William D. Boswell

Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin.

PURPOSE Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU. MATERIALS AND METHODS Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient. RESULTS TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02). CONCLUSION For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.

Primary central nervous system lymphoma in homosexual men. Clinical, immunologic, and pathologic features☆

Primary central nervous system lymphoma constitutes one of the criteria for the acquired immune deficiency syndrome (AIDS), yet a paucity of information is currently available regarding the clinical, immunologic, or pathologic features of these patients. Six homosexual men presenting with primary central nervous system lymphoma were evaluated. Five of these patients presented with altered mental status. All lymphomas were intracranial. B cell immunoblastic sarcoma was found in five. Immune phenotyping studies performed in five patients revealed monoclonal lambda light chain in three, whereas one expressed only IgG heavy chain, and one demonstrated another B cell (LN-1) surface antigen. Hypodense, contrast-enhancing lesions were apparent on computed axial tomographic scanning of the brain, in sharp contrast to isodense or hyperdense lesions reported in primary central nervous system lymphomas without underlying immunodeficiency. Immunologic abnormalities in these patients were similar to those in AIDS presenting as Kaposis sarcoma or with opportunistic infections. In spite of therapeutic interventions, survival was short, and only one patient is currently alive.

Primary mediastinal lymphoma in adults

The incidence of primary mediastinal lymphoma in adults was investigated in 184 patients with non-Hodgkins lymphoma. This entity was defined as disease within the mediastinum in patients who presented with symptoms due to an enlarging mediastinal mass. Of 184 patients, 17 presented with primary mediastinal lymphoma. All had a diffuse histologic pattern. The most common pathologic type was poorly differentiated lymphocytic lymphoma, diffuse (PDL-D), (11 cases). In nine of these 11 cases the patients had tumors of convoluted lymphocytes. The presentation was rapid in onset, with heart failure, pericarditis, dyspnea and superior vena caval syndrome predominating. Eleven of the 17 were clinical stage I or II, but eight of these had widespread disease on pathologic staging or rapid dissemination soon after diagnosis. In conclusion (1) primary mediastinal lymphoma is always diffuse in histology. (2) The most frequent pathologic type is PDL-D, with convoluted morphology. (3) Compression of vital intra-thoracic structures is common. (4) Although seemingly localized at presentation, this entity usually implies disseminated disease.

Unsuspected Pulmonary Emboli in Cancer Patients: Clinical Correlates and Relevance

PURPOSE Advances in computed tomography (CT) scanning have led to the detection of unsuspected pulmonary emboli (PE) on routine cancer staging scans. We hypothesized that these patients had signs or symptoms suggestive of PE that may have been overlooked by their health care providers. PATIENTS AND METHODS A retrospective chart review was performed on 59 patients found on routine cancer staging CT scans to have unsuspected PE. Information on patient demographics, malignancy characteristics, risk factors for venous thromboembolism (VTE), and symptoms was recorded. A retrospective case-control analysis was then performed using two age- and stage-matched control patients for each patient who had similar staging CT scans performed during the same period. RESULTS Fifty-two patients with unsuspected PE were identified. Forty-four percent had signs or symptoms commonly associated with PE; when fatigue was included, 75% were symptomatic. Ninety-two control patients were identified for 46 of the case patients. Patients with unsuspected PE were significantly more likely to have had a prior history of VTE (20% v 3%; P = .007). The patients with PE were significantly more likely than control patients to complain of fatigue (54% v 20%; P = .0002) and shortness of breath (22% v 8%; P = .02). There was no difference between the groups in administration of chemotherapy within 30 days, central venous catheter use, or erythropoietin therapy. CONCLUSION Seventy-five percent of patients found to have unsuspected PE on cancer staging CT scans were symptomatic. Fatigue and shortness of breath were significantly more common in patients with unsuspected PE than in control patients.

Primary central nervous system lymphoma in AIDS. Results of radiation therapy.

Primary central nervous system (CNS) lymphoma is one of the clinical presentations of the acquired immune deficiency syndrome (AIDS). Ten patients had biopsy‐proven high‐grade lymphomas that were confirmed by further staging as limited to the CNS. All ten patients received cranial irradiation (total dose, 2200 to 5000 cGy). Six patients demonstrated complete response (CR) of the intracranial masses at the time of repeat computed tomography (CT) scan, whereas one attained a partial response (PR). Two of the CR patients died multiple opportunistic infections, two experienced relapse of lymphoma, and died at 7 and 16 months diagnosis, and two were alive without evidence of disease at 8 and 14 months from diagnosis. The moon survival of the whole group was 5.5 months (range, 2 to 16 months). Patients with AIDS‐related primary CNS lymphoma may respond to radiation treatment; however, response duration is usually short, and survival is influenced by refractory disease or systemic opportunistic infections.

Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-fluorouracil and weekly leucovorin in disseminated colorectal cancers: Preliminary report from an ongoing trial

A clinical trial for patients with measurable, disseminated colorectal cancer is being conducted to determine: (1) if intratumoral expression of thymidylate synthase (TS) affects response to protracted-infusion 5-fluorouracil (5FU); and (2) whether intratumoral expression of TS increases when clinical resistance is found after response to 5-FU. Polymerase chain reaction technology is employed to determine TS expression. Using beta-actin as an internal standard, TS expressions for 26 patients range from 0.5 x 10(-3) to 22.6 x 10(-3). Currently, 22 patients are evaluable for response and TS quantitation of their measurable tumour. 8 patients (36%) have had partial responses; 3 responding patients had been previously treated with 5-FU. A strong statistical association between TS expression and resistance to therapy has been found (P = 0.004). No patient with TS expression of 4.0 x 10(-3) or greater has responded. On average, patients previously treated with 5-FU have slightly higher levels of TS expression in their measurable tumours (P = 0.4). Whether responding patients will develop increased expressions of TS upon clinical progression of their cancer remains to be determined. Confirmation of these results in a larger cohort could lead to a scientific rationale for deciding upon specific therapy for patients with disseminated colorectal cancers.

MR Imaging of Neurocysticercosis

Magnetic resonance (MR) was performed in 50 patients with neurocysticercosis. Comparison was made with other neuroradiological imaging modalities including CT, myelography, CT ventriculography, and CT myelocisternography. Eighteen patients were found to have intraventricular cysts. In several patients, these were multiple and 22 intraventricular cysts were discovered. Although 4 of the 22 ventricular cysts were missed by MR, T1-weighted images can play a significant role in the early detection of intraventricular cysticercosis cysts, showing the cyst wall (9 of 22), a high intensity mural nodule (6 of 22), and increased signal intensity of the cyst fluid (5 of 22). Cisternal cysts (14 cysts in 10 patients) could be identified; they appear similar to intraventricular cysts, but mural nodules are infrequently seen (1 of 14). Twenty-nine patients had 69 parenchymal cysts. An attempt was made to assess the viability of these parenchymal lesions by matching the CT and MR findings with the Escobar pathologic staging system. Neuroimaging findings seemed compatible with early parenchymal lesions in the vesicular stage in 11 instances. Findings in cases with later stage cysts tend to support the concept that a dying larva provokes pronounced inflammatory reaction in the adjacent brain. Computed tomography remains the superior modality for depicting parenchymal calcifications within dead larvae. A case of a spinal cysticercosis cyst demonstrated with MR (in a patient with extensive intracranial cisternal cysts and a fourth ventricular cyst) is described.

Benign retroperitoneal schwannoma: a case series and review of the literature.

OBJECTIVES To present our experience with four retroperitoneal schwannomas treated by surgical excision and review the current literature. Retroperitoneal schwannomas are rare, benign tumors and infrequently present to the urologist. METHODS From 1997 through 2002, the charts of 164 patients with a diagnosis of benign retroperitoneal soft tissue mass were reviewed. Of those, four had a pathologic diagnosis of retroperitoneal schwannoma. RESULTS Three of the 4 patients were women, with a median age of 54 years (range 46 to 80). The average tumor size was 13.7 cm (range 8.8 to 20). All patients underwent magnetic resonance imaging, computed tomography, or ultrasonography, and 3 of the 4 patients underwent a computed tomography-guided fine needle aspiration biopsy (all were either inaccurate or inconclusive). All patients underwent complete tumor excision with free margins of resection and tolerated surgery without any complications. None of the patients have had any evidence of recurrence at a mean follow-up of 26 months (range 10 to 48). CONCLUSIONS Retroperitoneal schwannomas are difficult to diagnose preoperatively. Computed tomography-guided fine needle aspiration biopsy does not appear to provide an accurate preoperative diagnosis. The surgical approach should focus on complete excision of the mass. Patients undergoing complete surgical resection tend to do well without evidence of early recurrence.

Renal biopsy-related hemorrhage: frequency and comparison of CT and sonography

To evaluate the frequency of retroperitoneal hemorrhage related to renal biopsy, we prospectively assessed 182 patients (200 biopsies) using state-of-the-art CT and ultrasound. Our study revealed definite CT evidence of hemorrhage after 90.9% of biopsies. In a blinded analysis of images obtained in biopsied patients and in unbiopsied control patients the overall accuracy of CT was 93.8 versus 76.4% for ultrasound. Our data suggest that detectable hemorrhage is virtually always seen after renal biopsy and its frequency is much higher than noted in earlier studies.

Liposome-Encapsulated Doxorubicin in Combination With Standard Agents (cyclophosphamide, vincristine, prednisone) in Patients With Newly Diagnosed AIDS-Related Non-Hodgkin's Lymphoma: Results of Therapy and Correlates of Response

PURPOSE To evaluate the safety and efficacy of liposomal doxorubicin (Myocet; Medeus Pharma Ltd, Herts,UK) when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkins lymphoma (AIDS-NHL). Secondary objectives were to assess the impact of HIV viral control on response and survival, and to correlate MDR-1 expression with outcome. PATIENTS AND METHODS Liposomal doxorubicin at doses of 40, 50, 60, and 80 mg/m(2) was given with fixed doses of cyclophosphamide, vincristine, and prednisone every 21 days. All patients received concurrent highly active antiretroviral therapy. NHL tissues were evaluated for multidrug resistance (MDR-1) expression. RESULTS Twenty-four patients were accrued. 67% had high or high-intermediate International Prognostic Index scores; the median CD4 lymphocyte count was 112/mm(3) (range, 19/mm(3) to 791/mm(3)). No dose-limiting toxicities were observed at any level, with myelosuppression being the most frequent toxicity. Overall response rate was 88%, with 75% complete responses (CRs), and 13% partial responses. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Effective HIV viral control during chemotherapy was associated with significantly improved survival (P =.027), but CRs were attained independent of HIV viral control. MDR-1 expression did not correlate with response, suggesting that the liposomal doxorubicin may evade this resistance mechanism. CONCLUSION Liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is active in AIDS-NHL, with complete remissions achieved in 75% independent of HIV viral control or tissue MDR-1 expression. HIV viral control is associated with a significant improvement in survival. Additional studies are warranted.