Alexia Bertuzzi

Phase II Study of Imatinib in Advanced Chordoma

PURPOSE To explore the antitumor activity of imatinib in patients with advanced platelet-derived growth factor β (PDGFB)/PDGF receptor β (PDGFRB)-positive chordomas. PATIENTS AND METHODS In a collaborative Italian-Swiss, prospective, phase II clinical study conducted from November 2004 through April 2006, 56 patients with advanced PDGFB and/or PDGFRB chordoma received 800 mg/d of imatinib until progression. The primary end point was the overall tumor response rate (ORR), defined by RECIST. Secondary, exploratory end points included tissue response (ie, changes in tumor density or signal intensity/contrast enhancement, and/or [18F]-fluorodeoxyglucose positron emission tomography [PET] uptake), overall survival, progression-free survival (PFS), and pain score. RESULTS Among 50 patients evaluable by RECIST, the best response was one partial response (PR) obtained at 6 months (ORR, 2%). There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST complete response + PR + SD ≥ 6 months). A minor dimensional response (< 20%) was detected in nine patients. A maximum standard uptake value decrease ≥ 25% was observed in 10 (39%) of 26 patients evaluable for PET response at 3 months. Changes in the Brief Pain Inventory score were consistent with the response assessment. Median PFS (intention-to-treat population, 56 patients) was 9 months. No unexpected toxicities were observed. CONCLUSION This is the largest phase II study in chordoma to date. It confirms anecdotal evidence that imatinib has antitumor activity in this orphan disease, and therefore, it is worth further investigation.

High-Dose Chemotherapy in Poor-Prognosis Adult Small Round-Cell Tumors: Clinical and Molecular Results From a Prospective Study

PURPOSE The prognosis of metastatic/high-risk localized small round-cell tumors (SRCTs) treated conventionally is dismal. In this phase II study, we explored a high-dose chemotherapy (HD-CT) approach and analyzed the clinical significance of fusion transcripts detection. PATIENTS AND METHODS From June 1997 to November 1999, 28 SRCT patients (median age, 26 years; 14 peripheral primitive neuroectodermal tumors [pPNETs], seven rhabdomyosarcomas [RMSs], and seven desmoplastic small round-cell tumors [DSRCTs]) received induction chemotherapy with ifosfamide, epirubicin, and vincristine followed by HD-CT. Local treatment (radiotherapy and/or surgery) was performed when possible. Molecular analysis was performed on peripheral-blood and leukapheresis products by reverse-transcriptase polymerase chain reaction. RESULTS Overall response (OR) was 65% (18 of 28), with 40% complete response and 25% partial response. According to histology, the OR rate was 86% in pPNET and 43% in both RMS DSRCT. With a median follow-up of 35 months, median overall survival was 16 months and median progression-free survival (PFS) was 10 months. PFS was statistically better in pPNET than other histologic types (P =.0045). No correlation was found between the fusion transcript and clinical outcome during follow-up. Furthermore, transcript detection in leukapheretic products was not of prognostic significance. CONCLUSION Intensive HD-CT seems to enhance the response rate and survival when compared with conventional treatment in poor-prognosis pPNET. The poor results of this treatment in RMS and DSRCT do not support the inclusion of such an approach in these patient subsets. No definitive conclusions can currently be drawn concerning the clinical implications of the detection of fusion transcripts during treatment or follow-up.

Clinical and Pharmacologic Study of the Epirubicin and Paclitaxel Combination in Women With Metastatic Breast Cancer

PURPOSE A pharmacokinetic interaction may cause increased cardiotoxicity of paclitaxel (PTX) and high cumulative dose of doxorubicin. We tested antitumor activity, tolerability, and pharmacokinetics of the lesser cardiotoxic epirubicin (EPI) and PTX (ET combination). PATIENTS AND METHODS Twenty-seven women with untreated metastatic breast cancer, median age of 56 years, and prominent visceral involvement (74%) were studied. Three-weekly EPI (90 mg/m(2)) and PTX (200 mg/m(2) over 3 hours) were given for a maximum nine cycles. EPI was administered 24 hours before PTX (E --> T) in cycle 1, and 15 minutes before PTX (ET) thereafter. EPI, epirubicinol (EOL), EPI-glucuronide (EPI-glu), EOL-glucuronide (EOL-glu), PTX, and 6alpha-OH-PTX were measured in plasma and urine in 14 women. RESULTS Patients received 205 cycles of ET and a median EPI dose of 720 mg/m(2). Grade 4 neutropenia (49% of cycles) was the most frequent toxicity. Cardiac contractility was decreased in five patients. Mild congestive heart failure occurred in two (7.4%). Response rate was 76% (28% complete). Median overall survival was 29 months. On the basis of intrapatient comparison in the first 24 hours of E --> T and ET cycles, PTX did not affect EPI disposition, but significantly increased plasma exposure to EOL (by 137%), EPI-glu (threefold) and EOL-glu (twofold). Urinary excretion of EPI dose went from 8.2% in E --> T to 11.8% in ET cycles. Clearance of PTX was 30% slower in ET than E --> T. ET cycles caused lower neutrophil nadir than E --> T (644 +/- 327 v 195 +/- 91, P <.05) CONCLUSION ET is feasible, devoid of excessive cardiac toxicity, and active. A reciprocal pharmacokinetic interference between the two drugs has pharmacodynamic consequences, and suggests a direct effect of PTX on EPI metabolism requiring ad hoc investigation.

Prospective study of high-dose chemotherapy and autologous peripheral stem cell transplantation in adult patients with advanced desmoplastic small round-cell tumour.

A total of 10 desmoplastic small round-cell tumour patients were treated by high-dose chemotherapy with stem cell support. After high-dose chemotherapy, no complete response conversion was obtained and EWS-WT1 fusion transcript detection was positive in the peripheral blood during follow-up in all patients. High-dose chemotherapy did not seem to change the results in desmoplastic small round-cell tumour.

Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation

Stromal tumors of the prostate are rare and only a few cases have been described in the literature, including exceptional cases of stromal tumors with unknown malignant potential (STUMP) and a fatal outcome in young patients. Morphologically distinguishing a STUMP from a stromal sarcoma of the prostate (PSS) is still a challenge. We describe the histopathological and immunohistochemical findings in a 34-year-old man with a malignant specialized cell stromal tumor of the prostate that was diagnosed initially as STUMP, and he developed lung metastases within a few months. The patient attended our hospital because of lower urinary tract symptoms, after having excreted tissue through the urethra a few months before. Ultrasonography and urethrocystoscopy examinations showed a mass arising from the verumontanum, and a transurethral resection (TUR) revealed a highgrade spindle cell sarcoma reminiscent of a phyllode tumor of the breast. The tumor cells were immunoreactive for vimentin, progesterone receptor and, focally, CD34. The preliminary histological findings were subsequently confirmed after radical prostatectomy. The patient developed bilateral lung metastases and died 25 months after the initial diagnosis. Although rare in young patients, the challenging differential diagnosis of STUMP and PSS means that a prostate STUMP diagnosis made on the basis of biopsy or TUR specimens also requires urethrocystoscopic monitoring for the early detection of any progression to PSS. Radical prostatectomy should also be carefully considered.

Juxtaglomerular Cell Tumor: Multicentric Synchronous Disease Associated With Paraneoplastic Syndrome

Case Report A 50-year-old white man presented to the emergency department for a hypertensive crisis that was causing headache and nausea. Blood pressure was 200/120 mmHg, the physical examination was unremarkable, whereas blood tests showed sodium levels of 116 mmol/L and potassium levels of 3.2 mmol/L. Past medical history included a myocardial infarction 10 years before, ischemic heart disease, diabetes, and arterial hypertension, which was poorly controlled by a calcium-channel blocker and an angiotensin-converting enzyme inhibitor. In the previous months, the patient had begun to suffer from abdominal pain, dyspepsia, and vomiting that had resulted in weight loss of 16 kg in 7 months. Gastroscopy and colonoscopy were negative, whereas an abdominal ultrasound revealed the presence of a splenic cyst that measured 4.5 cm in maximum diameter. The patient was admitted to the nephrology department for diagnosis and determination of a therapeutic approach. Laboratory values confirmed hypotonic euvolemic hyponatremia; levels of thryroid-stimulating hormone, cortisol, and adrenocorticotropic hormone were in the normal ranges, whereas urinary sodium was strongly elevated (111 mmol/L). Water restriction and hypertonic administration failed to raise sodium levels, thus ruling out primary polydipsia. Coexistence of hypotonic hyponatremia, without signs of depletion or expansion of blood volume or of hormonal imbalances, was consistent with diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH; Table 1). Pharmacologic causes of SIADH were ruled out, and we turned our attention toward locating a neoplasm responsible for the syndrome, considering the history of weight loss and abdominal pain. The patient underwent a thoraco-abdominal computed tomography (CT) scan that revealed the presence of a splenic mass that measured 9.1 7.6 cm, a left renal lesion that measured 2.1 cm, and a hepatic lesion that measured 1.6 cm. Subsequently, the patient underwent a splenic CT-guided biopsy. Histology showed the presence of a mesenchymal neoplasm with smooth muscle/ myopericitic differentiation that was suggestive of hemangiopericytoma/malignant glomus tumor. On the basis of the histologic findings, the limited extent of the disease, and the patient’s good performance status (Eastern Cooperative Oncology Group [ECOG] performance status of 0), in March 2008, a splenectomy, partial nephrectomy, and hepatic segmentectomy were performed. Histopathology confirmed the presence of multiple localizations of a malignant mesenchymal neoplasm that was characterized by proliferation of epithelioid cells with focal areas of necrosis and a perivascular pattern of growth. The immunophenotype was as follows: positivity for CD34, smooth muscle actin (focal), CD 138, Vimentin, collagen IV (focal) and negativity for CD31, the melanosome-related antigens HMB45 and Melan-A, cytokeratin 5/6, cytokeratin MNF116, epithelial membrane antigen, calretinin, CD56, S100, C-kit, and desmin. Morphologic and immunophenotypic features were inconsistent with the diagnosis of hemangiopericytoma and raised the suspicion of a juxtaglomerular cell tumor that originated from the kidney (Fig 1, hematoxylin and eosin staining; Fig 2, immunohistochemistry for CD34; original magnification 200). Therefore, plasmatic renin levels were determined by chemiluminescence (Immulite System, Siemens Healthcare Diagnostics, Genova, Italy; reference range, 3.3-41 mU/L), thus confirming strongly elevated values (147 mU/L). A definitive diagnosis was reached by the evidence of immunohistochemical positivity for renin in tumor cells (Fig 3; note strong cytoplasmic immunoreactivity for antirenin antibody in tumor cells). There were no data found in the literature on systemic therapy in this rare histologic subtype of a mesenchymal tumor. However, the Table 1. Diagnostic Criteria for SIADH

The "old drug" DTIC as a second/third line chemotherapy in advanced soft tissue sarcomas (STS)

9032 Background: There is not a standard second line chemotherapy in advanced STS. DTIC is one of the most active drugs in the treatment of STS with a response rate (RR) of 17%. As a second line chemotherapy the data available confirm these interesting results. Therefore we conducted a retrospective analysis about 44 patients (pts) treated in our Institute with DTIC as second/third line therapy between May 1997 and October 2003. The aim of our analysis was to evaluate the RR, the progression free survival (PFS) and the median duration of response. METHODS About 44 pts anlysed, 36 were evaluable; 8 pts, after first cycle, were treated elsewhere. The median age was 55,5 (range 24-75). The 75% of pts (27/36) were metastatic and the 72% (26/36) had a disease grading 2-3. DTIC was done as second line chemotherapy in 70% of pts(25/36). The 75% of pts (27/36) and the 25% (9/36) had respectively progressive and relapsed disease before to start the treatment. DTIC was given every 21 days with three different schedules: DTIC 800 mg/sqm day 1 (20 pts); DTIC 400 mg/sqm days 1 and 2 (6 pts); DTIC 300 mg/sqm days 1, 2 and 3 (10 pts). RESULTS Among 36 evaluable pts, 3 (8%) achieved partial response (PR) and 7 (19%) stable disease (SD), with an overall disease control of 28%. No complete response was observed. As second line therapy DTIC achieved 2/25 PR and 5/25 SD. The median PFS and the median duration of response were respectively 2 and 8 months. The progression free rate at 3 and 6 months was respectively 33% (SE 7.86%) and 25% (SE 7.2%). No grade 3-4 hematologic and non-hematologic toxicity according to W.H.O. was observed. CONCLUSIONS Our results suggest that DTIC as a second/third line therapy yields a satisfactory disease control in progressive STS; its activity seems to be comparable to other treatments, such as the high dose of ifosfamide or ET-743, but with a lower toxicity profile. The increse of dose-intensity to obtain a better RR is questionable considering cost-benefit ratio in terms of toxicities and overall survival. No significant financial relationships to disclose.