Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4⁺ T cells were profoundly depleted by ATG, while CD8⁺ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4⁺ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4⁻CCR6⁻ effector/memory CD4⁺ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4⁺ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.

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Immunological hallmarks of cis -DDP-resistant Lewis lung carcinoma cells

Abstract

Purpose

Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.

Methods

Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.

Results

When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.

Conclusion

Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

http://ift.tt/2BWBtDO

Immunological hallmarks of cis -DDP-resistant Lewis lung carcinoma cells

Abstract

Purpose

Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.

Methods

Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.

Results

When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.

Conclusion

Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.

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Progression to bone-marrow carcinomatosis and extraosseous legion during treatment with radium-223 for multiple bone metastases

Abstract

A 67-year-old man with metastatic prostate cancer presented with progression to castration-resistant prostate cancer. After sequential therapies with flutamide, estramustine phosphate, docetaxel, enzalutamide, and cabazitaxel for castration-resistant prostate cancer, radium-223 was initiated and continued up to 4 cycles. However, concurrently with radiological and clinical progressions, pancytopenia was observed due to bone-marrow carcinomatosis by prostatic adenocarcinoma. This case suggested that radium-223 should be employed at appropriated timing before appearances of extraosseous and bone-marrow lesions in addition to visceral metastasis.

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Progression to bone-marrow carcinomatosis and extraosseous legion during treatment with radium-223 for multiple bone metastases

Abstract

A 67-year-old man with metastatic prostate cancer presented with progression to castration-resistant prostate cancer. After sequential therapies with flutamide, estramustine phosphate, docetaxel, enzalutamide, and cabazitaxel for castration-resistant prostate cancer, radium-223 was initiated and continued up to 4 cycles. However, concurrently with radiological and clinical progressions, pancytopenia was observed due to bone-marrow carcinomatosis by prostatic adenocarcinoma. This case suggested that radium-223 should be employed at appropriated timing before appearances of extraosseous and bone-marrow lesions in addition to visceral metastasis.

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Difference in causes and prognostic factors of early death between cohorts with de novo and relapsed acute promyelocytic leukemia

Abstract

Early death (ED) remains the most critical issue in the current care of patients with acute promyelocytic leukemia (APL). Very limited data are available regarding ED in patients with relapsed APL. In this retrospective study, 285 de novo and 79 relapsed patients were included. All patients received single-agent arsenic trioxide as induction therapy. The differences in baseline clinical features, incidence, causes, and prognostic factors of ED were compared between the two patient cohorts. The relapse cohort exhibited a better overall condition than the de novo cohort upon hospital admission. The ED rate in the relapsed patients (24.1%) was somewhat higher than that in the de novo patients (17.9%), although the difference was not significant (P = 0.219). For both cohorts, hemorrhage was the main cause of ED, followed by differentiation syndrome, infection, and other causes. Increased serum creatinine level, older age, male sex, white blood cell (WBC) count > 10 × 10⁹/L, and fibrinogen < 1 g/L were independently risk factors for ED in the de novo patients, whereas WBC count > 10 × 10⁹/L, elevated serum uric acid level, and D-dimer > 4 mg/L were independent risk factors for ED in the relapsed patients. These data furnish clinically relevant information that might be useful for designing more appropriate risk-adapted treatment protocols aimed at reducing ED rate in patients with relapsed APL.

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Pediatric radiology: practical imaging evaluation of infants and children (1st edn), by Edward Lee (ed)

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Pediatric radiology: practical imaging evaluation of infants and children (1st edn), by Edward Lee (ed)

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RING-finger protein 6 amplification activates JAK/STAT3 pathway by modifying SHP-1 ubiquitylation and associates with poor outcome in colorectal cancer

Objective The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer (CRC). We aimed to explore the mechanical, biological and clinical role of RNF6 in CRC initiation and progression. Design The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real time PCR, western blot and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and vitro. Role of RNF6 in modulating SHP-1 expression was examined by co-immunoprecipitation and confocal microscopy respectively. Results The copy number of RNF6 was significantly amplified in CRC and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with CRC patients with poor prognosis. GSEA analysis revealed cell proliferation and invasion-related genes were enriched in RNF6 high-expressed CRC cells as well as in patients from TCGA dataset. Down-regulation of RNF6 impaired the CRC cell proliferation and invasion in vitro and vivo. RNF6 may activate JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1. Conclusions Genomic amplification drives RNF6 overexpression in CRC. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors.

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Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer - Early Results from the COMPASS Trial.

Purpose: To perform real time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.  Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results:Sixty three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared to those with the basal-like subtype (P=0.004). The best progression free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Conclusions:Prospective genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.

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CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only two years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by 1) depleting mouse macrophages in nude mice with liposomal clodronate injection, and 2) injecting tumor cells into nude vs. NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival. Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival. Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients.

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RING-finger protein 6 amplification activates JAK/STAT3 pathway by modifying SHP-1 ubiquitylation and associates with poor outcome in colorectal cancer

Objective The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer (CRC). We aimed to explore the mechanical, biological and clinical role of RNF6 in CRC initiation and progression. Design The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real time PCR, western blot and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and vitro. Role of RNF6 in modulating SHP-1 expression was examined by co-immunoprecipitation and confocal microscopy respectively. Results The copy number of RNF6 was significantly amplified in CRC and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with CRC patients with poor prognosis. GSEA analysis revealed cell proliferation and invasion-related genes were enriched in RNF6 high-expressed CRC cells as well as in patients from TCGA dataset. Down-regulation of RNF6 impaired the CRC cell proliferation and invasion in vitro and vivo. RNF6 may activate JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1. Conclusions Genomic amplification drives RNF6 overexpression in CRC. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors.

http://ift.tt/2zO6Z5d

Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer - Early Results from the COMPASS Trial.

Purpose: To perform real time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.  Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results:Sixty three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared to those with the basal-like subtype (P=0.004). The best progression free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Conclusions:Prospective genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.

http://ift.tt/2CbDGiT

CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only two years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival. Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by 1) depleting mouse macrophages in nude mice with liposomal clodronate injection, and 2) injecting tumor cells into nude vs. NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival. Results: In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival. Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients.

http://ift.tt/2zO8lN1

Trial design for brain metastases: The Lancet Oncology: Jan 2018

Ross Camidge discusses RANO's papers on clinical trial design for patients with brain metastases.

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[Clinical Picture] A rare location of palpebral rhabdomyosarcoma

We report the case of a 2-year-old child with a tumour of the left upper eyelid, which had been growing rapidly for the past 2 weeks before he presented at the paediatric emergency department in July, 2014. On examination, the child was in good general health, afebrile, and presented with a substantial chemosis of the left eye, which was complicated with ptosis and preseptal cellulitis. On admission to the emergency department, several potential diagnoses were discussed: cellulitis, insect sting, post-traumatic haematoma, vascular tumour, and rhabdomyosarcoma (figure, A).

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[Perspectives] Yale Cancer Center Precision Medicine Tumor Board: two patients, one targeted therapy, different outcomes

A 71-year-old male patient was diagnosed with localised prostate cancer with a Gleason score of 10 and was initially treated with radiotherapy and leuprolide. 2 years later, he developed oligometastatic recurrence in the scapula, which was irradiated, and he continued on leuprolide therapy. After another 3 years, he developed recurrence with widespread adenopathy, for which he received multiple lines of therapy including docetaxel, sipleucel-T, enzalutamide, and abiraterone over 5 years. He was then referred to the Yale Cancer Center and enrolled in two successive clinical trials, with disease progression.

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[Review] Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints.

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[Perspectives] Embracing the imperfect: new beginnings after cancer

If you had visited the Visual Arts Centre in Singapore in late May this year, you would have found yourself surrounded by a profusion of strange and beautiful spheroid objects, ranging in size from a grapefruit to a large pumpkin, but looking more like colossal pebbles washed up on a giant's cove. Made up of 174 unique sculptures, Beginnings represents the 174 lymph nodes removed from ceramicist Suan Ong's neck and chest after she was diagnosed with stage IV thyroid cancer. Using the bean-shaped lymph node as her inspiration, she spent 3 years creating the works, and through the process learned a lesson in accepting fallibility in her art that would allow her to accept it in herself.

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[Perspectives] A rare case of osteoblastoma from medieval Tuscany

In antiquity, tumours were less common conditions than nowadays, probably due to the shorter life expectancy of our ancestors, their different lifestyle and dietary habits, and their reduced exposure to risk factors such as environmental pollution. Additionally, it is not possible to obtain reliable cancer estimates through the analysis of ancient human remains. However, the field of paleopathology is inevitably biased because only bone lesions can be detected, limiting the evidence available to bone tumours, or metastasis to the bones originating from soft-tissue tumours.

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[Editorial] The NHS: failing to deliver on Beveridge's promise?

Just over 75 years have passed since Sir William Beveridge published his report outlining the parameters for a social welfare state for the UK, which crucially included "comprehensive health and rehabilitation services for prevention and cure of disease". Beveridge's report inspired Labour Minister of Health Aneurin Bevan to establish the National Health Service (NHS). Although the vision of Beveridge and Bevan—to provide free, adequate, and equally accessible health care for all—remains in high regard today, the execution and delivery of their goal is currently falling short.

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[Comment] Complications during minimal invasive thoracic surgery: are new surgeons prepared?

The approach to surgery of the thorax has substantially evolved in the past decade. Although open techniques (thoracotomy) are still used in lung cancer surgery today, most lung resections can be safely done by video-assisted thoracic surgery. In the past 5 years, robotic-assisted thoracic surgery has also used new technology to facilitate minimal invasive surgery. In 2017, it is already well established that minimal invasive surgery to resect lung tumours provides equivalent oncological benefits to, with less pain and more rapid recovery than, open surgery procedures.

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[Correspondence] Carfilzomib for relapsed or refractory multiple myeloma

In the second interim analysis of the randomised phase 3 ENDEAVOR study published in The Lancet Oncology, Meletios Dimopoulos and colleagues1 found that, with long-term follow-up, patients with relapsed or refractory multiple myeloma treated with carfilzomib and dexamethasone (median 47·6 months [95% CI 42·5-not evaluable]) had significantly longer overall survival than those who were treated with bortezomib and dexamethasone (40·0 months [32·6–42·3]; hazard ratio 0·791 [95% CI 0·648–0·964]). Although the study was done as an open-label study because of the different dosing schedules for the two proteasome inhibitors, baseline clinical and treatment characteristics, including various prognostic factors and subsequent antimyeloma therapies, were generally balanced between groups.

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[Comment] Perspectives: call for papers

Since its launch in 2000, The Lancet Oncology has been committed to publishing content that advances clinical practice, challenges the status quo, and advocates change in health policy. During these years, the Cancer and Society section has explored the intersection between clinical practice, the portrayal of cancer in the wider world or mainstream media, and the perception of oncology with patients and an informed lay audience. In 2018, we refresh this section of the journal to focus articles on the views and experiences of clinicians in practice and the art of medicine.

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[Review] Systematic review of health-related quality of life and patient-reported outcome measures in gestational trophoblastic disease: a parallel synthesis approach

Gestational trophoblastic disease is a rare complication of pregnancy that can develop into cancer. Medical outcomes of gestational trophoblastic disease are well researched, but the effect of the disease on health-related quality of life (HRQOL) requires attention if care is to be improved. This systematic review was designed to establish the effect of gestational trophoblastic disease and its treatment on HRQOL and to identify the appropriateness of HRQOL measures. Quantitative studies found HRQOL in long-term survivors of gestational trophoblastic disease to be at or above population norms.

http://ift.tt/2C9wGD7

[Review] Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs.

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[Review] Leptomeningeal metastases in non-small-cell lung cancer

Leptomeningeal metastasis is a complication of advanced non-small-cell lung cancer (NSCLC). Diagnosis and monitoring of leptomeningeal metastasis are challenging, and are based on neurological, radiographic, and cerebrospinal fluid findings. Substantial progress has been made in several key aspects of management of leptomeningeal metastasis, including improved characterisation of the genetic profiles, generation of clinically relevant animal models, advances in cerebrospinal fluid liquid biopsy with improved cytology and genotyping analysis, and the development of therapeutic agents with greater CNS penetration.

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[Comment] Introduction to the Yale Precision Medicine Tumor Board

The Precision Medicine Tumor Board (PMTB) at the Yale Cancer Center (New Haven, CT, USA) was established to integrate tumour molecular profiling data with clinical care. The PMTB exists alongside disease-specific tumour boards at the Yale Cancer Center, and primarily serves patients with refractory disease and those with actionable somatic alterations.

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[Correspondence] Carfilzomib for relapsed or refractory multiple myeloma – Authors' reply

In the randomised, phase 3 ENDEAVOR trial in patients with relapsed or refractory multiple myeloma, we showed that treatment with carfilzomib and dexamethasone compared with bortezomib and dexamethasone significantly improved progression-free survival (18·7 months with carfilzomib vs 9·4 months with bortezomib; hazard ratio [HR] 0·53 [95% CI 0·44–0·65]; p<0·0001) and overall survival (47·6 vs 40·0 months; HR 0·79 [0·65–0·96], p=0·010).1,2 ENDEAVOR was the first head-to-head study of two different proteasome inhibitors in relapsed or refractory multiple myeloma, and these results established the combination of carfilzomib administered at 56 mg/m2 twice weekly with dexamethasone as a new standard of care in this disease setting.

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[Correspondence] Dacomitinib in NSCLC: a positive trial with little clinical impact

I have read with great interest the report of the ARCHER 1050 trial by Li-Yong Wu and colleagues.1 The findings showed the superiority of dacomitinib over gefitinib in terms of progression-free survival in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) with the common EGFR mutation. The results were initially presented at the 2017 ASCO Annual Meeting and, at that time, it was the first time that a second-generation EGFR tyrosine kinase inhibitor (TKI) showed a clear and clinically significant improvement in terms of progression-free survival (14·7 months [95% CI 11·1–16·6] with dacomitinib vs 9·2 months [9·1–11·0] with gefitinib).

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[Correspondence] Implementation of a community-based breast cancer management programme

In their Series paper, Catherine Duggan and colleagues1 state that a community-based programme for breast health is a successful example of an intervention to increase breast health-care capacity in a country like Peru. The authors indicate that 75% of breast cancers detected are in advanced stages;1 a situation that can be improved through effective and early community detection.

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[Correspondence] Dacomitinib in NSCLC: a positive trial with little clinical impact – Authors' reply

Alfredo Addeo has noted two issues in our trial1 of dacomitinib versus gefitinib in patients with non-small-cell lung cancer (NSCLC): the fact that we did not discuss central nervous system (CNS) penetration by dacomitinib and the similar progression-free survival in the Asian and non-Asian intention-to-treat (ITT) subpopulations.

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[Correspondence] PD-1 inhibition in sarcoma still needs investigation

In their Article, Hussein Tawbi and colleagues1 suggest that pembrolizumab might have clinical activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. However, the SARC028 trial was not designed to specifically assess the activity of pembrolizumab in undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma, and this study was negative for its primary endpoint.

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[Correspondence] PD-1 inhibition in sarcoma still needs investigation – Authors’ reply

We appreciate the opportunity to respond to Maud Toulmonde and Antoine Italiano's letter. SARC028 was a phase 2 study evaluating the safety and activity of PD-1 inhibition in advanced bone and soft tissue sarcomas and emphasised collection of biospecimens to explore immune-related biomarkers.1 We used objective response as our primary endpoint because this was a signal-finding study. We limited the soft tissue sarcoma cohort to ten patients in each of four common soft tissue sarcoma subtypes to obtain pilot data.

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[Corrections] Correction to Lancet Oncol 2017; 18: 1493–501

Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 2017; 18: 1493–501—The appendix of this Article has been updated. This correction has been made to the online version as of Dec 29, 2017.

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Hypofractionated radiation therapy (HFRT) versus conventional fractionated radiation therapy (CRT) for newly diagnosed glioblastoma patients. A propensity score matched analysis

The current treatment for newly diagnosed glioblastoma consists of surgery followed by conventional radiotherapy (CRT) with concomitant and adjuvant chemotherapy. Hypofractionated radiation therapy (HFRT) has been investigated and it resulted feasible and safe. The aim of this study was to evaluate whether HFRT can be comparable to CRT.

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Proceedings of the National Cancer Institute Workshop on Charged Particle Radiobiology

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Radhe Mohan, Kathryn D. Held, Michael D. Story, David Grosshans, Jacek Capala
In April 2016, the National Cancer Institute (NCI) hosted a multidisciplinary workshop to discuss current knowledge of the radiobiological aspects of charged particles used in cancer therapy, to identify gaps in that knowledge that may hinder the effective clinical use of charged particles and to propose research that may help fill those gaps. The workshop was organized into ten topics ranging from biophysical models to clinical trials and included treatment optimization, relative biological effectiveness (RBE) of tumors and normal tissues, hypofractionation with particles, combination with immunotherapy, omics, hypoxia and particle-induced second malignancies. Given that the most commonly used charged particle in the clinic currently is protons, much of the discussion revolved around evaluating the state of knowledge and current practice of using an RBE of 1.1 for protons. Discussion also included the potential advantages of heavier ions, notably carbon ions, due to their increased biological effectiveness, particularly for tumors frequently considered to be radiation resistant, increased effectiveness in hypoxic cells and potential for differentially altering immune responses. The participants identified a large number of research areas in which information is needed to inform the most effective use of charged particles in the future in clinical radiotherapy. This unique form of radiation therapy holds great promise for improving cancer treatment.



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Proceedings of the National Cancer Institute Workshop on Charged Particle Radiobiology

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Radhe Mohan, Kathryn D. Held, Michael D. Story, David Grosshans, Jacek Capala
In April 2016, the National Cancer Institute (NCI) hosted a multidisciplinary workshop to discuss current knowledge of the radiobiological aspects of charged particles used in cancer therapy, to identify gaps in that knowledge that may hinder the effective clinical use of charged particles and to propose research that may help fill those gaps. The workshop was organized into ten topics ranging from biophysical models to clinical trials and included treatment optimization, relative biological effectiveness (RBE) of tumors and normal tissues, hypofractionation with particles, combination with immunotherapy, omics, hypoxia and particle-induced second malignancies. Given that the most commonly used charged particle in the clinic currently is protons, much of the discussion revolved around evaluating the state of knowledge and current practice of using an RBE of 1.1 for protons. Discussion also included the potential advantages of heavier ions, notably carbon ions, due to their increased biological effectiveness, particularly for tumors frequently considered to be radiation resistant, increased effectiveness in hypoxic cells and potential for differentially altering immune responses. The participants identified a large number of research areas in which information is needed to inform the most effective use of charged particles in the future in clinical radiotherapy. This unique form of radiation therapy holds great promise for improving cancer treatment.



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Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region s...

http://ift.tt/2CaFA38

Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the i...

http://ift.tt/2zLJt8F

Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation

Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibi...

http://ift.tt/2Cae3Pt

Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation

Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibi...

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Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region s...

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Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number

Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the i...

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Survey of gynecological carcinosarcomas in families with breast and ovarian cancer predisposition

Publication date: Available online 29 December 2017
Source:Cancer Genetics
Author(s): Carla B. Ripamonti, Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Maria Luisa Carcangiu, Paolo Radice
Carcinosarcomas (CSs) are biphasic neoplasms composed of high grade, malignant, epithelial and mesenchymal elements. The incidence of gynecological CSs (GCSs) is 0.4/100,000 women per year. Patients affected with GCSs have been occasionally reported in Hereditary Breast Ovarian Cancer (HBOC) families, including a few cases with pathogenic variants in BRCA1/BRCA2 genes. The prevalence and the association of GCSs in HBOC families have not been systematically investigated. Thus, we searched for families with GCSs in the HBOC registry of the National Cancer Institute of Milan. Eleven families, including four BRCA1-positive and four BRCA2-positive, presented a case of GCS. In the three BRCA1-mutated patients for whom surgical specimens was available, DNA fragment and sequencing analyses revealed the loss of the constitutionally wild-type BRCA1 allele. All tumors presented also TP53 mutations and stained negative for the expression of the protein product by immunoistochemistry. Our results suggest that GCSs may be found not infrequently in HBOC families and assimilate the analyzed CSs to BRCA1-related breast/ovarian carcinomas, where the above findings are frequently observed. Exploring the role of BRCA genes in prospective unselected series of GCSs might improve the knowledge of the genesis of these malignancies and guide the proposition of prophylactic surgery and targeted therapy.



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MiRNA signature predicts the response of patients with advanced lung adenocarcinoma to platinum-based treatment

Abstract

Background

Accumulating literature proved that miRNAs can regulate the sensitivity of platinum and act as a promising candidate to predict the response of patients with lung adenocarcinoma to chemotherapy. However, most studies on miRNAs were restricted to in vitro experiments. This study aimed to evaluate whether miRNAs alone or in combination (miRNA signature) can act as predictive biomarkers of platinum-based chemotherapy in patients with lung adenocarcinoma.

Methods

Eight miRNAs that most probably predict the efficacy of platinum were screened in 111 tumor tissues of lung adenocarcinoma. Univariate and multivariate Cox analyses, Kaplan–Meier survival curve analysis, Chi-square test, and univariate and multivariate logistic regression analyses were employed to determine whether miRNA expression is associated with the response of patients to platinum-based chemotherapy. The maximum significant odds ratio value was acquired by multiple cycles of multivariate logistic regression analysis. The cut-off points of miRNAs were obtained. A miRNA chemo-sensibility index (CI) formula was established, and its prediction performance was confirmed in another independent set (n = 31).

Results

Underexpression of three miRNAs (miRNA-21, miRNA-125b, and miRNA-224) was independently associated with the chemotherapy sensitivity of patients with lung adenocarcinoma. The miRNA CI formula containing these three miRNAs was calculated as (1.364 × miR-21) + (1.323 × miR-125b) + (1.131 × miR-224). A high CI was related to platinum-based chemotherapy resistance, and its prediction performance was confirmed in the testing set. The MAPK, PI3K-Akt, Ras, and cGMP-PKG signaling pathways were considered to be most probably correlated with platinum resistance.

Conclusion

Our miRNA CI formula can act as an independent predictor to predict the response of patients with lung adenocarcinoma to platinum-based chemotherapy.

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MiRNA signature predicts the response of patients with advanced lung adenocarcinoma to platinum-based treatment

Abstract

Background

Accumulating literature proved that miRNAs can regulate the sensitivity of platinum and act as a promising candidate to predict the response of patients with lung adenocarcinoma to chemotherapy. However, most studies on miRNAs were restricted to in vitro experiments. This study aimed to evaluate whether miRNAs alone or in combination (miRNA signature) can act as predictive biomarkers of platinum-based chemotherapy in patients with lung adenocarcinoma.

Methods

Eight miRNAs that most probably predict the efficacy of platinum were screened in 111 tumor tissues of lung adenocarcinoma. Univariate and multivariate Cox analyses, Kaplan–Meier survival curve analysis, Chi-square test, and univariate and multivariate logistic regression analyses were employed to determine whether miRNA expression is associated with the response of patients to platinum-based chemotherapy. The maximum significant odds ratio value was acquired by multiple cycles of multivariate logistic regression analysis. The cut-off points of miRNAs were obtained. A miRNA chemo-sensibility index (CI) formula was established, and its prediction performance was confirmed in another independent set (n = 31).

Results

Underexpression of three miRNAs (miRNA-21, miRNA-125b, and miRNA-224) was independently associated with the chemotherapy sensitivity of patients with lung adenocarcinoma. The miRNA CI formula containing these three miRNAs was calculated as (1.364 × miR-21) + (1.323 × miR-125b) + (1.131 × miR-224). A high CI was related to platinum-based chemotherapy resistance, and its prediction performance was confirmed in the testing set. The MAPK, PI3K-Akt, Ras, and cGMP-PKG signaling pathways were considered to be most probably correlated with platinum resistance.

Conclusion

Our miRNA CI formula can act as an independent predictor to predict the response of patients with lung adenocarcinoma to platinum-based chemotherapy.

http://ift.tt/2ConMyH

First-line treatment with bendamustine and rituximab, in patients with intermediate-/high-risk splenic marginal zone lymphomas

Abstract

Splenic marginal zone lymphomas (SMZLs) are rare indolent B cell neoplasms that affect the spleen, bone marrow, and blood. Although they have an indolent course in the majority of patients, who have a median survival of 8–10 years, ∼ 30% may experience a worse outcome. The prognostic criteria of progression are lymph node and extra-nodal involvement, high lymphocyte counts, anaemia, and thrombocytopenia. The treatment of SMZLs include a "wait and watch strategy", splenectomy, and alkylating agents ± rituximab. We here describe data relating to 70 patients with intermediate-/high-risk SMZLs, who received rituximab/bendamustine as first-line treatment for a median of 60 days (range 1–75) after diagnosis. Sixty patients (86%) achieved a complete response (CR), and seven (10%) a partial response (PR). Three patients (4.3%) experienced disease progression (PD). The median duration of remission was 18 months. Side effects were generally mild. Our findings suggest that rituximab/bendamustine is a feasible treatment option in patients with intermediate-/high-risk SMZLs.

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First-line treatment with bendamustine and rituximab, in patients with intermediate-/high-risk splenic marginal zone lymphomas

Abstract

Splenic marginal zone lymphomas (SMZLs) are rare indolent B cell neoplasms that affect the spleen, bone marrow, and blood. Although they have an indolent course in the majority of patients, who have a median survival of 8–10 years, ∼ 30% may experience a worse outcome. The prognostic criteria of progression are lymph node and extra-nodal involvement, high lymphocyte counts, anaemia, and thrombocytopenia. The treatment of SMZLs include a "wait and watch strategy", splenectomy, and alkylating agents ± rituximab. We here describe data relating to 70 patients with intermediate-/high-risk SMZLs, who received rituximab/bendamustine as first-line treatment for a median of 60 days (range 1–75) after diagnosis. Sixty patients (86%) achieved a complete response (CR), and seven (10%) a partial response (PR). Three patients (4.3%) experienced disease progression (PD). The median duration of remission was 18 months. Side effects were generally mild. Our findings suggest that rituximab/bendamustine is a feasible treatment option in patients with intermediate-/high-risk SMZLs.

http://ift.tt/2CjpoMd

Gamma-aminobutyric acid-B limbic encephalitis and asystolic cardiac arrest: a case report

Gamma-aminobutyric acid-B receptor autoantibodies are becoming an increasingly recognized contributor to the spectrum of autoimmune limbic encephalitis. They are classically associated with seizures and behavi...

http://ift.tt/2Efcdu6

Pulmonary arterial hypertension in a patient treated with dasatinib: a case report

There have been several reports on dasatinib-induced reversible pulmonary hypertension. This is the first reported case in Latvia; the patient did not discontinue the drug after the first adverse effects in th...

http://ift.tt/2pUTsZX

Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes

Abstract

Purpose

Propofol infusion syndrome (PRIS) is a lethal condition caused by propofol overdose. Previous studies suggest that pathophysiological mechanisms underlying PRIS involve mitochondrial dysfunction; however, these mechanisms have not been fully elucidated. This study aimed to establish an experimental model of propofol-induced cytotoxicity using cultured human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to determine the mechanisms behind propofol-induced mitochondrial dysfunction, and to evaluate the protective effects of coenzyme Q10 (CoQ10).

Methods

Human iPSC-derived cardiomyocytes were exposed to propofol (0, 2, 10, or 50 µg/ml) with or without 5 µM CoQ10. Mitochondrial function was assessed by measuring intracellular ATP, lactate concentrations in culture media, NAD⁺/NADH ratio, and the mitochondrial membrane potential. Propofol-induced cytotoxicity was evaluated by analysis of cell viability. Expression levels of genes associated with mitochondrial energy metabolism were determined by PCR. Intracellular morphological changes were analyzed by confocal microscopy.

Results

Treatment with 50 µg/ml propofol for 48 h reduced cell viability. High concentrations of propofol (≥ 10 µg/ml) induced mitochondrial dysfunction accompanied by downregulation of gene expression of PGC-1alpha and its downstream targets (NDUFS8 and SDHB, which are involved in the respiratory chain reaction; and CPT1B, which regulates beta-oxidation). Cardiomyocytes co-treated with 5 µM CoQ10 exhibited resistance to propofol-induced toxicity through recovery of gene expression.

Conclusions

Propofol-induced cytotoxicity in human iPSC-derived cardiomyocytes may be associated with mitochondrial dysfunction via downregulation of PGC-1alpha-regulated genes associated with mitochondrial energy metabolism. Co-treatment with CoQ10 protected cardiomyocytes from propofol-induced cytotoxicity.

http://ift.tt/2zMtB5V

Methylphenidate disrupts cytoskeletal homeostasis and reduces membrane-associated lipid content in juvenile rat hippocampus

Abstract

Although methylphenidate (MPH) is ubiquitously prescribed to children and adolescents, the consequences of chronic utilization of this psychostimulant are poorly understood. In this study, we investigated the effects of MPH on cytoskeletal homeostasis and lipid content in rat hippocampus. Wistar rats received intraperitoneal injections of MPH (2.0 mg/kg) or saline solution (controls), once a day, from the 15th to the 44th day of age. Results showed that MPH provoked hypophosphorylation of glial fibrillary acidic protein (GFAP) and reduced its immunocontent. Middle and high molecular weight neurofilament subunits (NF-M, NF-H) were hypophosphorylated by MPH on KSP repeat tail domains, while NFL, NFM and NFH immunocontents were not altered. MPH increased protein phosphatase 1 (PP1) and 2A (PP2A) immunocontents. MPH also decreased the total content of ganglioside and phospholipid, as well as the main brain gangliosides (GM1, GD1a, and GD1b) and the major brain phospholipids (sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). Total cholesterol content was also reduced in the hippocampi of juvenile rats treated with MPH. These results provide evidence that disruptions of cytoskeletal and lipid homeostasis in hippocampus of juvenile rats are triggers by chronic MPH treatment and present a new basis for understanding the effects and consequences associated with chronic use of this psychostimulant during the development of the central nervous system.

http://ift.tt/2lim7Dm

Predicting bacterial infections among pediatric cancer patients with febrile neutropenia: External validation of the PICNICC model

Abstract

Introduction

The Predicting Infectious Complications in Neutropenic Children and Young People with Cancer (PICNICC) model was recently developed for antibiotic stewardship among pediatric cancer patients, but limited information is available about its clinical usefulness. We aimed to assess the performance of the PICNICC model for predicting microbiologically documented bacterial infections among pediatric cancer patients with febrile neutropenia.

Materials and methods

We used data for febrile neutropenia episodes at a pediatric cancer center in Aarhus, Denmark between 2000 and 2016. We assessed the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness (i.e., net benefit). We also recalibrated the model using statistical updating methods.

Results

We observed 306 microbiologically documented bacterial infections among 1,892 episodes of febrile neutropenia. The AUC of the model was 0.73 (95% confidence limits [CL]: 0.71–0.75). The calibration intercept (calibration-in-the-large) was −0.69 (95% CL: −0.86 to −0.51) and the slope was 0.77 (95% CL: 0.65–0.89). Modest net benefit was observed at a decision threshold of 5%. Recalibration improved calibration but did not improve net benefit.

Conclusions

The PICNICC model has potential for reducing unnecessary antibiotic exposure for pediatric cancer patients with febrile neutropenia, but continued validation and refinement is necessary to optimize clinical usefulness.

http://ift.tt/2CljMRR

Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study

Abstract

Purpose

In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development.

Patients and methods

Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies—yolk sac tumor, embryonal carcinoma, or choriocarcinoma—were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS).

Results

Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2–87.8%) and for non-GD patients was 88.8% (95% CI 80.2–93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7–98.1%) and for non-GD patients was 97.6% (95% CI of 90.6–99.4%).

Conclusion

Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

http://ift.tt/2BQWa41

Isolated late testicular relapse of B-cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response-based testicular radiation: A Children's Oncology Group study

Abstract

Background

The incidence of isolated testicular relapse (ITR) of acute lymphoblastic leukemia (ALL) has decreased with contemporary treatment strategies, but outcomes are suboptimal with a 58% 5-year overall survival (OS). This study aimed to improve outcome in patients with ITR of B-cell ALL (B-ALL) occurring after 18 months of first clinical remission using intensive systemic chemotherapy and to decrease long-term sequelae by limiting use of testicular radiation.

Procedure

Forty patients in first ITR of B-ALL were enrolled. Induction (dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy) was preceded by one dose of high-dose methotrexate (MTX, 5 g/m²). Following induction, 25 of 26 patients who had persistent testicular enlargement underwent testicular biopsy. Eleven had biopsy-proven disease and received bilateral testicular radiation (24 Gy), whereas twenty-nine did not.

Results

Overall 5-year event-free survival (EFS)/OS was 65.0 ± 8.8%/73.1 ± 8.3%, with 5-year EFS 62.1 ± 11.0% vs. 72.7 ± 14.4% for patients who did not receive radiation therapy (XRT) (n = 29) compared with those who did (n = 11), respectively (P = 0.64). There were six second bone marrow relapses and six second ITRs. The proportion of second relapses was similar in the patients that received testicular radiation and those who did not. However, the 5-year OS was similar for patients who did not receive XRT (72.6 ± 10.2%) compared with those who did (72.7 ± 14.4%) (P = 0.85).

Conclusions

A 5-year OS rate of 73.1 ± 8.3% was obtained in children with first ITR of B-ALL occurring after 18 months of CR1 (length of first clinical remission) using intensive chemotherapy and limiting testicular radiation.

http://ift.tt/2CmvziE

Children and adolescents with marginal zone lymphoma have an excellent prognosis with limited chemotherapy or a watch-and-wait strategy after complete resection

Abstract

Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were <18 years old. Forty-four (67%) had an extranodal MZL (EMZL), 21 (32%) a nodal MZL (NMZL), and one patient a splenic MZL. Thirty-three patients (50%) received a variable combination of adjuvant chemotherapy/immunotherapy/radiotherapy, while the remainder, including 20 of 21 with NMZL, entered an active observation period. Overall survival was excellent (98 ± 2%), although 11 patients relapsed (17%; NMZL, n = 1; EMZL, n = 10), seven after any therapy and four after complete resection only. In conclusion, outcome of NZML, in particular, seems to be excellent after (in)complete resection and observation only.

http://ift.tt/2BSiE4L

High incidence of acute kidney injury during chemotherapy for childhood acute myeloid leukemia

Abstract

Background/objectives

Childhood acute myeloid leukemia (AML) is a rare and heterogeneous disease. Pediatric data on the epidemiology of acute kidney injury (AKI) in AML are limited. We report on the incidence of AKI in childhood AML and the risk factors associated with AKI episodes.

Methods

A retrospective cohort of 53 patients (≤18 years), with de novo AML, receiving chemotherapy over a 10-year period. All serum creatinine (SCr) levels during therapy-related hospitalizations were assessed to stage AKI episodes as per Kidney Disease: Improving Global Outcomes criteria. Severe AKI was defined as AKI stages 2 or 3 and urine output criteria were not used. AKI risk factors were assessed independently in both cycle 1 alone and combining all chemotherapy cycles.

Results

AKI developed in 34 patients (64%) with multiple AKI episodes in 10 patients (46 total episodes). Twenty-four severe AKI episodes occurred in 23 patients (43.4%) with a mean duration of 26.1 days (SD 7.3). In cycle 1, hyperleukocytosis was not predictive of AKI, but severe sepsis was an independent risk factor of severe AKI (odds ratio [OR]: 13.4; 95% CI 1.9–94.9). With cycles combined, all subjects with AKI had severe sepsis and older age (≥10 years) was associated with severe AKI (OR: 20.8; 95% CI 3.8–112.2).

Conclusion

There was a high incidence of AKI in our AML cohort with a strong association with older age (≥10 years) and severe sepsis. Larger prospective studies are needed to confirm the high burden of AKI and risk factors in this susceptible population.

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Comment on: “Successful use of nitrous oxide during lumbar punctures: A call for nitrous oxide in pediatric oncology clinics”

http://ift.tt/2BVeau7

Identifying patient- and family-centered outcomes relevant to inpatient versus at-home management of neutropenia in children with acute myeloid leukemia

Abstract

Efficacy of therapeutic strategies relative to patient- and family-centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at-home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.

http://ift.tt/2Cmvz28

Crizotinib in ALK+ inflammatory myofibroblastic tumors—Current experience and future perspectives

Abstract

Inflammatory myofibroblastic tumor (IMT) and its subtype epithelioid inflammatory myofibroblastic sarcoma (EIMS) are rare soft-tissue tumors. As about 50% of IMT and 100% of EIMS contain activating rearrangements of the anaplastic lymphoma kinase (ALK) gene, targeted kinase inhibition of ALK by compounds such as crizotinib is a potential treatment option. We performed a literature review and analyzed a total of 30 patients with IMT/EIMS treated with crizotinib. A total of 12 patients achieved complete or partial remission. As preliminary data are promising, a prospective study evaluating crizotinib treatment in patients with unresectable/multifocal ALK⁺ IMT/EIMS is warranted.

http://ift.tt/2BQW8Jr

Musculoskeletal complications following total body irradiation in hematopoietic stem cell transplant patients

Abstract

Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life-saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI.

http://ift.tt/2CjiFC4

Modifying bone mineral density, physical function, and quality of life in children with acute lymphoblastic leukemia

Abstract

Background

The early effects of childhood acute lymphoblastic leukemia (ALL) include decreased physical function, bone mineral density (BMD/g/cm²), and health-related quality of life (HRQL). We assessed the capacity of a physical therapy and motivation-based intervention, beginning after diagnosis and continuing through the end of treatment, to positively modify these factors.

Procedure

A 2.5-year randomized controlled trial of 73 patients aged 4–18.99 years within 10 days of ALL diagnosis assessed BMD at baseline (T⁰) and end of therapy (T³), strength, range of motion, endurance, motor skills, and HRQL at baseline (T⁰), 8 (T¹), 15 (T²), and 135 (T³) weeks.

Results

There were no significant changes between groups (intervention, n = 33; usual care, n = 40) in BMD (P = 0.059) at T³ or physical function and HRQL at T⁰–T³. While BMD declined in both the intervention (T⁰ = −0.21, T³ = −0.55) and usual care (T⁰ = −0.62, T³ = −0.78) groups, rates of decline did not differ between groups (P = 0.56). Univariate analysis (n = 73) showed associations of higher T³ bone density with body mass index T¹ (P = 0.01), T² (P = <0.0001), T³ (P = 0.01), T³ ankle flexibility/strength (P = 0.001), and T² parent (P = 0.02)/T⁰ child (P = 0.03) perceptions of less bodily pain.

Conclusions

The intervention delivered during treatment was not successful in modifying BMD, physical function, or HRQL. Physical activity, at the level and intensity required to modify these factors, may not be feasible during early treatment owing to the child's responses to the disease and treatment. Future studies will consider intervention implementation during late maintenance therapy, extending into survivorship.

http://ift.tt/2BRLSR9

Methylphenidate disrupts cytoskeletal homeostasis and reduces membrane-associated lipid content in juvenile rat hippocampus

Abstract

Although methylphenidate (MPH) is ubiquitously prescribed to children and adolescents, the consequences of chronic utilization of this psychostimulant are poorly understood. In this study, we investigated the effects of MPH on cytoskeletal homeostasis and lipid content in rat hippocampus. Wistar rats received intraperitoneal injections of MPH (2.0 mg/kg) or saline solution (controls), once a day, from the 15th to the 44th day of age. Results showed that MPH provoked hypophosphorylation of glial fibrillary acidic protein (GFAP) and reduced its immunocontent. Middle and high molecular weight neurofilament subunits (NF-M, NF-H) were hypophosphorylated by MPH on KSP repeat tail domains, while NFL, NFM and NFH immunocontents were not altered. MPH increased protein phosphatase 1 (PP1) and 2A (PP2A) immunocontents. MPH also decreased the total content of ganglioside and phospholipid, as well as the main brain gangliosides (GM1, GD1a, and GD1b) and the major brain phospholipids (sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). Total cholesterol content was also reduced in the hippocampi of juvenile rats treated with MPH. These results provide evidence that disruptions of cytoskeletal and lipid homeostasis in hippocampus of juvenile rats are triggers by chronic MPH treatment and present a new basis for understanding the effects and consequences associated with chronic use of this psychostimulant during the development of the central nervous system.

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Family history-taking practices and genetic confidence in primary and tertiary care providers for childhood cancer survivors

Abstract

Background

There is growing impetus for increased genetic screening in childhood cancer survivors. Family history-taking is a critical first step in determining survivors' suitability. However, the family history-taking practices of providers of pediatric oncology survivorship care and the confidence of these providers to discuss cancer risks to relatives are unknown.

Procedure

Fifty-four providers completed semistructured interviews in total, which included eight tertiary providers representing nine hospitals across two countries (63% male, 63% oncologists, 37% nurses) and 46 primary care providers (PCPs) nominated by a survivor (59% male, 35% regional practice). We used content analysis and descriptive statistics/regression to analyze the data.

Results

Few tertiary (38%) or primary (35%) providers regularly collected survivors' family histories, often relying on survivors/parents to initiate discussions. Providers mostly took two-generation pedigrees (63% tertiary and 81% primary). Primary providers focused on adult cancers. Lack of time, alternative priorities, and perceived lack of relevance were common barriers. Half of all tertiary providers felt moderately comfortable discussing genetic cancer risk to children of survivors (88% felt similarly discussing risks to other relatives). Most primary providers lacked confidence: 41% felt confident regarding risks to survivors' children and 48% regarding risks to other relatives.

Conclusions

While family history-taking will not identify all survivors suitable for genetics assessment, recommendations for regular history-taking are not being implemented in tertiary or primary care. Additional PCP-targeted genetic education is warranted given that they are well placed to review family histories of pediatric cancer survivors.

http://ift.tt/2Clk9Mf

Intracranial metastasis in fibrolamellar hepatocellular carcinoma

Abstract

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1–PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.

http://ift.tt/2BTKGga

Utilization of frozen plasma, cryoprecipitate, and recombinant factor VIIa for children with hemostatic impairments: An audit of transfusion appropriateness

Abstract

Background

Blood transfusions and fractionated products are not without risk and may lead to acute and long-term adverse events. The objective of this study was to evaluate the appropriateness of usage of frozen plasma (FP), cryoprecipitate (CRYO), and recombinant factor VIIa (rVIIa) in a pediatric setting.

Methods

All orders for FP, CRYO, and rVIIa were prospectively audited over 6 weeks. Data collected included demographics, laboratory values, indication, and adverse reactions. The appropriateness of each order was independently evaluated using adjudication criteria rated by two hematologists.

Results

Two hundred sixty-five products were ordered; 67% of the orders were issued to operating rooms or intensive care units. The most common indication for all products was cardiac surgery. FP was ordered as fluid replacement (15/215; 7%) to correct abnormal coagulation tests (23/215; 11%) and for patients with minor or no bleeding (111/242; 46%). FP was more likely to alter the international normalized ratio (INR) if the INR was over 2.0 (P < 0.0001). The rate of inappropriate products was judged as FP 19%, CRYO 21%, and rVIIa 91%.

Conclusion

FP, CRYO, and rVIIa are most commonly used in the operating room and intensive care units. FP was often used for fluid resuscitation and for patients with mild to no bleeding. FP was only effective in lowering the INR when the INR was over 2.0. Use of rVIIa was rarely ordered for an appropriate indication. Results of this study inform its readers where trials of pediatric transfusion should be performed to clarify how these products should be used in clinical practice.

http://ift.tt/2CljsT9

Cytoreductive surgery and hyperthermic intraperitoneal perfusion with chemotherapy in children with peritoneal tumor spread: A French nationwide study over 14 years

Abstract

Background

Efficacy and role of cytoreductive surgery (CRS) and hyperthermic peritoneal perfusion with chemotherapy (HIPEC) remain poorly documented in pediatric tumors.

Methods

This retrospective national study analyzed all pediatric patients with peritoneal tumor spread treated by CRS and HIPEC as part of a multimodal therapy in France from 2001 to 2015.

Results

Twenty-two patients (nine males and 13 females) were selected. The median age at diagnosis was 14.8 years (4.2–17.6). Seven had peritoneal mesotheliomas; seven, desmoplastic small round cells tumors (DSRCT); and eight, other histologic types. A complete macroscopic resection (CC-0, where CC is completeness of cytoreduction) was achieved in 16 (73%) cases. Incomplete resections were classified as CC-1 in four (18%) cases and CC-2 in two (9%) cases. Fourteen (64%) patients had complications within 30 days from HIPEC, requiring an urgent laparotomy in eight (36%) cases. Thirteen (59%) patients received adjuvant chemotherapy and four (18%) received total abdominal radiotherapy after surgery. Sixteen (72%) patients had relapse after a median time of 9.6 months (1.4–86.4) and nine (41%) eventually died after a median time of 5.3 months (0.1–36.1) from relapse. Six (27%) patients (four mesotheliomas, one pseudopapillary pancreatic tumor, and one DSRCT) were alive and in complete remission after a median follow-up of 25.0 months (5.3–78.2).

The mean overall survival (OS) and disease-free survival (DFS) were 57.5 months (95% CI [38.59–76.32]) and 30.9 months (95% CI [14.96–46.77]). Patients with a peritoneal mesothelioma had a significantly better OS (p = 0.015) and DFS (p = 0.028) than other histologic type.

Conclusions

In this national series, outcomes of HIPEC are encouraging for the treatment of peritoneal mesothelioma in children.

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Systematic review of pharmacogenomics and adverse drug reactions in paediatric oncology patients

Abstract

Many paediatric patients with cancer experience significant chemotherapy side effects. Predisposition to drug reactions is governed by single nucleotide polymorphisms (SNPs). We performed a systematic review of the literature from 2006 through 2016. Outcomes of interest included patient characteristics, cancer type drug of interest, genes investigated, toxicity identified and genetic polymorphisms implicated. The primary toxicities studied were neurotoxicity cardiotoxicity, osteonecrosis, and thromboembolism and hypersensitivity reactions. The retrieved studies were grouped according to toxicity reported and SNP associations. This review highlights the discoveries to date in pharmacogenomics and paediatric oncology along with highlighting some of the important limitations in the area.

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Denosumab treatment in aneurysmal bone cyst: Evaluation of nine cases

Abstract

Background

Aneurysmal bone cyst (ABC) is a benign bone tumor. Curettage and bone grafting is the common treatment. Here, we retrospectively evaluate nine patients treated with denosumab.

Procedure

Nine patients with ABC, mostly pelvic and vertebral, treated with denosumab were analyzed retrospectively. A 70 mg/m² denosumab dose was used weekly in the first month, and then monthly. Clinical and radiological responses to treatment were evaluated.

Results

In all patients, clinical symptoms including pain and limping regressed completely within 3 months. Radiological evaluation revealed changes in lesion size and content. In six patients, overall volume reduction in the range of 18–82% was detected. Decreases in the size and number of cysts were detected in eight patients. In five patients, fat signal appeared on follow-up imaging. No major side effects were observed during treatment. Median follow-up time after treatment was 15 months. At 5 months, severe hypercalcemia was observed in two patients due to rebound increase in osteoclastic activity. Subsequent to denosumab treatment, three patients underwent surgery for clinical or radiological recurrence.

Conclusions

Our results showed that denosumab provided a meaningful clinical and radiological improvement in ABC. It may be a treatment option, especially in spinal and pelvic tumors with potentially high surgical morbidity. However, late rebound hypercalcemia may restrict its use. Studies with more cases are required for routine use of denosumab in ABC.

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ETV6–NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study

Abstract

Background

Congenital mesoblastic nephroma (MN) is a rare pediatric renal tumor representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically: classical, cellular, and mixed. A frequent genetic alteration is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular MN. The aim of this study was to determine translocation status of a large cohort of MN with respect to tumor subtype and outcome.

Procedure

In total, clinical data from 111 patients were available. Sixty-seven tumors were classical MN (51%), 29 cellular MN (31%), and 15 were mixed MN (18%). From these 111 cases, 79 were analyzed by FISH and RT-PCR.

Results

All classical and mixed MN were translocation negative. Seventeen out of 29 (58%) cellular MN harbored the ETV6–NTRK3 translocation. Five-year relapse-free survival (RFS) and overall survival (OS) were 93.2% and 96.8% for the complete cohort. All seven relapses occurred in translocation negative tumors. Five-year RFS was significantly inferior for cellular and mixed MN compared to classic MN (89%, 80%, and 98%), whereas 5-year OS was similar (93%, 96%, and 98%). Within the group of cellular MN, patients having translocation-positive tumors had a significantly superior RFS (5-year RFS: 100% vs. 73%).

Conclusion

The majority of cellular MNs harbor the ETV6–NTKR3 gene fusion, whereas all classic- and mixed-type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS.

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Hypothalamic involvement in craniopharyngioma—Implications for surgical, radiooncological, and molecularly targeted treatment strategies

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MYH9-macrothrombocytopenia caused by a novel variant (E1421K) initially presenting as apparent neonatal alloimmune thrombocytopenia

Abstract

MYH9-related disease is a rare cause of thrombocytopenia. We report an infant girl who presented with severe thrombocytopenia at birth and was initially diagnosed with and treated for neonatal alloimmune thrombocytopenia. However, persistent thrombocytopenia led to the suspicion of congenital thrombocytopenia and subsequent identification of a novel variant in MYH9 (E1421K). In silico analysis strongly predicts that this is a disruptive substitution. Immunofluorescent analysis of neutrophils demonstrates abnormal aggregates of MYH9 protein. This case also suggests that a very high immature platelet fraction (≥40%) may be useful for rapidly differentiating MYH9-related disease from other causes of neonatal thrombocytopenia.

http://ift.tt/2CjiDKs

ETV6–NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study

Abstract

Background

Congenital mesoblastic nephroma (MN) is a rare pediatric renal tumor representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically: classical, cellular, and mixed. A frequent genetic alteration is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular MN. The aim of this study was to determine translocation status of a large cohort of MN with respect to tumor subtype and outcome.

Procedure

In total, clinical data from 111 patients were available. Sixty-seven tumors were classical MN (51%), 29 cellular MN (31%), and 15 were mixed MN (18%). From these 111 cases, 79 were analyzed by FISH and RT-PCR.

Results

All classical and mixed MN were translocation negative. Seventeen out of 29 (58%) cellular MN harbored the ETV6–NTRK3 translocation. Five-year relapse-free survival (RFS) and overall survival (OS) were 93.2% and 96.8% for the complete cohort. All seven relapses occurred in translocation negative tumors. Five-year RFS was significantly inferior for cellular and mixed MN compared to classic MN (89%, 80%, and 98%), whereas 5-year OS was similar (93%, 96%, and 98%). Within the group of cellular MN, patients having translocation-positive tumors had a significantly superior RFS (5-year RFS: 100% vs. 73%).

Conclusion

The majority of cellular MNs harbor the ETV6–NTKR3 gene fusion, whereas all classic- and mixed-type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS.

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Predicting bacterial infections among pediatric cancer patients with febrile neutropenia: External validation of the PICNICC model

Abstract

Introduction

The Predicting Infectious Complications in Neutropenic Children and Young People with Cancer (PICNICC) model was recently developed for antibiotic stewardship among pediatric cancer patients, but limited information is available about its clinical usefulness. We aimed to assess the performance of the PICNICC model for predicting microbiologically documented bacterial infections among pediatric cancer patients with febrile neutropenia.

Materials and methods

We used data for febrile neutropenia episodes at a pediatric cancer center in Aarhus, Denmark between 2000 and 2016. We assessed the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness (i.e., net benefit). We also recalibrated the model using statistical updating methods.

Results

We observed 306 microbiologically documented bacterial infections among 1,892 episodes of febrile neutropenia. The AUC of the model was 0.73 (95% confidence limits [CL]: 0.71–0.75). The calibration intercept (calibration-in-the-large) was −0.69 (95% CL: −0.86 to −0.51) and the slope was 0.77 (95% CL: 0.65–0.89). Modest net benefit was observed at a decision threshold of 5%. Recalibration improved calibration but did not improve net benefit.

Conclusions

The PICNICC model has potential for reducing unnecessary antibiotic exposure for pediatric cancer patients with febrile neutropenia, but continued validation and refinement is necessary to optimize clinical usefulness.

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Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study

Abstract

Purpose

In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development.

Patients and methods

Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies—yolk sac tumor, embryonal carcinoma, or choriocarcinoma—were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS).

Results

Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2–87.8%) and for non-GD patients was 88.8% (95% CI 80.2–93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7–98.1%) and for non-GD patients was 97.6% (95% CI of 90.6–99.4%).

Conclusion

Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

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High incidence of acute kidney injury during chemotherapy for childhood acute myeloid leukemia

Abstract

Background/objectives

Childhood acute myeloid leukemia (AML) is a rare and heterogeneous disease. Pediatric data on the epidemiology of acute kidney injury (AKI) in AML are limited. We report on the incidence of AKI in childhood AML and the risk factors associated with AKI episodes.

Methods

A retrospective cohort of 53 patients (≤18 years), with de novo AML, receiving chemotherapy over a 10-year period. All serum creatinine (SCr) levels during therapy-related hospitalizations were assessed to stage AKI episodes as per Kidney Disease: Improving Global Outcomes criteria. Severe AKI was defined as AKI stages 2 or 3 and urine output criteria were not used. AKI risk factors were assessed independently in both cycle 1 alone and combining all chemotherapy cycles.

Results

AKI developed in 34 patients (64%) with multiple AKI episodes in 10 patients (46 total episodes). Twenty-four severe AKI episodes occurred in 23 patients (43.4%) with a mean duration of 26.1 days (SD 7.3). In cycle 1, hyperleukocytosis was not predictive of AKI, but severe sepsis was an independent risk factor of severe AKI (odds ratio [OR]: 13.4; 95% CI 1.9–94.9). With cycles combined, all subjects with AKI had severe sepsis and older age (≥10 years) was associated with severe AKI (OR: 20.8; 95% CI 3.8–112.2).

Conclusion

There was a high incidence of AKI in our AML cohort with a strong association with older age (≥10 years) and severe sepsis. Larger prospective studies are needed to confirm the high burden of AKI and risk factors in this susceptible population.

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Isolated late testicular relapse of B-cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response-based testicular radiation: A Children's Oncology Group study

Abstract

Background

The incidence of isolated testicular relapse (ITR) of acute lymphoblastic leukemia (ALL) has decreased with contemporary treatment strategies, but outcomes are suboptimal with a 58% 5-year overall survival (OS). This study aimed to improve outcome in patients with ITR of B-cell ALL (B-ALL) occurring after 18 months of first clinical remission using intensive systemic chemotherapy and to decrease long-term sequelae by limiting use of testicular radiation.

Procedure

Forty patients in first ITR of B-ALL were enrolled. Induction (dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy) was preceded by one dose of high-dose methotrexate (MTX, 5 g/m²). Following induction, 25 of 26 patients who had persistent testicular enlargement underwent testicular biopsy. Eleven had biopsy-proven disease and received bilateral testicular radiation (24 Gy), whereas twenty-nine did not.

Results

Overall 5-year event-free survival (EFS)/OS was 65.0 ± 8.8%/73.1 ± 8.3%, with 5-year EFS 62.1 ± 11.0% vs. 72.7 ± 14.4% for patients who did not receive radiation therapy (XRT) (n = 29) compared with those who did (n = 11), respectively (P = 0.64). There were six second bone marrow relapses and six second ITRs. The proportion of second relapses was similar in the patients that received testicular radiation and those who did not. However, the 5-year OS was similar for patients who did not receive XRT (72.6 ± 10.2%) compared with those who did (72.7 ± 14.4%) (P = 0.85).

Conclusions

A 5-year OS rate of 73.1 ± 8.3% was obtained in children with first ITR of B-ALL occurring after 18 months of CR1 (length of first clinical remission) using intensive chemotherapy and limiting testicular radiation.

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Children and adolescents with marginal zone lymphoma have an excellent prognosis with limited chemotherapy or a watch-and-wait strategy after complete resection

Abstract

Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were <18 years old. Forty-four (67%) had an extranodal MZL (EMZL), 21 (32%) a nodal MZL (NMZL), and one patient a splenic MZL. Thirty-three patients (50%) received a variable combination of adjuvant chemotherapy/immunotherapy/radiotherapy, while the remainder, including 20 of 21 with NMZL, entered an active observation period. Overall survival was excellent (98 ± 2%), although 11 patients relapsed (17%; NMZL, n = 1; EMZL, n = 10), seven after any therapy and four after complete resection only. In conclusion, outcome of NZML, in particular, seems to be excellent after (in)complete resection and observation only.

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Crizotinib in ALK+ inflammatory myofibroblastic tumors—Current experience and future perspectives

Abstract

Inflammatory myofibroblastic tumor (IMT) and its subtype epithelioid inflammatory myofibroblastic sarcoma (EIMS) are rare soft-tissue tumors. As about 50% of IMT and 100% of EIMS contain activating rearrangements of the anaplastic lymphoma kinase (ALK) gene, targeted kinase inhibition of ALK by compounds such as crizotinib is a potential treatment option. We performed a literature review and analyzed a total of 30 patients with IMT/EIMS treated with crizotinib. A total of 12 patients achieved complete or partial remission. As preliminary data are promising, a prospective study evaluating crizotinib treatment in patients with unresectable/multifocal ALK⁺ IMT/EIMS is warranted.

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Comment on: “Successful use of nitrous oxide during lumbar punctures: A call for nitrous oxide in pediatric oncology clinics”

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Identifying patient- and family-centered outcomes relevant to inpatient versus at-home management of neutropenia in children with acute myeloid leukemia

Abstract

Efficacy of therapeutic strategies relative to patient- and family-centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at-home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.

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Musculoskeletal complications following total body irradiation in hematopoietic stem cell transplant patients

Abstract

Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life-saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI.

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Modifying bone mineral density, physical function, and quality of life in children with acute lymphoblastic leukemia

Abstract

Background

The early effects of childhood acute lymphoblastic leukemia (ALL) include decreased physical function, bone mineral density (BMD/g/cm²), and health-related quality of life (HRQL). We assessed the capacity of a physical therapy and motivation-based intervention, beginning after diagnosis and continuing through the end of treatment, to positively modify these factors.

Procedure

A 2.5-year randomized controlled trial of 73 patients aged 4–18.99 years within 10 days of ALL diagnosis assessed BMD at baseline (T⁰) and end of therapy (T³), strength, range of motion, endurance, motor skills, and HRQL at baseline (T⁰), 8 (T¹), 15 (T²), and 135 (T³) weeks.

Results

There were no significant changes between groups (intervention, n = 33; usual care, n = 40) in BMD (P = 0.059) at T³ or physical function and HRQL at T⁰–T³. While BMD declined in both the intervention (T⁰ = −0.21, T³ = −0.55) and usual care (T⁰ = −0.62, T³ = −0.78) groups, rates of decline did not differ between groups (P = 0.56). Univariate analysis (n = 73) showed associations of higher T³ bone density with body mass index T¹ (P = 0.01), T² (P = <0.0001), T³ (P = 0.01), T³ ankle flexibility/strength (P = 0.001), and T² parent (P = 0.02)/T⁰ child (P = 0.03) perceptions of less bodily pain.

Conclusions

The intervention delivered during treatment was not successful in modifying BMD, physical function, or HRQL. Physical activity, at the level and intensity required to modify these factors, may not be feasible during early treatment owing to the child's responses to the disease and treatment. Future studies will consider intervention implementation during late maintenance therapy, extending into survivorship.

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Family history-taking practices and genetic confidence in primary and tertiary care providers for childhood cancer survivors

Abstract

Background

There is growing impetus for increased genetic screening in childhood cancer survivors. Family history-taking is a critical first step in determining survivors' suitability. However, the family history-taking practices of providers of pediatric oncology survivorship care and the confidence of these providers to discuss cancer risks to relatives are unknown.

Procedure

Fifty-four providers completed semistructured interviews in total, which included eight tertiary providers representing nine hospitals across two countries (63% male, 63% oncologists, 37% nurses) and 46 primary care providers (PCPs) nominated by a survivor (59% male, 35% regional practice). We used content analysis and descriptive statistics/regression to analyze the data.

Results

Few tertiary (38%) or primary (35%) providers regularly collected survivors' family histories, often relying on survivors/parents to initiate discussions. Providers mostly took two-generation pedigrees (63% tertiary and 81% primary). Primary providers focused on adult cancers. Lack of time, alternative priorities, and perceived lack of relevance were common barriers. Half of all tertiary providers felt moderately comfortable discussing genetic cancer risk to children of survivors (88% felt similarly discussing risks to other relatives). Most primary providers lacked confidence: 41% felt confident regarding risks to survivors' children and 48% regarding risks to other relatives.

Conclusions

While family history-taking will not identify all survivors suitable for genetics assessment, recommendations for regular history-taking are not being implemented in tertiary or primary care. Additional PCP-targeted genetic education is warranted given that they are well placed to review family histories of pediatric cancer survivors.

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Intracranial metastasis in fibrolamellar hepatocellular carcinoma

Abstract

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1–PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.

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Utilization of frozen plasma, cryoprecipitate, and recombinant factor VIIa for children with hemostatic impairments: An audit of transfusion appropriateness

Abstract

Background

Blood transfusions and fractionated products are not without risk and may lead to acute and long-term adverse events. The objective of this study was to evaluate the appropriateness of usage of frozen plasma (FP), cryoprecipitate (CRYO), and recombinant factor VIIa (rVIIa) in a pediatric setting.

Methods

All orders for FP, CRYO, and rVIIa were prospectively audited over 6 weeks. Data collected included demographics, laboratory values, indication, and adverse reactions. The appropriateness of each order was independently evaluated using adjudication criteria rated by two hematologists.

Results

Two hundred sixty-five products were ordered; 67% of the orders were issued to operating rooms or intensive care units. The most common indication for all products was cardiac surgery. FP was ordered as fluid replacement (15/215; 7%) to correct abnormal coagulation tests (23/215; 11%) and for patients with minor or no bleeding (111/242; 46%). FP was more likely to alter the international normalized ratio (INR) if the INR was over 2.0 (P < 0.0001). The rate of inappropriate products was judged as FP 19%, CRYO 21%, and rVIIa 91%.

Conclusion

FP, CRYO, and rVIIa are most commonly used in the operating room and intensive care units. FP was often used for fluid resuscitation and for patients with mild to no bleeding. FP was only effective in lowering the INR when the INR was over 2.0. Use of rVIIa was rarely ordered for an appropriate indication. Results of this study inform its readers where trials of pediatric transfusion should be performed to clarify how these products should be used in clinical practice.

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Cytoreductive surgery and hyperthermic intraperitoneal perfusion with chemotherapy in children with peritoneal tumor spread: A French nationwide study over 14 years

Abstract

Background

Efficacy and role of cytoreductive surgery (CRS) and hyperthermic peritoneal perfusion with chemotherapy (HIPEC) remain poorly documented in pediatric tumors.

Methods

This retrospective national study analyzed all pediatric patients with peritoneal tumor spread treated by CRS and HIPEC as part of a multimodal therapy in France from 2001 to 2015.

Results

Twenty-two patients (nine males and 13 females) were selected. The median age at diagnosis was 14.8 years (4.2–17.6). Seven had peritoneal mesotheliomas; seven, desmoplastic small round cells tumors (DSRCT); and eight, other histologic types. A complete macroscopic resection (CC-0, where CC is completeness of cytoreduction) was achieved in 16 (73%) cases. Incomplete resections were classified as CC-1 in four (18%) cases and CC-2 in two (9%) cases. Fourteen (64%) patients had complications within 30 days from HIPEC, requiring an urgent laparotomy in eight (36%) cases. Thirteen (59%) patients received adjuvant chemotherapy and four (18%) received total abdominal radiotherapy after surgery. Sixteen (72%) patients had relapse after a median time of 9.6 months (1.4–86.4) and nine (41%) eventually died after a median time of 5.3 months (0.1–36.1) from relapse. Six (27%) patients (four mesotheliomas, one pseudopapillary pancreatic tumor, and one DSRCT) were alive and in complete remission after a median follow-up of 25.0 months (5.3–78.2).

The mean overall survival (OS) and disease-free survival (DFS) were 57.5 months (95% CI [38.59–76.32]) and 30.9 months (95% CI [14.96–46.77]). Patients with a peritoneal mesothelioma had a significantly better OS (p = 0.015) and DFS (p = 0.028) than other histologic type.

Conclusions

In this national series, outcomes of HIPEC are encouraging for the treatment of peritoneal mesothelioma in children.

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