Phase II study of bendamustine combined with rituximab in relapsed/refractory mantle cell lymphoma: efficacy, tolerability, and safety findings.

In most cases of relapsed/refractory mantle cell lymphoma (MCL), patients respond to salvage therapy, though typically responses are partial and/or transient followed by disease progression, even with newer agents (e.g., ibrutinib). In this multicenter, open-label, single-arm, phase II study, patients with relapsed/refractory non-blastoid MCL received bendamustine 90 mg/m(2) (days 1 and 2) and rituximab 375 mg/m(2) (day 1) for 6 planned 28-day cycles. Functional imaging with 18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) was conducted at baseline and after cycle 6. Forty-five patients were enrolled (median age, 70 years; 82 % stage IV disease; median number of prior chemotherapies, 2 [range, 1-4]), showing an overall response rate (ORR; primary efficacy measure) of 82 % (complete response [CR], 40 %; partial response, 42 %). In the 32 patients with complete 18F-FDG PET/CT data, 75 % achieved a complete metabolic response. Median duration of response was 1.6 years, 1-year progression-free survival was 67 %, and 3-year overall survival was 55 %. Main non-hematologic adverse events were nausea (69 %), fatigue (56 %), decreased appetite (42 %), constipation (38 %), diarrhea (36 %), vomiting (36 %), and decreased weight (31 %). Grade 3/4 neutropenia and lymphopenia occurred in 44 and 89 % of patients, respectively. ORR and CR rate compared favorably with single-agent ibrutinib (ORR, 67 %; CR, 23 %); bendamustine-rituximab is an effective therapy with manageable toxicity in relapsed/refractory MCL.

High prevalence of early-onset osteopenia/osteoporosis after allogeneic stem cell transplantation and improvement after bisphosphonate therapy.

Osteopenia/osteoporosis (O/O) has been associated with allogeneic stem cell transplantation (alloSCT). We retrospectively reviewed 102 patients undergoing a first alloSCT from 2000 to 2005 at our center to evaluate the prevalence of O/O < or =6 and >6 months post-alloSCT. Fifty-six patients did not have a dual energy X-ray absorptiometry (DXA) scan following alloSCT. Approximately half (n=13/27) of those with a first DXA scan < or =6 months post-alloSCT had O/O and a similar rate (n=9/19) was seen in those with a first DXA scan >6 months. There were no significant differences in patient characteristics between the normal and O/O groups. The dual femur (DF) appeared to be more vulnerable to alloSCT-induced bone mineral density (BMD) loss than the lumbar spine (LS), regardless of screening time. O/O patients were treated with bisphosphonates and 41% had a repeat DXA scan post-treatment. No patient developed jaw osteonecrosis and significant BMD improvement was seen at the LS (mean BMD, 1.03+/-0.13 vs 1.08+/-0.12, P=0.004) but not the DF (mean BMD, 0.84+/-0.06 vs 0.85+/-0.08, P=0.29), indicating BMD loss at the DF is more resistant than the LS to antiresorptive therapy. Our results demonstrate that O/O is an early and late complication post-alloSCT and bisphosphonate treatment reverses BMD loss at the LS.

Caracterizaço da linguagem na síndrome do X-frágil: estudo bibliográfico / Language characterization in the X-fragile syndrome: a review study

BACKGROUND: X-Fragile Syndrome. AIM: To compile information about the language, cognitive and behavior alterations in the X-Fragile Syndrome, using the results of previously published studies and to present the standardized instruments used as testing materials. CONCLUSION: studies used formal and informal testing to assess language. The results present variability regarding the linguistic deficits, which are influenced by the level of the cognitive deficit and behavior alterations. Alterations of the oral praxes and of speech articulation are also expected.

Tema: síndrome do X-Frágil. Objetivo: compilar informações sobre as alterações de linguagem, cognição e comportamento na Síndrome do X-Frágil por meio do resultado de estudobibliográfico e apresentar os instrumentos padronizados usados nas avaliações. Conclusão: os estudos utilizaram procedimentos formais e informais para a avaliação da linguagem. Os resultados apresentaram variabilidade quanto às alterações lingüísticas, sofrendo influênciaquanto ao grau de retardo mental, e distúrbios comportamentais. Alterações práxicas orais e fonoarticulatórias também são previstas.

Radioimmunoscintigraphy (RIS) with bectumomab (Tc99m labeled IMMU-LL2, Lymphoscan) in the assessment of recurrent non-Hodgkin's lymphoma (NHL).

UNLABELLED: The efficacy of a Tc99m-labeled anti-lymphoma antibody fragment, bectumomab [LymphoScan], was retrospectively examined in the staging of recurrent or newly diagnosed non-Hodgkin's lymphoma (NHL) [7 patients] and to assess targeting before radioimmunotherapy (RIT) [14 patients]. Performance was graded relative to conventional imaging. Tumors included 7 low-grade, 11 intermediate-grade, and 3 high-grade histologic subtypes. Computed x-ray tomography, radiogallium imaging, FDG-PET, and bone marrow biopsy defined 117 sites. Bectumomab revealed 56% of these sites. In 4 patients bectumomab uncovered five sites not evident by conventional imaging. In addition, it uncovered one site in the brain, an area not covered in the standard work-up of asymptomatic patients. Bectumomab imaging most often failed in central abdominal and thoracic locations, and excelled in revealing disease in the head and neck. Relative to Ga67 citrate imaging, the performance of bectumomab was variable, with no clear relation to anatomic location; there was better targeting of low and intermediate grade NHL. Radiogallium out-performed bectumomab imaging in 23 sites, 19 of which were in patients with high or intermediate-grade disease. Bectumomab was superior to radiogallium at six sites, five of which involved low-grade tumor. CONCLUSION: Bectumomab shows promise as a pre-RIT probe for targeting of B-cell NHL. It excelled at defining small volume, low-grade disease. However, as a purely diagnostic agent, its performance was variable.

Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

UNLABELLED: Radiation dosimetry studies were performed in patients with non-Hodgkin's lymphoma (NHL) treated with 90Y Zevalin (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) on a Phase III open-label prospectively randomized multicenter trial. The trial was designed to evaluate the efficacy and safety of 90Y Zevalin radioimmunotherapy compared to rituximab (Rituxan, MabThera) immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed NHL. An important secondary objective was to determine if radiation dosimetry prior to 90Y Zevalin administration is required for safe treatment in this patient population. METHODS: Patients randomized into the Zevalin arm were given a tracer dose of 5 mCi (185 MBq) (111)In Zevalin (111indium ibritumomab tiuxetan) on Day 0, evaluated with dosimetry, and then administered a therapeutic dose of 0.4 mCi/kg (15 MBq/kg) 90Y Zevalin on Day 7. Both Zevalin doses were preceded by an infusion of 250 mg/m(2) rituximab to clear peripheral B-cells and improve Zevalin biodistribution. Following administration of (111)In Zevalin, serial anterior and posterior whole-body scans were acquired and blood samples were obtained. Residence times for 90Y were estimated for major organs, and the MIRDOSE3 computer software program was used to calculate organ-specific and total body radiation absorbed dose. Patients randomized into the rituximab arm received a standard course of rituximab immunotherapy (375 mg/m(2) weekly x 4). RESULTS: In a prospectively defined 90 patient interim analysis, the overall response rate was 80% for Zevalin vs. 44% for rituximab. For all patients with Zevalin dosimetry data (N=72), radiation absorbed doses were estimated to be below the protocol-defined upper limits of 300 cGy to red marrow and 2000 cGy to normal organs. The median estimated radiation absorbed doses were 71 cGy to red marrow (range: 18-221 cGy), 216 cGy to lungs (94-457 cGy), 532 cGy to liver (range: 234-1856 cGy), 848 cGy to spleen (range: 76-1902 cGy), 15 cGy to kidneys (0.27-76 cGy) and 1484 cGy to tumor (range: 61-24274 cGy). Toxicity was primarily hematologic, transient, and reversible. The severity of hematologic nadir did not correlate with estimates of effective half-life (half-life) or residence time of 90Y in blood, or radiation absorbed dose to the red marrow or total body. CONCLUSION: 90Y Zevalin administered to NHL patients at non-myeloablative maximum tolerated doses delivers acceptable radiation absorbed doses to uninvolved organs. Lack of correlation between dosimetric or pharmacokinetic parameters and the severity of hematologic nadir suggest that hematologic toxicity is more dependent on bone marrow reserve in this heavily pre-treated population. Based on these findings, it is safe to administer 90Y Zevalin in this defined patient population without pre-treatment (111)In-based radiation dosimetry.

Sentinel node biopsy in breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SNB) in breast cancer may be used in place of axillary lymph node dissection (ALND) if SNB accurately stages the axilla. This study assessed the success and accuracy of axillary SNB with isosulfan blue (ISB) and technetium-99 sulfur colloid (TSC) compared to ALND. METHODS: Forty-two women with T1 or T2 breast cancer underwent SNB and ALND. Sixty to 90 minutes before anesthetic induction, a mixture of 3 mL ISB and 1 mCi TSC was injected around the primary cancer or prior biopsy site. Intraoperatively, the SLN was identified using a gamma detector (Neoprobe 1000) or by visualization of the blue-stained lymph node and afferent lymphatics. The SLN was excised separately, and a level I/II ALND was completed. The histologic findings of the axillary contents and SLN were compared. RESULTS: An axillary SLN was found in 38 of 42 (90%) cases. SLN localization rate and predictive value were the same for women who had and those who had not undergone excisional biopsy before the date of SNB. Fifteen of 42 (36%) patients had lymph node metastases. The SLN was positive in all women with axillary metastases (negative predictive value, 100%). CONCLUSIONS: If confirmed by larger series, a negative SNB may eliminate the need for ALND for select women with breast cancer.

Staging of primary colorectal carcinomas with fluorine-18 fluorodeoxyglucose whole-body PET: correlation with histopathologic and CT findings.

PURPOSE: To evaluate the diagnostic usefulness of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in patients with primary colorectal carcinomas. MATERIALS AND METHODS: Forty-eight patients with biopsy-proved (n = 44) or high clinical suspicion for (n = 4) colorectal cancer underwent whole-body PET after intravenous administration of 10 mCi (370 MBq) of FDG. FDG PET results were correlated with computed tomographic (CT), surgical, and histopathologic findings. RESULTS: PET depicted all known intraluminal carcinomas in 37 patients (including two in situ carcinomas) (sensitivity, 100%), but findings were false-positive in four of seven patients without cancer (three with inflammatory bowel conditions, one who had undergone polypectomy). Specificity was 43% (three of seven patients); positive predictive value, 90% (37 of 41 patients); and negative predictive value, 100% (three of three patients). No FDG accumulation was noted in 35 hyperplastic polyps. FDG PET depicted lymph node metastases in four of 14 patients (sensitivity, 29%). Results were similar to those obtained with CT (true-positive, two of seven patients [sensitivity, 29%]; true-negative, 22 of 26 patients [specificity, 85%]). FDG PET depicted liver metastases in seven of eight patients and was superior to CT, which depicted liver metastases in three patients (sensitivity of 88% and 38%, respectively). FDG PET and CT, respectively, correctly depicted the absence of liver metastases in 35 and 32 patients (specificity, 100% and 97%; negative predictive value, 97% and 86%). CONCLUSION: FDG PET has a high sensitivity and specificity for detection of colorectal carcinomas (primary and liver metastases) and appears to be superior to CT in the staging of primary colorectal carcinoma.

Positron emission tomography in the evaluation of the N0 neck.

The presence of cervical lymph node metastasis in patients with head and neck cancer is associated with an unfavorable prognosis. Reports vary as to whether various conventional radiographic studies, such as computed tomography (CT) and magnetic resonance imaging, confer an advantage over physical examination in the patient without clinical findings of cervical metastasis (N0). Positron emission tomography (PET) is a functional imaging modality that has recently been used for head and neck neoplasms. The use of PET in the evaluation of the N0-staged neck in 14 consecutive patients with squamous cell carcinoma (SCC) of the upper aerodigestive tract is reported. Seven patients (50%) undergoing 13 neck dissections had pathologic evidence of disease. PET scans were positive in five patients with pathologically confirmed cervical metastasis. PET scans were negative in seven patients (11 neck dissections) with no pathologic evidence of disease. PET scans were positive for unilateral cervical metastasis in two of three patients with involvement of a single lymph node. PET scans were positive in two of three patients with more than two lymph nodes involved. PET had an accuracy of 100% in the eight patients with SCC of the oral cavity. In patients with oropharyngeal or hypopharyngeal carcinoma PET localized cervical metastasis in two of four patients with neck metastasis. In the patient with an N0-staged neck on clinical examination, PET was found to have an overall sensitivity of 78%, specificity of 100%, positive predictive value of 100%, negative predictive value of 88%, and accuracy of 92%. CT demonstrated sensitivity of 57%, specificity of 90%, positive predictive value of 80%, negative predictive value of 75%, and accuracy of 76%. PET showed a trend in increased accuracy (P = 0.11) over CT. PET appears to be a promising diagnostic aid that may be applied when evaluating the N0-staged neck, especially for SCC of the oral cavity.

Wernicke-Korsakoff syndrome caused by psychogenic food refusal: MR findings.

A 37-year-old woman developed Wernicke encephalopathy after prolonged psychogenic food refusal. MR revealed characteristic signal abnormalities in the midbrain and dorsal thalamus. Follow-up scans showed atrophy and third ventricular enlargement. Wernicke encephalopathy can occur in nonalcoholics, and MR imaging is useful in both the diagnosis and follow-up.

Adenosine inhibition of catecholamine-stimulated cardiac membrane adenylate cyclase.

Adenosine inhibition of hormone-sensitive adenylate cyclase activity was investigated using isolated myocardial membranes prepared from rat hearts. When cyclase activity was determined in membranes, using [alpha-32P]ATP as substrate, 10(-5) M adenosine inhibited isoproterenol-stimulated adenylate cyclase activity by 25% but did not inhibit basal activity or fluoride (5 mM) activation of the enzyme. The adenosine reduction of isoproterenol-sensitive cyclase activity was dependent on GTP but was not prevented by 10(-3) M theophylline. Adenosine neither appeared to compete with ATP for the substrate converting site of the enzyme nor reduced 5'-guanylyl imidodiphosphate activation of the enzyme. Inasmuch as lower concentrations of adenosine had no influence on enzyme activity, endogenous adenosine may be present in the adenylate cyclase assay. To obviate the effects of endogenous adenosine, the adenylate cyclase assay was then modified to a 2'-deoxy system with [alpha-32P]dATP used as the substrate in the presence of adenosine deaminase. With this assay system, the 15% inhibition of isoproterenol-stimulated adenylate cyclase activity produced by the adenosine receptor agonists, 10(-8) M 2-chloroadenosine or phenylisopropyladenosine, was prevented by 10(-4) M 8-phenyltheophylline or isobutylmethylxanthine (IBMX), respectively. While under these assay conditions, 10(-7) M 2',5'-dideoxyadenosine, a P-site analogue, did not influence the hormone-sensitive cyclase activity. The 35% reduction of the hormone-sensitive enzyme produced by this analogue at 10(-5) M was not prevented by IBMX. These results suggest that nanomolar concentrations of adenosine analogues interact with a methylxanthine-sensitive adenosine receptor that mediates the attention of membrane hormone-sensitive adenylate cyclase activity.