Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in patients with germ cell tumors undergoing 5-day cisplatin-based chemotherapy: a Hoosier Cancer Research Network study

Purpose

A phase III study adding aprepitant to a 5HT3 receptor antagonist (5HT3-RA) plus dexamethasone in germ cell tumor (GCT) patients treated with 5-day cisplatin combination chemotherapy demonstrated a significant improvement in complete response (CR) (J Clin Onc 30:3998-4003, 2012). Fosaprepitant has demonstrated non-inferiority compared to aprepitant in single-day cisplatin chemotherapy and is approved as a single-dose alternative. This single-arm phase II study is the first clinical trial evaluating fosaprepitant in patients receiving multi-day cisplatin regimen.

Methods

GCT patients receiving a 5-day cisplatin combination chemotherapy were enrolled. Fosaprepitant 150 mg was given IV on days 3 and 5. A 5HT3-RA days 1–5 (days 1, 3, and 5, if palonosetron) plus dexamethasone 20 mg days 1 and 2 and 4 mg po bid days 6, 7, and 8 was administered. Rescue antiemetics were allowed. The primary objective was to determine the CR rate—no emetic episodes or use of rescue medications. Accrual of 64 patients was planned with expected CR?>?27 %.

Results

Sixty-five patients were enrolled of whom 54 were eligible for analysis. Median age was 33. Fifty-one patients received bleomycin, etoposide, and cisplatin (BEP) chemotherapy. CR was observed in 13 (24.1 %) patients (95 % Agresti-Coull binomial C.I. 14.5 %, 37.1 %).

Conclusion

The data in this phase II study, in contrast to our prior phase III study, appears to indicate a lower CR rate with the substitution of fosaprepitant for aprepitant. It is unknown whether the substitution of fosaprepitant for aprepitant provides the same benefit in multi-day cisplatin that was achieved with single-day cisplatin. Trial registration Clinical trial information NCT01736917

     

Transitory hypocalcemia complicating measles

During an epidemic of measles, 12 young adults developed hypocalcemia associated with a decrease in parathyroid hormone level. Calcium and parathyroid hormone levels returned to normal in five of the 12 patients for whom convalescent data were available.     

Safety of simultaneous bilateral total knee arthroplasty. A meta-analysis

BACKGROUND: The safety of simultaneous bilateral total knee replacement remains controversial. Some studies have demonstrated a higher rate of serious complications, including death, following bilateral procedures, whereas others have suggested no increase in the complication rate. The objective of this meta-analysis was to compare the safety of simultaneous bilateral total knee replacement with that of staged bilateral and unilateral total knee replacements. METHODS: A computerized literature search was conducted to identify all citations, from 1966 to 2005, concerning bilateral total knee replacement. All of the English-language abstracts were obtained. A multistage assessment was then performed to identify articles fulfilling the inclusion criteria for the study. All randomized, prospective studies reporting the outcome of bilateral total knee replacement were included. The details of the reported data were extracted, and an extensive analysis of relevant variables was carried out. RESULTS: One hundred and fifty published articles were identified, and eighteen that included a total of 27,807 patients (44,684 knees) were included in the meta-analysis. There were 10,930 unilateral total knee replacements, 16,419 simultaneous bilateral total knee replacements, and 458 staged bilateral total knee replacements with at least three months between the operative procedures. The prevalences of pulmonary embolism (odds ratio = 1.8), cardiac complications (odds ratio = 2.49), and mortality (odds ratio = 2.2) were higher after simultaneous bilateral total knee replacement. The prevalence of deep venous thrombosis was lower after simultaneous bilateral total knee replacement, but this difference was not significant. The complication rates after the staged bilateral total knee replacements were similar to those in the patients who had undergone unilateral total knee replacement only. CONCLUSIONS: Compared with staged bilateral or unilateral total knee replacement, simultaneous bilateral total knee replacement carries a higher risk of serious cardiac complications, pulmonary complications, and mortality. The period of time between staged procedures that would eliminate these increased risks could not be determined from this study. LEVEL OF EVIDENCE: Therapeutic Level III.     

Neuroimaging of disseminated germ cell neoplasms

The purpose of this study was to determine the role of neuroimaging in the management of patients with metastatic germ cell tumors. Retrospective evaluation of 299 patients treated in 1986 and 1987 for initial presentation or recurrence of testicular, retroperitoneal, and mediastinal germ cell tumors was performed to determine indications for neuroimaging, frequency and site of CNS metastases, and occurrence of other CNS abnormalities. Sixty-six patients required CNS imaging with myelography, CT, or MR. Studies were normal in 24 patients. Twenty patients had CNS metastases including 11 with intracranial metastases, eight with spine lesions, and one with both brain and spine involvement. Sixteen had cerebral or cerebellar atrophy of unclear origin and functional significance. Two patients had ventriculomegaly without symptoms of hydrocephalus. Four patients had questionable lesions that were never confirmed. None of the 25 asymptomatic patients with elevated serum tumor markers had brain metastases. Fifteen of 17 patients with focal neurologic deficits and three of six patients with seizures had CNS metastases. CNS imaging to detect germ cell tumor metastases is most useful in the presence of neurologic deficits or seizures but is not useful in patients with unexplained elevation of serum tumor markers in the absence of neurologic deficits.     

Etoposide, ifosfamide, and cisplatin in extensive small cell lung cancer.

From December 1987 through April 1989, 40 patients with extensive-stage small cell carcinoma of the lung were enrolled in a Hoosier Oncology Group (HOG) trial using etoposide, ifosfamide, and cisplatin (VIP). Patients with extensive disease were eligible if they had not received prior chemotherapy, had a Karnofsky performance status of 50 or more, and had adequate renal function (creatinine, less than 1.5 mg/dl) and bone marrow reserve (granulocyte count, greater than or equal to 2500/microliters; platelets, greater than or equal to 125,000/microliters). Doses of therapy were: etoposide 75 mg/m2/day on days 1 to 5, ifosfamide 1.2 g/m2/day on days 1 to 5, and cisplatin 20 mg/m2/day on days 1 to 5. The first 11 patients received a 5-day course; this was repeated every 21 days for four cycles, but therapy was shortened to 4 days when unacceptable toxicity was noticed in these patients. Overall, 14 (37%) had a complete remission (overall response rate, 71.1%) with a median survival of 42 weeks (28 weeks on 5-day regimen and 45 weeks on 4-day regimen). There were five early deaths. Although toxic, VIP produces a high complete remission rate in patients with extensive disease and warrants further evaluation. A prospective randomized trial comparing cisplatin and etoposide to the VIP regimen is underway through HOG.     

Spatial and temporal expression of fibril-forming minor collagen genes (types V and XI) during fracture healing

Skeletal development involves the coordinated participation of several types of collagen, including both major and minor fibrillar collagens. Although much is known about the major fibrillar collagens, such as types I and II, less is known about the minor fibrillar collagens, and their role in the repair and regeneration of bone has not been extensively studied. To clarify the role of minor fibrillar collagens in Fracture repair, we examined the spatial and temporal expression of mRNAs for pro-α2(V) collagen and pro-α1(XI) collagen in healing fractures in the rat by in situ hybridization and compared their patterns of expression with those Of mRNAs for pro-α1(I) collagen, pro-α1(II) collagen, and osteocalcin. A strong signal for pro-α2(V) was detected in the periosteal osteoprogenitor cells, whereas osteocalcin mRNA was strongly expressed only in the deep layers of the hard callus. The distribution of the pro-α2(V) signal was correlated with that of pro-α1(I) but was mutually exclusive of that of pro-α1(II).The expression of pro-α1(Xl) mRNA was synchronously regulated with that of pro-α1(II) during chondrogenesis in the soft callus. In the hard callus, pro-α1(XI) signal Was found in osteoblastic cells at the site of intramembranous and endochondral ossification. These cells simultaneously expressed pro-α2(V), although they were negative for pro-α1(II). These findings suggest that the, α2(V) collagen chain participates in the formation of the noncartilaginous fibrillar network in the hard callus and preferentially contributes to the initial stage of the intramembranous bone formation. Recent reports have, revealed that type-XI collagen, which had been classified as a cartilage-type collagen, is not necessarily specific for cartilage. The present results advanced this recognition and demonstrated a coexpression of α1(XI) mRNA and α2(V) mRNA in the noncartilaginous tissues in the fracture callus; this suggests the presence of tissue-specific and stage-specific heterotrimers consisting of α1(XI) and α2(V) collagen chains and the association of such hybrid trimers with the major fibrillar collagens in the process of fracture healing.     

Biosynthesis of glycophospholipid bound and secreted murine class I Qa-2 polypeptides

Murine T cells synthesize and express a cell-surface glycophospholipid anchored 40 kDa and a secreted water-soluble 39 kDa Qa-2 polypeptide. We have examined the biosynthetic pathways which lead to the production of the membrane-bound and water-soluble isoforms of the Qa-2 molecule. Using the detergent TX-114, both detergent (membrane)-bound and soluble Qa-2 polypeptides can be identified in cell lysates and can be distinguished by charge and molecular weight. Two membrane-bound forms, a 40-kDa Endo H resistant cell-surface form and a 38 kDa-Endo H sensitive form can be identified, both of which can be biosynthetically labeled with 3H-ethanolamine and can be converted to water soluble forms by digestion with a phosphatidylinositol specific phospholipase C. In addition, several water soluble polypeptides at 39, 37, 35 kDa, and a minor species at 33 kDa were identified, none of which radiolabel with 3H-ethanolamine. While the 39-kDa polypeptide was Endo H resistant, the other isoforms were sensitive to Endo H digestion. Pulse chase experiments and molecular weights of the deglycosylated core polypeptides suggest a precursor to product relationship between the intracellular water-soluble species and the mature 39-kDa secreted Qa-2 molecule. This relationship is supported by the observation that murine L cells transfected with the Qa-2 encoding class I gene Q7 fail to express membrane-bound Qa-2 molecules yet synthesize both intracellular water-soluble and secreted Qa-2 molecules. These findings argue for a pathway in which secreted soluble Qa-2 molecules are derived from intracellular precursors.