A comparison of the in vitro and in vivo activities of IgG and F(ab')2 fragments of a mixture of three monoclonal anti-Her-2 antibodies.

PURPOSE: We have demonstrated previously that a mixture of three anti-Her-2 monoclonal antibodies (MAbs) that bind to different epitopes on the extracellular domain of Her-2 expressed on a human breast cancer cell line has more potent antitumor activity than the individual MAbs both in vitro and in xenografted severe combined immunodeficient mice. Because the activity of Herceptin is Fc dependent, we determined whether this would also be the case when a mixture of these three anti-Her-2 MAbs was used. EXPERIMENTAL DESIGN: IgG and highly purified F(ab')(2) fragments of the anti-Her-2 MAbs and Herceptin were prepared and evaluated for their ability to induce cell death, inhibit vascular endothelial growth factor secretion, and mediate antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity in vitro. They were also compared for their abilities to induce regression of large BT474 tumors in severe combined immunodeficient mice. RESULTS: All of the F(ab')(2) fragments were >95% pure and, as expected, did not mediate antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity in vitro. The in vitro antiproliferative and proapoptotic effects of the IgGs and F(ab')(2) fragments were similar. In contrast, the IgGs had significant antitumor activity in vivo, whereas their F(ab')(2) fragments were only marginally effective even at 5-fold higher doses to offset their shorter half-lives. CONCLUSIONS: These results confirm the importance of the Fc portion of Herceptin for optimal in vivo activity and demonstrate that even a mixture of three anti-Her-2 MAbs that are highly effective at inducing cell death in vitro requires Fc-mediated effector function for optimal in vivo activity.     

Unexpected toxicity after low-dose docetaxel treatment of a cancer patient with clinically latent HCV-positive hepatic cirrhosis

We report a case with unexpected toxicity after low-dose docetaxel chemotherapy. The patient had a history of clinically latent HCV-positive hepatic cirrhosis when she presented with inoperable pulmonary adenocarcinoma. She was recruited in a protocol combining standard radiotherapy (RT) with docetaxel (30 mg/m2 week). On day 7, after the 1st docetaxel infusion, grade III neutropenia (980 neutrophils), grade II platelet toxicity (90,000/ml) and lymphopenia (486/ml) had developed. Chemotherapy and RT were interrupted and the neutrophil counts were partially restored (1400/ml), while the platelet counts were back to normal (140,000/ml) and the lymphocyte counts were further reduced (320/ml), on day 15. Bilateral leg oedema and hair loss appreared. On day 21, there was a full restoration of neutrophil counts (1890/ml), while there was persistent lymphocytopenia (300/ml). Alopecia grade III was now evident. Dysphagia grade II complicated with fungal oropharyngeal infection appeared on day 24 (24 Gy of RT). One more dose of docetaxel of 30 mg/m2 was given on day 36 Grade II neutropenia (1050/ml) and grade III platelet toxicity (48,000/ml) were observed 14 days after the second docetaxel dose, while dysphagia grade II appeared once again. After a one-week delay, RT was continued to a total dose of 54 Gy. Liver function tests remained unchanged throughout the treatment. Post-RT CT-scan of the chest and upper abdomen showed complete response of the lung lesion. We suggest that, when docetaxel is chosen to treat cancer patients with HCV-positive hepatic cirrhosis, a starting dose schedule reduced by at least 50% should be considered before escalating to the standard dose.     

Feasibility of azithromycin prophylaxis during a pertussis outbreak among healthcare workers in a university hospital in Paris.

The objective of the present study was to evaluate the feasibility of azithromycin prophylaxis with respect to tolerability and compliance during a pertussis outbreak among healthcare workers in a university hospital ward. Compliance with the prophylaxis regimen was 89%; compliance was 75% from intent-to-treat perspective. The rate of adverse events was 33%. Female sex was associated with reporting of adverse events. Nonstudents and healthcare workers who reported adverse events were less compliant with the prophylaxis regimen.     

Psychosocial effects and evaluation of the health-related quality of life in patients suffering from well-controlled epilepsy

Abstract.Purpose: To record the impact of epilepsy on the psychological health and HRQOL of patients suffering from mild epilepsy in a rural area of southeastern Greece.Patients and methods: We studied fifty outpatients suffering from well-controlled uncomplicated epilepsy who experienced from none up to four seizures per year and had the ability to sustain a regular job. We tried to record the psychosocial effects resulting from epilepsy and to evaluate their HRQOL, comparing them to 50 healthy controls with similar demographic characteristics. To patients and controls were given the Short-Form Health Survey (SF-36) and a questionnaire based on the Hamilton and Mandrs depression scales.Results: According to the two depression and anxiety scales used, a mild degree of anxiety and depression was diagnosed but with unimportant statistical difference (p = ns) between patients and healthy controls. Self-perceived HRQOL of patients appeared to be affected,with vitality (p < 0.002), physical (p<0.001) and social functioning (p < 0.003) as the most impaired subscales of the SF-36. The deterioration in their HRQOL was mainly related to the post-diagnosis alteration of their socioeconomic status. As assessed by the multiple regression analyses, none of the disease history and medication-related variables were found to have any influence on the results of the SF-36 subtests.Conclusion: Despite the fact that we studied a relatively small sample of patients with mild epilepsy, our results showed that their HRQOL was obviously affected, while their psychological health remained nearly unaffected.     

Breast carcinoma metastasis to the orbit and paranasal sinuses: a case report

This is the case of a 34 years old female patient, with known history of disseminated, invasive, ductal adenocarcinoma, grade II, of the left breast, who presented with two distinct localizations of metastasis affecting the orbits. One in the right orbit and a second one in the frontal sinuses, the latter infiltrating the cognate ethmoid, exerting pressure on the inner wall of the left orbit. We present the symptoms, the ophthalmic signs and the imaging techniques that aided the localization of these metastasis, while literature review shows that such combination is rare.     

Intravenous administration of vitamin B12 in the treatment of hyperhomocysteinemia associated with end-stage renal disease

BACKGROUND: High serum levels of total homocysteine (tHcy) are common in dialysis patients with end-stage renal disease (ESRD). We assumed that these patients may have decreased response to conventional folic acid (FOL) and vitamin B12 (B12) administered orally. This study aimed to evaluate the efficacy of an intravenous (i.v.) B12 regimen in ESRD patients and compare it with the conventional regimen. METHODS: We designed an open label, crossover, non-randomized study of 72 ESRD patients. Our patients were hemodialyzed in two hospitals (HOSP1 and HOSP2). In HOSP1, patients were on 1 mg of FOL and 600 micog of B12 orally for 3 months, and then switching to 1 mg of B12 i.v. for 3 additional months, while the FOL dosage was constant. In HOSP2, patients received the same treatment in reverse. RESULTS: Patients in HOSP1 (n = 37) after i.v. B12 treatment, had significantly lower tHcy (p < 0.001) and FOL (p < 0.05) serum levels, compared with those at the end of oral B12 treatment. On the contrary in HOSP2 patients, serum tHcy levels increased significantly (n = 35, p < 0.0001) when i.v. was switched to oral treatment. There was a significant inverse correlation between tHcy and B12 (p < 0.0001) at the end of the i.v. treatment period; while treatment there was no correlation between tHcy and FOL serum levels. At the end of the oral treatment period, there was no significant correlation between tHcy and B12 serum levels, while tHcy and FOL serum levels had a significant inverse correlation (p = 0.002). CONCLUSIONS: Our results suggest that ESRD patients on dialysis have 'B12 resistance', and that they should have, in addition to their FOL therapeutic regimen, i.v. B12 treatment to reduce their elevated tHcy levels.     

A case of relapsing Guillain-Barré syndrome associated with exacerbation of chronic hepatitis B virus hepatitis

A patient with two episodes of acute polyradiculoneuropathy (Guillain-Barré syndrome) that both occurred during exacerbation of chronic hepatitis B and separated by a 2-year asymptomatic interval is described. The possible causative relation between the neuropathy and the chronic hepatitis B is discussed.