 41.9% ± 9.6 and 27.9% ± 9.2, respectively. Patients receiving trimodal treatment (surgery, chemotherapy, and radiotherapy) exhibited significantly better median overall survival time compared to their counterparts (P value < .001). CONCLUSIONS: Atypical teratoid rhabdoid tumor is rare and aggressive central nervous system tumor. Despite the limitations of the study, our results support several of clinical practice development. Utilization of postoperative radiotherapy and the adoption of trimodal therapy are associated with significant improvement of median survival. Prompt management with aggressive trimodal therapy should be the standard for future treatment protocols.

Comparison of 18F-labelled fluoro-2-deoxyglucose-PET with conventional computed tomography for staging and response assessment in paediatric and adult patients with nodular lymphocyte-predominant Hodgkin's lymphoma.

BACKGROUND: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of Hodgkin lymphoma. Data are limited regarding 18F-labelled fluoro-2-deoxyglucose (FDG)-PET use in NLPHL. We are reporting our experience with FDG-PET utility in staging and response assessment NLPHL patients. METHODS: We retrospectively studied a population of all newly diagnosed or relapsed/refractory patients who underwent both pre-treatment contrast-enhanced computed tomography (CeCT) and an FDG-PET and also at the end of planned treatment. RESULTS: We identified 68 patients found to have in total 312 scans, 78 paired pre-therapeutic and post-treatment CeCT and FDG-PET scans. Among them, 55 were male, with a median follow-up was 48 months. Median SUV-max was 8.3 (2.0-21.0). FDG-PET and CeCT were concordant in 80% (62/78) of staging scans. In 20% (16/78) of patients in whom a discordance was observed, FDG-PET resulted in upstaging in 13 scans and downstaging in 3 scans. The sensitivity of CeCT was 92% for nodal staging and 42% for extralymphatic staging when compared to FDG-PET. The specificity of CeCT was 98% as compared to FDG-PET. For response assessment, there was poor agreement between the CeCT and FDG-PET in assigning complete remission of disease scores as FDG-PET was able to identify the absence of disease despite the presence of a radiologically evident residual mass on CeCT. The sensitivity for CeCT compared to FDG-PET was 100% while the specificity was 43% for detection of post-treatment response. CONCLUSION: For NLPHL, pre-therapeutic FDG-PET scan is better than CeCT staging. FDG-PET has much better specificity for response assessment than CeCT.

Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells.

Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antagonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas.