Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

How best to interpret mixed human papillomavirus genotypes in high-grade cervical intraepithelial neoplasia lesions

Objectives

This study aimed to determine human papillomavirus (HPV) genotypes present in biopsy sections from young women of vaccine eligible age living in Victoria, Australia, with confirmed cervical intraepithelial neoplasia grade 3 (CIN3) or adenocarcinoma in situ (AIS) using laser capture microdissection (LCM).

Methods

Histologically confirmed CIN3 or AIS positive biopsies from vaccine eligible women (born after 30th June 1981, n = 169), between May 2011 and March 2013, were identified. CIN3 or AIS lesions were isolated from biopsy material using LCM, and the HPV genotypes present in whole tissue sections (WTS) as well as LCM-isolated lesion tissue were determined by a sensitive reverse hybridisation assay; RHA kit HPV SPF10-LiPA25, version 1 (Labo Bio-medical Products, Rijswijk, The Netherlands).

Results

One hundred and sixty-eight cases were shown to be HPV positive (99%), of which 20 (12%) had more than one HPV genotype detected using WTS-PCR. Evaluation by LCM of individual biopsies with mixed infections showed 18 cases (90%) had only one HPV genotype associated with each CIN3 lesion. HPV 16 was the most common HPV type, found in 95/168 cases (57%).

Conclusion

LCM-PCR allowed us to confirm the presence of a single HPV genotype associated with each biologically separate CIN3 lesion, supporting the theory that only one virus type causes each independent CIN lesion. LCM will provide an important tool in assessing vaccine effectiveness in HPV vaccine programs.     

Detection of high-grade cervical disease among women referred directly to colposcopy after a positive HPV screening test varies with age and cytology findings

Australia's new HPV-based cervical screening program is based on an algorithm that incorporates reflex cytology to guide decisions about further follow-up with colposcopy and, if indicated, biopsy. We reviewed results for 2300 women referred directly for colposcopy after their first positive HPV screening test, to determine the proportion that had underlying histological high-grade abnormality (HGA). Overall, HGA was detected in 24.3% of women. Among HPV16/18 positive women, 18.0% had HGA, increasing from 6.6% among women with negative cytology to 79.7% among women with high-grade squamous lesion or worse, or any glandular lesion on cytology (HSIL+; P-trend < .001). For this latter group, the proportion with HGA was higher among HPV16/18 positive women than among those positive for other oncogenic types (68.8%; P = .029). Among women with ASC-H cytology, 51.8% had HGA, with no difference between HPV groups (P = .314). In analyses by age-groups, detection of HGA was highest, at 36.4%, among women younger than 35 years, then decreased significantly to 5.9%, among women aged 65 to 74 years (P-trend < .001). The relationship of decreasing HGA detection with increasing age was strong for women with negative cytology, and those with ASC-H cytology (P-trend < .001 for each). For women with HSIL+ cytology, detection of HGA was high and stable, regardless of age (P-trend = .211). This report describes the first follow-up colposcopy findings in Australia's new HPV-based cervical screening program. The results demonstrate the additional value of reflex cytology in managing HPV positive women and suggest that further refinement of the risk-based algorithm to account for age may be warranted.     

Taking a Better History for Behavioral Issues Pre‐ and Post‐Deep Brain Stimulation: Issues Missed by Standardized Scales

Objectives: To screen for potentially underreported behavioral changes in patients with idiopathic Parkinson's disease (PD) pre‐ and post‐deep brain stimulation (DBS), a retrospective data base review was performed. Methods: In total, 113 patients who underwent unilateral or bilateral DBS at the University of Florida in either subthalamic nucleus or globus pallidus internus for PD were screened for behavioral issues by asking about the presence or absence of seven neuropsychiatric symptoms (panic, fear, paranoia, anger, suicidal flashes, crying, and laughing). Results: There was a high prevalence of fear (16.3%), panic (14.0%), and anger (11.6%) at baseline in this cohort. In the first six months following DBS implantation, anger (32.6%), fear (26.7%), and uncontrollable crying (26.7%) were the most frequent symptoms reported. Those symptoms also were present following six months of DBS surgery (30.2%, 29.1%, and 19.8%, respectively). New uncontrollable crying occurred more in the acute postoperative stage (less than or equal to six months) (p= 0.033), while new anger occurred more in the chronic postoperative stage (greater than six months) (p= 0.017). The frequency of uncontrollable laughing significantly increased with bilateral DBS (p= 0.033). Conclusions: Many of the neuropsychiatric issues were identified at preoperative baseline and their overall occurrence was more than expected. There was a potential for worsening of these issues post‐DBS. There were subtle differences in time course, and in unilateral vs. bilateral implantations. Clinicians should be aware of these potential behavioral issues that may emerge following DBS therapy, and should consider including screening questions in preoperative and postoperative interviews. Standardized scales may miss the presence or absence of these clinically relevant issues.     

Laparoscopic ultrasound vs triphasic computed tomography for detecting liver tumors

BACKGROUND: Accurate staging of malignant tumors in the liver has major implications in defining prognosis and guiding both surgical and nonsurgical therapy. Intraoperative ultrasound in open surgery compares favorably with computed tomography (CT) in the detection of liver tumors; however, there is little experience with laparoscopic ultrasound (LUS). HYPOTHESIS: Laparoscopic ultrasound is more sensitive than triphasic CT for detecting primary and metastatic liver tumors. DESIGN: Prospective study. SETTING: University hospital. PATIENTS: Fifty-five patients with a total of 222 lesions, including primary and metastatic liver tumors, who underwent both CT examinations and LUS as a part of a tumor ablation procedure. INTERVENTIONS: Triphasic spiral CT scans of the liver were obtained within 1 week before surgery. Liver LUS was performed with a linear 7.5-MHz side-viewing laparoscopic transducer. RESULTS: The LUS detected all 201 tumors seen on preoperative CT and detected 21 additional tumors (9.5%) in 11 patients (20.0%). These tumors missed by CT ranged in size from 0.3 to 2.7 cm. Smaller tumors tended to be missed by CT scan (28.6% of the lesions <1 cm, 15.8% of those 1-2 cm, 4% of those 2-3 cm, and 0% of those >3 cm), as did those in segments III and IV. There was good correlation between the size of lesions imaged by the 2 modalities (Pearson r = 0.86; P<.001). CONCLUSION: Laparoscopic ultrasound offers increased sensitivity over CT for the detection of liver tumors, especially for smaller lesions. This study documents the ability of LUS in detecting liver tumors and argues for more widespread use in laparoscopic staging procedures.     

Role of oral pamidronate in preventing bone loss in postmenopausal women

We have performed a 2-year prospective double-masked study to determine whether the bisphosphonate pamidronate can prevent bone loss in postmenopausal women and its optimal dosage regimen. One hundred and twenty-one such women (mean ± SD age 57.6±3.4 years; mean ± SD time since menopause 7.5±3.5 years) were randomized to receive either oral pamidronate (300 mg/day) for 4 weeks every 4 months (group A), oral pamidronate (150 mg/day) for 4 weeks every 2 months (group B) or identical placebo capsules (group C). Bone mineral density (BMD) measurements at the lumbar spine and proximal femur were performed at baseline and at 6-month intervals for 2 years using dual-energy X-ray absorptiometry. BMD at the lumbar spine (L2–4) increased significantly in groups A and B after 2 years of treatment (mean ± SD 2.8±2.1% and 3.0±2.9% respectively, bothp<0.001) but decreased in the placebo group (–1.6±3.1%,p<0.01). Identical results were seen for BMD at the femoral neck, which increased significantly in groups A and B after 2 years of treatment (1.2±2.3% and 1.3±2.9% respectively, bothp<0.05) but decreased in the placebo group (–1.9±3.9%,p<0.05). There were significant differences over 2 years between the groups at all anatomical sites (lumbar spine, femoral neck and trochanteric region, allp<0.001; Ward's triangle,p<0.01). However, there were no significant differences between groups A and B, suggesting that the two treatment regimens were equally effective in conserving BMD. There were, however, marked differences in tolerability between the two treatment regimens: 13 women (34%) in group A withdrew from the study because of side-effects, but only 5 women (12%) in group B, which was comparable with placebo. These data demonstrate that intermittent oral pamidronate will prevent bone loss from the lumbar spine and proximal femur of postmenopausal women, and that the more frequent but lower dose regimen is well tolerated.