Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases.

PURPOSE: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. RESULTS: Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients. CONCLUSION: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.     

Coexistence of Low and High Grade Squamous Intraepithelial Lesions of the Cervix: Morphologic Progression or Multiple Papillomaviruses?

Background.The diagnosis of both low (LSIL) and high (HSIL) grade squamous intraepithelial lesions in the same cervical specimen may reflect classification variation, morphologic progressionin situ,and, conceivably, different HPV infections. We addressed these possibilities in cervical specimens previously diagnosed as containing both LSIL (condyloma/CIN1) and HSIL (CIN2/3).Methods.All cases with a histologic diagnosis of LSIL and HSIL from 1994–1996 were reviewed. On review, lesions were scored as (1) no significant variation in lesion grade (classification discrepancies) and showing a (2) one (CIN1–2) or (3) two (CIN1–3) grade shift in the same case. In cases in which a one or two grade shift was confirmed, low (CIN1) and high (CIN2–3) grade foci were microdissected and extracted DNA analyzed for HPV by PCR and RFLP analysis.Results.Of 98 cases available for review, 58 (59%) did not exhibit significant variation in grade (classification discrepancy), and 40 (41%) showed a one (25) or two (15) grade shift. Of the latter group both LSIL and HSIL foci were HPV(+) in 26 (65.0%). The same HPV was present in both LSIL and HSIL foci in 15/15 lesions with a one grade shift (CIN1–2). In contrast, a significantly higher proportion of lesions with a two grade shift (CIN1–3) contained two different HPV types (4/11 vs 0/15;P= 0.01). Combinations of HPVs in the low/high grade foci, respectively, included HPV 11/16 (1), 11/16 + 18 (1), and HPV39/16 (2).Conclusions.Lesions containing LSIL and HSIL which span two grades (CIN1 and CIN2) most likely represent morphologic progression in a single infection. Lesions containing CIN1 and CIN 3 may be attributed to both lesion progression and two coincident infections; the latter sometimes present in the same histologic section. The latter phenomenon has implications for both the diagnosis of CIN and interpretation of “morphologic progression” from very low to high grade in the same case.     

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

The differential molecular mechanisms underlying proenkephalin mRNA expression induced by forskolin and phorbol-12-myristic-13-acetate in primary cultured astrocytes

In rat astrocytes, forskolin (FSK; 5 microM) and phorbol-12-myristic-13-acetate (PMA; 2.5 microM) increase the proenkephalin (proENK) mRNA level via different pathways. FSK-induced proENK mRNA expression is independent of protein de novo synthesis, and well correlated with CREB phosphorylation. This is in contrast to PMA-induced proENK mRNA expression that is dependent on protein de novo synthesis and is well correlated with the increase of AP-1 DNA binding activity rather than CREB phosphorylation. Differential regulation of AP-1 proteins by PMA and FSK was also observed. While c-Fos, Fra-2 and JunB were increased in response to either stimuli, only Fra-1, c-Jun and JunD were increased by PMA. The combined treatment with FSK and PMA additively increased the proENK mRNA level, which was correlated with AP-1 or ENKCRE-2 DNA binding activity, and CREB phosphorylation. Dexamethasone (DEX; 1 microM) further enhanced FSK- or PMA-induced proENK mRNA expression, which was not correlated with the activation of AP-1 expression and CREB phosphorylation, suggesting that synergistic interaction of glucocorticoid with PKA or PKC pathway for the regulation of proENK mRNA expression appears to be mediated by other pathways rather than CREB and AP-1 families.     

Alveolar soft part sarcoma: MR and angiographic findings

Objective. To present the MR and angiographic findings of alveolar soft part sarcoma (ASPS). Design and patients. MR examinations (12 tumors of 10 patients) of ASPS performed at multiple hospitals were retrospectively reviewed. The tumors were found in the thigh (n=4), lower leg (n=4), femur (n=2, local metastasis), scalp (n=1) and arm (n=1). The MR signal characteristics including signal intensity, homogeneity and signal void of lesions and bony invasion including direct invasion or local metastasis were evaluated. Angiographic findings (n=4) and post-embolotherapy follow-up MR imaging (n=2) findings were also assessed. Results. Local bony metastasis was found in two cases. Seven tumors showed heterogeneous high signal intensity on T1- and T2-weighted images with good enhancement. One tumor had a very high signal on T1-weighted images. Eight tumors (67%) showed numerous signal voids in or near the tumors. All four angiographic studies showed numerous enlarged vessels, arteriovenous shunts and delayed washout. Two cases mimicked arteriovenous malformations on angiographic studies but MR images demonstrated solid soft tissue components as well as tortuous vessels. Conclusions. High signal on T1-weighted image and numerous signal voids are highly suggestive of ASPS, although they are not universal as has been suggested and arteriovenous malformation should be included in the differential diagnosis. Local bony metastases in ASPS were seen in two cases and should be carefully investigated. Received: 12 April 2000 Revision requested: 27 June 2000, 8 August 2000 Revision received: 2 August 2000, 21 August 2000 Accepted: 22 August 2000     

Surgical treatment of intractable epilepsy accompanying cortical dysplasia

OBJECT: Surgical treatment of cortical dysplasia (CD) together with intractable seizures is challenging because both visualization and localization of the lesion are difficult, correlation with seizure foci requires comprehensive study, and the surgical outcomes reported thus far are unsatisfactory. The authors report their experience in the surgical treatment of CD classified according to a surgical point of view. METHODS: The definition of CD used in this study was a dysplastic lesion visible on magnetic resonance (MR) images or a lesion that, although not visible on MR images, was diagnosed as moderate-to-severe dysplasia by using pathological analysis. During the last 4.5 years, the authors treated 36 patients with intractable epilepsy accompanied by CD. They divided the 36 cases of CD into four characteristic groups: Group A, diffuse bilateral hemispheric dysplasia; Group B, diffuse lobar dysplasia; Group C, focal dysplasia; and Group D, a moderate to severe degree of CD with a normal appearance on MR images. All but one patient in Group C were monitored in the epilepsy monitoring unit by using subdural electrodes for seizure localization and functional mapping. The incidence of CD among a cohort of 291 patients who had undergone epilepsy surgery at the authors' center during the study period was 12.4%. The mean age of the 36 patients was 21.3 years and the mean age at seizure onset was 8.5 years. The mean follow-up period was 26 months. Twenty-six patients (72.2%) belonged to Engel Class I or II (20 and six, respectively). There were five cases in Group A, nine in Group B, nine in Group C, and 13 in Group D. Patients in Groups A and B were significantly younger at seizure onset and had significantly poorer surgical outcomes compared with patients in Groups C and D (p < 0.05). If outcome is compared on the basis of the extent of removal of CD, patients in whom CD was completely removed had significantly better outcomes than those in whom CD was only partially removed (p < 0.001). CONCLUSIONS: The authors conclude that intractable epilepsy accompanied by CD can be treated surgically using comprehensive preoperative approaches. Deliberate resective procedures aimed at complete removal of dysplastic tissue ensure excellent seizure control without permanent neurological deficit.     

Subtle CD20 positivity in the bone marrow of a patient who has a mucosa‐associated lymphoid tissue lymphoma should not be regarded as evidence of involvement in the bone marrow

Aims: Bone marrow (BM) biopsies of some mucosa‐associated lymphoid tissue (MALT) lymphoma patients show scattered or small clusters of CD20+ cells without definite lesions (subtle CD20 positivity). The aim of this study was to evaluate the clinical significance of BM involvement and subtle CD20 positivity in 122 patients diagnosed with MALT lymphoma. Methods and results: Patients were divided into three categories: BM involvement [BM(+)], subtle CD20 positivity, and no BM involvement [BM(?)]. Eleven (9%) showed BM involvement, and 17 (14%) showed subtle CD20 positivity. BM(+) patients had significantly worse progression‐free survival (PFS) than BM(?) patients [hazard ratio (HR) 6.25, P = 0.01], but there was no significant difference between subtle CD20 positivity and BM(?) patients. Patients with >30 CD3+ cells among 100 nucleated cells in the areas with increased numbers of CD3+ cells had significantly worse PFS than those with <15 CD3+ cells (HR 5.49, P = 0.02). BM(+) patients with >30 CD3+ cells had worse PFS than those with ≤30 CD3+ cells (P = 0.029), with an extent of BM(+) involvement of >10% positively correlating with >30 CD3+ cells (P = 0.015). Conclusions: Patients with BM(+) MALT lymphoma showed significantly worse PFS than those with subtle CD20 positivity and BM(?) MALT lymphoma, but the PFS of patients with subtle CD20 positivity MALT lymphoma was not significantly different from that of those with BM(?) MALT lymphoma. Increased numbers of BM T cells in MALT lymphoma patients might be suggestive of a worse prognosis.     

Total Talar Extrusion without Soft Tissue Attachments

Total talar extrusion without a soft tissue attachment is an extremely rare injury and is rarely reported. Appropriate treatment remains controversial. We describe the long-term outcomes of two patients who had complete talar extrusion without remaining soft tissue attachment treated with arthrodesis. Both of our patients had complications such as infection and progressive osteolysis. We suggest reimplantation of the extruded talus after thorough debridement as soon as possible as a reasonable option unless the talus is contaminated or missing, because an open wound may arise from inside to outside.