Challenges and opportunities in providing palliative care services to children with a life-limiting illness: A systematic review

BACKGROUND Palliative care for children is an innovative approach that helps improve the quality of life of children suffering from life-limiting illnesses, and their family members. The WHO recognized palliative care as a part of universal health coverage. However, there is inadequate availability and inequitable distribution of palliative care services for children in most parts of the world. We reviewed the existing literature to assess (i) the challenges in providing palliative care services for children suffering from life-limiting illnesses and (ii) the strategies or opportunities to overcome these challenges. METHODS We conducted systematic searches in the PubMed and Scopus databases to find articles published in the past 10 years (January 2011 to December 2020). The population, concept and context (PCC) framework was used to devise a search strategy in an electronic database. RESULTS A total of 1562 articles were found by searching the database and other sources. Title and abstracts of articles were screened, and 206 articles were selected for full-text review. After scrutiny 28 articles met the inclusion criteria. Barriers to and opportunities in the provision of palliative care services for children were identified at policy, organizational, healthcare provider, and patient/family levels. CONCLUSION We found that the majority of barriers to provision of palliative care services for children with life-limiting illnesses can be addressed by adopting research-driven strategies. Adequate and equitable distribution of palliative care services is required for improving children and their family members’ quality of life.

Characteristics & outcomes of cancer patients with COVID-19: A multicentre retrospective study from India

Background & objectives: High mortality has been observed in the cancer population affected with COVID-19 during this pandemic. We undertook this study to determine the characteristics and outcomes of cancer patients with COVID-19 and assessed the factors predicting outcome. Methods: Patients of all age groups with a proven history of malignancy and a recent diagnosis of SARS-CoV-2 infection based on nasal/nasopharyngeal reverse transcriptase (RT)-PCR tests were included. Demographic, clinical and laboratory variables were compared between survivors and non-survivors groups, with respect to observed mortality. Results: Between May 11 and August 10, 2020, 134 patients were included from the three centres and observed mortality was 17.1 per cent. The median age was 53 yr (interquartile range 39-61 yr) and thirty four patients (25%) were asymptomatic. Solid tumours accounted for 69.1 per cent and breast cancer was the most common tumour type (20%). One hundred and five patients (70.5%) had received chemotherapy within the past four weeks and 25 patients (19.3%) had neutropenia at presentation. On multivariate analysis, age [odds ratio (OR) 7.99 (95% confidence interval [CI] 1.18-54.00); P=0.033], haemoglobin [OR 6.28 (95% CI 1.07-37.04); P=0.042] neutrophil–lymphocyte ratio [OR 12.02 (95% CI 2.08-69.51); P=0.005] and baseline serum albumin [OR 18.52 (95% CI 2.80-122.27); P=0.002], were associated with higher mortality. Recent chemotherapy, haematological tumours type and baseline neutropenia did not affect the outcome. Interpretation & conclusions: Higher mortality in moderate and severe infections was associated with baseline organ dysfunction and elderly age. Significant proportion of patients were asymptomatic and might remain undetected

Absolute Lymphocyte Count at the End of Induction as a Surrogate Marker for Minimal Residual Disease in T-cell Acute Lymphoblastic Leukemia

Objective: The relation of absolute lymphocyte count (ALC) with minimal residual disease(MRD) in T cell – acute lymphoblastic leukemia (T-ALL) is not known. The objective of thestudy was to correlate ALC with MRD, steroid-response and complete remission (CR).Methods: De-novo T- ALL patients (age 1-18 y) recruited prospectively; 52 enrolled, 9excluded, and 43 analyzed. 39 achieved CR and MRD was available for 28 patients; 23 wereMRD negative. Results: ALC did not correlate with steroid response and CR. Median (range)ALC at the end of induction was significantly higher in patients who were MRD negativecompared to MRD positive [1.24 (0.12, 6.69) vs 0.62 (0.15, 0.87); P=0.03], respectively.Patients having ALC ≥700 ×109 /L were significantly more likely to be MRD negative thanthose with lower values (P= 0.028) Conclusion: Our study suggests that ALC is a favorablefactor, and may act as surrogate marker for MRD

Predictors of Poor Response to Salvage Chemotherapy in Relapsed/ Refractory Pediatric Hodgkin Lymphoma- A Retrospective Analysis from Tertiary Cancer Centre in India

Background: Previous studies identified prognostic factors for survival in relapsed pediatric Hodgkin lymphoma (HL) who received salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, data regarding predictors of poor response to salvage chemotherapy is limited. Methods: We conducted retrospective study in all relapsed HLtreated from January 2003 to December 2013. Logistic regression analysis was done to identify predictors of response to salvage chemotherapy. Cox regression analysis was done to identify prognostic factors for Freedom from treatment failure (FFTF) and overall survival (OS). Results: Forty six patients had relapsed HL. Among 45 patients who received salvage chemotherapy only 34 (73.4%) underwent ASCT. Stage 4 disease (p=0.02) and bulky disease at relapse (p=0.03) were predictors of poor response to salvage chemotherapy. FFTF and OS at 5 yr for entire cohort were 50.1% and 63.3%, respectively, while the same for patients who underwent ASCT were 66.3% and 80.7%, respectively. Among ASCT patients, those who had primary refractory /early relapse [HR-4.7, (95% CI-1, 22); p=0.05] had significant impact on 5 yr FFTF whereas disease status at transplant (CR vs. No CR) had significant impact on 5 yr OS [HR-4.6, (95% CI-1.03, 20.5); p=0.04]. Conclusions: Identification of predictors of poor response to salvage chemotherapy is an unmet need in the management of pediatric HL since complete response (CR) before transplant is independent predictor of survival. Stage 4 and bulky disease at relapse are high risk factors to predict incomplete response. Future trials should explore newer agents for effective salvage for these patients to attain complete response before ASCT.

Cytogenetic Profiles of 472 Indian Children with Acute Myeloid Leukemia

Objective: To analyze the cytogenetic abnormalities of a largecohort of consecutive pediatric Acute Myeloid Leukemia (AML)patients, treated on a uniform protocol.Design: Review of case records.Setting: Pediatric Cancer Center of tertiary care hospital betweenJune 2003 and June 2016.Participants: 617 consecutive de novo pediatric AML patientswere screened and 472 patients were found eligible. Eligibilitycriteria included non M3 patients, successful cytogenetic profileand availability of complete recordsMain outcome measure: Cytogenetic profile.Results: Gum-hypertropy, chloromas and rate of completeremission were significantly different between EuropeanLeukemia Network classification (ELN) cytogenetic risk groups(P<0.01). t (8;21) (141, 29.8%), loss of Y chromosome (61,12.9%)and trisomy 8 (39, 8.3%) were the most common abnormalities.Among the chromosomal gains, trisomy 8 and trisomy 21 (bothP<0.01) were significantly different among the three ELN riskgroups. Among the chromosome losses, monosomy 5, 7 (bothP<0.01) and 9 (P=0.03), loss of X and loss of Y (both P<0.01)were statistically different amongst three cytogenetic risk groups.Event-free survival (P<0.01) and overall survival (P<0.01) werefound to be significantly different among the three risk groups.Conclusions: The higher frequency of t (8; 21) and its associationwith chloroma in Indian pediatric patients is different from otherstudies around the world.

Peripheral Precocious Puberty Caused by Human Chorionic Gonadotropin Producing Pineal Gland Tumor

Background: Pineal gland lesions usually present with central precocious puberty.Case characteristics: A 3½-yr-old boy presented with precocious puberty. Clinically andbiochemically, it was gonadotropin releasing hormone (GnRH) independent. Serum andCSF beta-hCG levels were increased. Thin section magnetic resonance imaging of brainrevealed a pineal gland tumor. Outcome: He received chemotherapy followed byradiotherapy and responded well. Message: CSF ?-hCG should be measured in all cases ofperipheral precocity, and if CSF beta-hCG is elevated, thin section magnetic resonanceimaging of brain should be considered.

Non-pharmacological Interventions for Pediatric Cancer Patients: A Comparative Review and Emerging Needs in India

Context: Evidence-based research on psycho-oncology in last three decades lays emphasis upon the critical role of psychologicalservices for better illness adjustment, improved quality of life, reduced distress and cognitive problems among the rapidly increasingpediatric cancer population.Justification: This review aims to summarize the evidence-based psychological interventions in childhood cancer over the two decadesand addresses the wide gap that existed between intervention studies worldwide and India, thus highlighting the need for research andappropriate services.Evidence acquisition: We searched electronic databases such as MedLine, PubMed, PsycINFO, and Google Scholar. Key searchterms were pediatric cancer, psycho-oncology, children with cancer + psychological intervention, or multimodal treatment, psychotherapy,cognitive training, behavioral, social skills+ feasibility study, pilot, randomized controlled trial, case study, systematic reviews.Results: 28 full papers published between 1996 to 2016, including survivors and under-treatment children below 18 years, werereviewed. Various types of key interventions were psychosocial, physical, cognitive behavioral, cognitive, music art therapy and playtherapy. Generally, intervention settings were either hospital or home, and were designed to promote psychological well-being.Psychological interventions were more in customised formats in these studies. A generic intervention module was not available forreplication.Conclusion: Development of culture-specific generic intervention module and using the same in randomized control studies with largereffect size are needed in India for larger coverage of patients.

Nucleophosmin mutation analysis in acute myeloid leukaemia: Immunohistochemistry as a surrogate for molecular techniques.

Background & objectives: Mutation of nucleophosmin (NPM1) gene in the absence of FLT3-ITD (FMS related tyrosine kinase 3 - internal tandem duplications) mutation carries a good prognosis in cytogenetically normal acute myeloid leukaemia (AML). NPM1, a multifunctional nucleolar phosphoprotein that shuttles between nucleus and cytoplasm, gets trapped in the cytoplasm when mutated. Immunohistochemical (IHC) demonstration of its aberrant cytoplasmic location (NPMc+) has been suggested as a simple substitute for the standard screening molecular method. This study was aimed to assess the diagnostic utility of IHC on formalin fixed bone marrow biopsies in comparison with the reference molecular method (allele specific oligonucleotide - polymerase chain reaction; ASO-PCR) to predict NPM1 mutation status in AML patients. Methods: NPM protein IHC was performed using mouse anti-NPM monoclonal antibody on 35 paraffin-embedded bone marrow biopsies of patients with primary AML of any French-American-British (FAB) subtype. Results of IHC were compared with those of ASO-PCR. Results: Of the 35 AML patients, 21 (60%) were positive for NPM1 exon 12 gene mutation by ASO-PCR, 19 (90.47%) of these 21 were NPMc+. Thirteen of the 35 patients were negative by both the methods. One NPMc+ patient was not detected by ASO-PCR. IHC had a sensitivity and specificity of 90 and 93 per cent, respectively, compared to the molecular screening gold standard. Interpretation & conclusions: Mutation of NPM1 determined by the widely available and inexpensive IHC agrees closely with results of the standard molecular methods. Thus, technically and financially not well endowed laboratories can provide the prognostically and potentially therapeutically important information on NPM1 mutation using IHC.

High fms-like tyrosine kinase-3 (FLT3) receptor surface expression predicts poor outcome in FLT3 internal tandem duplication (ITD) negative patients in adult acute myeloid leukaemia: a prospective pilot study from India.

Background & objectives: Mutations in fms-like tyrosine kinase 3 (FLT3) receptor have significant role in assessing outcome in patients with acute myeloid leukaemia (AML). Data for FLT3 surface expression in relation to FLT3 internal tandem duplication (ITD) status and outcome are not available from India. The objective of the current study was to investigate adult patients with AML for FLT3 expression and FLT3 ITD mutation, and their association with long-term outcome. Methods: Total 51 consecutive de novo AML patients aged 18-60 yr were enrolled in the study. FLT3 ITD was detected by polymerase chain reaction (PCR); flowcytometry and qPCR (Taqman probe chemistry) were used for assessment of FLT3 protein and transcript, respectively. Kaplan Meier curves were obtained for survival analysis followed by log rank test. Results: FLT3 ITD was present in eight (16%) patients. Complete remission was achieved in 33 (64.6%) patients. At 57.3 months, event free survival (EFS) was 26.9±6.3 per cent, disease free survival (DFS) 52.0±9.2 per cent, and overall survival event (OS) 34.5±7.4 per cent. FLT3 surface expression was positive (>20%) by flow-cytometry in 38 (88%) of the 51 patients. FLT3 surface expression and transcripts were not associated with FLT3 ITD status. FLT3 expression was significantly associated with inferior EFS (P=0.026) and OS (P=0.018) in those who were negative for FLT3 ITD. Interpretation & conclusions: This study evaluated FLT3 ITD mutation along with FLT3 expression in AML patients, and associated with survival. Negative impact of FLT3 surface expression on survival was observed in AML patients who were FLT3 ITD negative.

Anti-emetic trials in oncology: What should be done next.

Weinstein C, Jordan K, Green SA, Camacho E, Khanani S, Beckford-Brathwaite E, Vallejos W, Liang LW, Noga SJ, Rapoport BL. (Merck & Co., Kenilworth, New Jersey, USA; Department of Hematology/Oncology, Martin Luther University HalleWittenberg, Halle, Germany; Department of Hematology and Medical Oncology, Comprehensive Cancer Center at the Desert Regional Medical Center, Palm Springs, California; Department of Hematology/Oncology, Reliant Medical Group, Worcester, Massachusetts; Department of Oncology, Weinberg Cancer Institute, Baltimore, Maryland, USA; Department of Medical Oncology, Medical Oncology Center of Rosebank, Johannesburg, South Africa). Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: Results of a randomized, double-blind phase III trial. Ann Oncol 2016;27:172–8.

Expression of Cathepsin L in tumor cells and tumor-associated macrophages in patients with Ewing sarcoma family of tumors: A pilot study.

Background: Cysteine protease Cathepsin L is involved in bone remodeling and expressed in activated macrophages. It is highly expressed in metastatic tumor tissue, especially with bone metastases. Aims: We evaluated immunohistochemical expression of Cathepsin L in tumor cells and tumorassociated macrophages (TAMs) in chemo-naive Ewing sarcoma. Settings and Design: Retrospective evaluation of archived specimens of Ewing sarcoma. Materials and Methods: Immunohistochemical staining was performed on archived blocks of chemo-naive patients with Ewing sarcoma treated with uniform chemotherapy at our institute between January 2009 and November 2011. Statistical Analysis: Immunohistochemical expression was co-related with baseline demographics and survival. Results: During the study period, we had evaluable baseline samples from 62 patients with median age 15 years (range: 2-40); 26 (42%) had metastases. Cathepsin L expression in tumor cells was observed in 8/62 (13%) specimens. None of the baseline clinical characteristics correlated with Cathepsin L expression. Cathepsin L positivity was associated with poor response to neoadjuvant chemotherapy (NACT) (P = 0.05), but did not infl uence either event-free-survival (EFS) or overall survival. Cathepsin L was expressed in TAMs in all specimens. Grade 3 TAMs (>10 TAMs/high power fi eld) was associated with better response to NACT (P = 0.05). On univariate analysis Grade 3 TAMs predicted superior EFS (median EFS 28.5 months in those with Grade 3 TAMs versus 14.8 months in those with grade ½ TAMs [P = 0.04]). Conclusions: Cathepsin L expression by immunohistochemistry was low in our patient cohort, and it did not affect the outcome. In addition, Grade 3 TAMs with Cathepsin L expression was associated with improved EFS.

Transfusion Related Acute Lung Injury in a Child with Leukemia.

Transfusion-related acute lung injury is a rare form of acute respiratory distress syndrome of possible immune etiology that develops immediately after a blood product transfusion. Clinicians need to be aware of this condition as prompt recognition and supportive management can prevent unwanted morbidity and mortality.

H1N1 Infection in Children with Hematological Malignancies.

In the recent pandemic of H1N1 infection, pediatric patients with haematological malignancies were considered high risk for severe illness. There is paucity of data regarding course of H1N1 infection in this subgroup. We describe H1N1 infection in 3 children with acute leukemia. All three patients presented with neutropenic fever; 2 had probable fungal pneumonia based on chest imaging and galactomanan estimation. Diagnosis of H1N1 infection was delayed in all 3 patients as it was not suspected initially. One patient died despite treatment. H1NI infection may coexist with other infections in febrile neutropenia.

Subcutaneous panniculitis-like T-cell lymphoma: A clinicopathologic study of 5 cases.

Background: Subcutaneous panniculitis-like T-cell lymphoma is as yet a poorly characterized subtype of cutaneous T-cell lymphomas. It is difficult to diagnose and lacks a standard treatment protocol. Materials and Methods: We report our experience with five such cases in patients with age ranging from 13 to 45 years, wherein we reviewed their clinical presentations, histopathological findings, treatment and clinical outcome. Results: Three out of the five cases are alive of which two are in complete remission. Our series stresses on the need to be aware of this uncommon entity in a dermatology clinic. Facial and upper extremity skin nodules with involvement of the lower dermis on light microscopical examination and suggestive immunohistochemical findings were frequently observed in our patients in contrast to previously described cases.

Ewing Sarcoma of the Clavicle: A Case Series.

Clavicle is a rare primary site for Ewing sarcoma (ES). We analyzed 4 patients with clavicular ES under our follow up and reviewed the literature on management of this rare tumor. All our patients were females with a median age of 16 years and were non metastatic at presentation. After a median follow-up of 21.5 months, 3 out of 4 patients are in complete remission. Clavicular ES in contrast to ES of other sites seems to have a female preponderance and outcomes are similar to non metastatic ES of other common sites.

Childhood Chronic Myeloid Leukemia with Monocytosis.

We report two cases of chronic myeloid leukemia (CML) in childhood presenting with monocytosis. History, physical examination and laboratory findings were in favor of juvenile myelomonocytic leukemia in both the cases, but reverse transcriptase polymerase chain reaction (RT-PCR) detected b2a2 and b3a2 transcript of p210 bcr-abl protein characteristic of major BCR breakpoint. Presence of monocytosis in early childhood suggests a viral infection or JMML but a possibility of CML with monocytosis needs to be considered.