Vikramjit S. Kanwar

Advanced small cell carcinoma of the ovary in a seventeen-year-old female, successfully treated with surgery and multi-agent chemotherapy

Advanced small cell carcinoma of the ovary (FIGO stage III or IV) is a rare and usually lethal tumor seen in adolescents and young women. In pediatric patients with advanced disease, there have been only two case reports of successful therapy, we report a third patient, diagnosed at 17 years of age, with an abdominal mass and metastatic disease to regional and distant lymph nodes, who was successfully treated with surgery and intensive multi‐agent chemotherapy. Imatinib, thalidomide, and celecoxib were also administered for up to 24 months following initial chemotherapy. She remains in remission 3 years from diagnosis. Pediatr Blood Cancer 2008;50:1060–1062.

Sacrococcygeal immature teratoma with malignant ependymoma component

To the Editor: The optimal therapy of childhood immature teratoma with malignant neuroepithelial elements (PNET), a condition associated with adverse outcome, remains poorly defined [1–4]. We report a 21-month-old female with this diagnosis who underwent multimodal therapy with a successful outcome. She originally presented with a pelvic mass, normal serum AFP and beta-HCG levels, and underwent surgical resection of an immature teratoma. Unfortunately, coccygectomy was deferred, and the patient was lost to follow up. Eight months later she presented with a recurrent mass (5 cm 3.7 cm 6.5 cm with a second component 1.8 cm 2.1 cm 2 cm). There was no evidence of metastastic disease and serum AFP and beta-HCG were normal. A biopsy revealed immature teratoma with a malignant neuroepithelial component having the appearance of anaplastic ependymoma. Neoadjuvant IV chemotherapy was administered with four sequential cycles of cisplatin (90 mg/m over 3 days), etoposide (450 mg/m over 3 days), and vincristine (1.5 mg/m), followed by three cycles of vincristine (1.5 mg/m) and cyclophosphamide (2.2 g/m). Scans performed prior to surgery showed decreased tumor size of 5 cm 4.6 cm 4.1 cm. Surgical resection of the mass was performed with intraoperative brachytherapy (12 Gy) administered to the sacral region. The resected tumor showed a teratoma with neuroepithelial elements, most of which exhibited the morphology of an anaplastic ependymoma. A minor component consisted of dense aggregates of small, primitive-appearing neuroepithelial cells containing tubules and rosettes lined by pseudostratified cells with apical cytoplasmic granularity and abluminal mitotic activity (‘‘ependymoblastic’’ rosettes) (Fig. 1). In view of surgical concern about residual disease, the patient postoperatively received three cycles of vincristine (1.5 mg/m), doxorubicin (30 mg/m) and cyclophosphamide (2.2 g/m). Three years from recurrence the patient remains in remission. Of interest, similar malignant ependymal elements were identified on slides of the original tumor on expert review. The main factors predisposing our patient to recurrence were sacrococcygeal location with absence of coccygectomy, and poor follow up [2,5,6]. Malignant elements in immature teratoma are usually yolk sac elements or choriocarcinoma [5], and PNET or anaplastic ependymoma are rare with limited data to guide therapy. Germ cell tumors with somatic malignant elements are best treated with chemotherapy directed against those elements [3,6], and in this case the somatic malignant components consisted principally of high-grade ependymoma. We therefore elected to treat with vincristine, cyclophosphamide, etoposide and cisplatinum, which had an overall response rate of 48% when used by Duffner et al. [7] to treat infant ependymoma. Intraoperative brachytherapy and three cycles of post-operative chemotherapy were administered to eradicate any microscopic residual disease, and the patient is currently in remission with no evidence of recurrence or sequelae (Fig. 1).

Hematopoietic Stem Cell Regulation by Type i and ii interferons in the Pathogenesis of Acquired Aplastic Anemia

Aplastic anemia (AA) occurs when the bone marrow fails to support production of all three lineages of blood cells, which are necessary for tissue oxygenation, infection control, and hemostasis. The etiology of acquired AA is elusive in the vast majority of cases but involves exhaustion of hematopoietic stem cells (HSC), which are usually present in the bone marrow in a dormant state, and are responsible for lifelong production of all cells within the hematopoietic system. This destruction is immune mediated and the role of interferons remains incompletely characterized. Interferon gamma (IFNγ) has been associated with AA and type I IFNs (alpha and beta) are well documented to cause bone marrow aplasia during viral infection. In models of infection and inflammation, IFNγ activates HSCs to differentiate and impairs their ability to self-renew, ultimately leading to HSC exhaustion. Recent evidence demonstrating that IFNγ also impacts the HSC microenvironment or niche, raises new questions regarding how IFNγ impairs HSC function in AA. Immune activation can also elicit type I interferons, which may exert effects both distinct from and overlapping with IFNγ on HSCs. IFNα/β increase HSC proliferation in models of sterile inflammation induced by polyinosinic:polycytidylic acid and lead to BM aplasia during viral infection. Moreover, patients being treated with IFNα exhibit cytopenias, in part due to BM suppression. Herein, we review the current understanding of how interferons contribute to the pathogenesis of acquired AA, and we explore additional potential mechanisms by which interferons directly and indirectly impair HSCs. A comprehensive understanding of how interferons impact hematopoiesis is necessary in order to identify novel therapeutic approaches for treating AA patients.

Germ Cell Tumors/Teratoma

Pediatric germ cell tumors (GCT) of the head and neck are rare lesions with a highly variable presentation. Teratomas are benign GCT that often present at birth, frequently resulting in significant upper airway obstruction and a high risk of mortality. Malignant GCT represent a minority of GCT of the head and neck in the pediatric population and typically respond well to a combination of surgical resection and chemotherapy. This chapter will discuss the pathophysiology and variable clinical presentation of both benign and malignant pediatric GCT of the head and neck as well as the diagnosis and management of these lesions. Particular emphasis is given to the prenatal diagnosis and perinatal management of neonatal teratomas of the head and neck, including prenatal MRI, the ex utero intrapartum treatment (EXIT) procedure, and airway management.

Acute renal failure in a 17‐year‐old female with ALL receiving escalating intravenous methotrexate without leukovorin

To the Editor: We read with interest the article by Gronroos et al. describing a possible mechanism for methotrexate-related nephrotoxicity [1]. We describe a 17-year-old female with ALL who developed acute renal failure after receiving escalating intravenous methotrexate without leukovorin (Capizzi I regimen). The patient with pre-B ALL was treated per the current Children’s Oncology Group high-risk protocol AALL0232. She began outpatient escalating doses of IV methotrexate on the Capizzi I regimen [2] and tolerated her first dose of 100 mg/m with no adverse side effects. Her baseline BUN was 6 mg/dl and creatinine was 0.8 mg/dl. She had a history of migraine and was taking oral zolmitriptan 2.5 mg (Zomig, AstraZeneca Pharmaceuticals, DE). Two days after her second dose of IV methotrexate (150 mg/m) she was admitted with nausea, low-grade fever, and a creatinine of 3.2 mg/dl, BUN 21 mg/dl, and a MTX level of 0.53. She was started on 3 L/m/day of alkalinized IV fluid with leukovorin rescue, but developed mucositis, skin rash, and myelosuppression with an ANC of 400/mm. Four days after admission, her MTX level had decreased to 0.06, and creatinine to 1.0 mg/dl. The cause of her methotrexate-related nephrotoxicity remained uncertain, but a Tc99-DTPA nuclear scan confirmed that 2 weeks after presentation her GFR was near normal (91.7 with normal 94.5–121.5), and a renal ultrasound scan showed no abnormalities. It was decided to discontinue zolmitriptan, and make sure she received adequate hydration. She received her next dose of methotrexate (150 mg/m) with pre-hydration of 1 L of alkalinized IVF over 4 hr and 2 L per day of alkalinized IVF for 2 days postmethotrexate. She tolerated subsequent escalation of methotrexate doses to 200 mg/m and then 250 mg/m with this hydration regimen and completed her Capizzi 1 schedule uneventfully. For her last three doses, 24 hr methotrexate levels varied from 0.14 to 0.7 and 48 hr levels from 0.02 to 0.09, with no toxicity noted. Acute renal failure at relatively low doses of methotrexate is rarely described. A Japanese case report documented acute renal failure in two adults who received 225 mg/m IV push methotrexate outpatient for ALL [3]. Doses of methotrexate as low as 15 mg per week have been shown to mildly impair renal function [4], and preexisting renal insufficiency potentiates this effect [5]. The renal nuclear scan indicated our patient had almost normal underlying renal function. Various drugs, such as indomethacin [6], amoxicillin [7], and iopamidol (an intravenous contrast agent) [8] are described as potentiating the nephrotoxic effect of methotrexate, but zolmitriptan has not been previously described as having such a role. We would suggest that patients who have acute renal failure following outpatient IV methotrexate have renal studies done when they recover, to confirm normal renal function, have all possible interacting medications withheld, and be allowed to receive increasing doses of methotrexate as scheduled with appropriate hydration and monitoring of MTX levels.

Neuroblastoma obeys “The law of small numbers”

distribution’’ was best described by von Bortkiewicz, who was commissioned by the Czar to review army records and predict the likelihood of a Prussian cavalryman being killed by the kick of a horse in a given period of time. Von Bortkiewicz published a monograph (‘‘The Law of Small Numbers’’), which essentially demonstrated that an exponential relationship existed between rare independent events, and the time interval between those events occurring. Such events would therefore often occur clustered together, followed by long intervals of time with no events [1]. We retrospectively reviewed the incidence of patients with neuroblastoma at Albany Medical Center, between January 1, 2006 and December 31, 2010, to confirm that the presentation of these cases conformed to a Poisson distribution. There were 16 patients with neuroblastoma diagnosed in 13 out of 60 months (Fig. 1), for an incidence rate of 0.2667 per month, and Poisson’s formula tables (not shown) predicted a p(0) of 78%, that is, there should be 47 months with no patients diagnosed with neuroblastoma, which was indeed the case. In confirming that the presentation of this childhood cancer to Albany Medical Center followed a Poisson distribution, we indirectly demonstrated that these were rare independent events. The inability of medical practitioners to explain temporal (or spatial) clustering of childhood cancers to the general public has sometimes led to unnecessary anxiety, with efforts to track down pos-

Isolated pulmonary Langerhans cell histiocytosis with recurrent bilateral pneumothoraces treated with chemotherapy and chemical pleurodesis

increased and prolonged calcium folinate rescue. Nevertheless, there is a certain incidence of subacute neurotoxicity independent of MTX pharmacokinetics. We observed delayed neurotoxicity in an osteosarcoma patient following a 4 hour 12 g/mMTX infusion and rescued by calcium folinate from hours 28 to 90. Even in protocols including administration of folinate after any single intrathecal MTX dosage subacute neurotoxicity is observed occasionally as recently reported [5]. The fact that in all of these protocols subacute neurotoxicity occurs in a small percentage of patients suggests that for the majority (>90%) of patients folinate seems to be adequately dosed since they never develop clinical signs of neurotoxicity. Therefore, instead of increasing the rescue dose for all patients it might be a more rational strategy to identify those patients who might benefit from more folinate independent of MTX pharmacokinetics. We observed that pretreatment CSF levels of 5-methyltetrahydrofolate exhibit considerable interindividual variability (35.2–91.9 nM) [6]. However, folinate rescuewas adjusted only to serum levels ofMTX, regardless of folate levels in the CSF. It is possible, in view of the results of Sterba et al. [4], that patients with low pretreatment CSF folate levels may benefit from more rescue. In our opinion, monitoring of CSF folate levels and investigating the relationship between folinate doses and the resulting increase of CSF folate could provide answers to the question of adequate calcium folinate doses. In addition, more attention should be paid to alternative, nonfolate rescue strategies. Neurotoxicity in our two reported patients has been associated with low CSF S-adenosylmethionine (SAM) levels [6]. Orally administered SAM has been shown to increase CSF levels and substitution of SAM to patients treated with high-dose and intrathecal MTX deserves further investigation. This strategy would have the advantage that neurotoxicity may be prevented without jeopardizing MTX efficacy [1,2]. Larger clinical studies are certainly warranted to achieve progress in the prevention of neurotoxicity of MTX.