Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics

This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0?C4 prior chemotherapy regimens. All received cyclophosphamide 50?mg daily, methotrexate 2.5?mg?days 1?C2?weekly, and vandetanib daily in 3 dose-escalation cohorts: 100?mg (C1), 200?mg (C2), and 300?mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22?% ended therapy for toxicity. Of the 20 response-evaluable patients, 10?% demonstrated partial response and 15?% stable disease ??24?weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200?mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.     

Preperitoneal bilateral inguinal herniorrhaphy

Background: Simultaneous repair of bilateral inguinal hernia remains controversial. Methods: Seventy-two consecutive patients underwent a preperitoneal prosthetic repair of bilateral groin hernia; 25 via laparoscopy. ASA classification, Nyhus type, hospitalization, convalescence time, and cost were examined. Mean follow-up was 36 and 12 months for the conventional and laparoscopic group respectively. Results: Sixty-nine patients were available for long-term follow-up. Average hospital stay, recurrence rate, perioperative urinary retention, transient thigh neuralgia, and return to normal activities were 48 hours, 5%, 9%, 6%, and 22 days as compared to 4 hours, 6%, 20%, 12%, and 9 days for the conventional and laparoscopic group respectively. The cost for laparoscopic repair was $500 greater. Conclusions: The preperitoneal approach to repair of bilateral hernias demonstrates an acceptable recurrence rate with low long-term morbidity. Experience with conventional preperitoneal technique greatly facilitates transition to laparoscopic repair.Presented at the annual meeting of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES), Orlando, Florida, USA, 11–14 March 1995     

Surface-modified nanocrystalline ceramics for drug delivery applications

Drug delivery systems comprised of various types of carriers have long been the object of pharmacological investigation. The search has been stimulated by the belief that carriers will lead to reduced drug toxicity, dosage requirements, enhanced cellular targeting and improved shelf-life. Among the carriers investigated are complex polymeric carbohydrates, synthetic proteins and liposomal structures. For the past four years, we have been experimenting with a radically new class of carriers comprised of surface-modified nanocrystalline ceramics. While the ceramics provide the structural stability of a largely immutable solid, the surface modification creates a glassy molecular stabilization film to which pharmacological agents may be bound non-covalently from an aqueous phase with minimal structural denaturation. As a consequence of maintained structural integrity and owing to concentration effects afforded by the surfaces of the nanocrystalline materials, drug activity following surface immobilization is preserved. We have used successfully surface-modified nanocrystalline ceramics to deliver viral antigens for the purpose of evoking an immune response, oxygenated haemoglobin for cell respiration and insulin for carbohydrate metabolism. The theoretical principles, technical details and experimental results are reviewed. Surface-modified nanocrystalline materials offer an exciting new approach to the well-recognized challenges of drug delivery. Biomaterials (1994) 15, 1201–1207     

非溶蚀型药物体系的释放动力学新模型──Fick第一扩散定律的修正及其应用

基于以下两点事实:Fick第一扩散定律中的扩散系数并非严格的常数,它随浓度变化;Fick第一扩散定律只适用于浓度梯度恒定的稳定扩散,而许多实验表明浓度梯度也是一个时间函数,本文对Fick第一扩散定律作出两点修正将原定律中浓度梯度和扩散系数分别修正为时间函数和浓度函数,从而导出关于非溶蚀型药物体系的释放动力学模型。该模型较其他常用释放模型有更好的拟合效果,其参数也有较为明确的物理意义。     

Macrophage apolipoprotein synthesis and endoneurial distribution as a response to segmental demyelination

The synthesis and endoneurial distribution of apolipoproteins in response to myelin degradation was elucidated morphologically and biochemically in rodent models of segmental demyelination. At the onset of acute demyelination induced by tellurium (Te) poisoning, macrophages infiltrated the endoneurium and then began to express cytoplasmic immunoreactivity for apolipoprotein E (apo E). When demyelinating nerve slices were incubated with S35-methionine, radiolabeled apo E was released, showing that apo E was actively synthesized by the macrophages. Macrophages secreted apo E into the endoneurial spaces, leading to dense endoneurial accumulations. Other apolipoproteins (apo A1 and albumin) were not synthesized in the endoneurium, but they entered edematous nerves, presumably through an early breakdown in the blood-nerve barrier. During the phagocytosis of myelin, plasma-derived apolipoproteins accumulated within some of the macrophages. In chronic demyelination caused by lead poisoning, the cellular and extracellular distribution of apolipoproteins was similar to Te neuropathy; the amount of apo E accumulation and the macrophage density were proportional to the prevalence of active demyelination in teased fibers. Similar patterns of endoneurial apo E were present in an inherited form of demyelination in the twitcher mouse, after antibody-mediated demyelination, and in demyelination secondary to axonal degeneration. Human sural nerve biopsies had patterns of apolipoprotein E antigenicity that were comparable to the rodent models. We conclude that secretion of apo E by infiltrating macrophages is a generalized response to demyelination, and that endoneurial edema leads to the accumulation of certain plasma apolipoproteins within macrophages. These data suggest that endoneurial apolipoproteins and macrophages might mediate important functions in patients recovering from primary and secondary demyelination.     

Mucociliary transference rate and mucus viscoelasticity dependence on dynamic storage and loss modulus.

Various samples of estrous bovine cervical mucus were collected, and their dynamic viscoelastic properties were determined at between 2.7 and 4.4 rad/s. Comparing the loss modulus with the rigidity (storage) modulus for the samples taken, the former was found to increase markedly as the latter increased. Limited exposure of mucus to increased temperatures removed crosslinks, whereas treatment with glutaraldehyde introduced additional ones. In the case of one sample, the number of crosslinks was altered in this way. As the number of crosslinks decreased or increased, the storage modulus decreased or increased, but the loss modulus remained relatively unaffected. The transference (ability to move particle loads) of native and modified samples on the ciliated epithelium of a frog palate depleted of mucus was determined. All data for transference rate correlated against changes in the storage modulus. The rate was maximal for a storage modulus of 1.6 dynes.cm-2 and decreased rather sharply to either side of this value. No such correlation could be found against the loss modulus. In fact, whereas very different values of the loss modulus corresponded to the same storage modulus, the transference rate was the same. Hence, the storage rather than the loss modulus determines transference rate.     

Time-course of local recurrence following conservative surgery and radiotherapy for early stage breast cancer

The time-course of local failure following conservative surgery and radiotherapy (S+RT) for early breast cancer is not well established. We therefore examined the time-course and patterns of breast recurrence as a first site of treatment failure in a group of 607 AJCC clinical Stage I or II invasive breast carcinomas treated from 1968-81. Sixty-seven patients had a breast failure (11%), corresponding to 5- and 10-year actuarial rates of 10% and 16%. The hazard rate (i.e., the risk per unit time of a failure) for any breast failure increased over the first 2 years, was fairly constant at about 2.5%/year over the period from 2 to 6 years after treatment, and then decreased to about 1%/year at 8 years. The majority of failures were at or near the primary tumor site (33 true recurrences (TR) and 15 marginal misses (MM). In addition there were 12 failures at sites at least several cm from the boosted volume (E), 6 recurrences in the skin without a parenchymal mass (S), and 1 patient with an unclassifiable failure. Recurrences at or near the primary site (TR/MM) occurred earlier (median 38.5 mo, range 12-87 mo) than recurrences at distant sites in the breast (E) (median 64.5 mo, range 26-90). The hazard rate for TR/MM increased over the first 2-1/2 years to reach approximately 2%/year, remained at that level till about 5 years after treatment, and then decreased to about 0.5%/year at 8 years following RT. By contrast, the hazard rate for E increased slowly with time to approximately 1%/year at 5 years, with little change in the rate after that time. We conclude that the time-course of the development of local recurrence after S+RT is protracted. The majority of failures appear at or near the primary tumor site; these are seen mainly in the first 7 years following RT. Recurrences at distant sites in the breast have an even more protracted time-course. Such recurrences are rare in the first 4 years following RT. Our results emphasize the need to obtain long follow-up in these patients, both to detect these recurrences promptly and to properly evaluate the results of S+RT.     

Radiology of knee joint replacement.

As total knee replacement becomes more successful due to advances in surgery and bioengineering, a greater number of patients will be offered this procedure as a viable alternative to arthrodesis. Radiologic consultation will be sought for evaluation of proper alignment as well as postoperative complications such as loosening, instability, dislocation, limitation of range of motion, fracture, and infection. This evaluation may be accomplished by plain films and arthrography. Radiographic aspects of these features are discussed and illustrated.     

Prospective trial of the six hour rule in stab wounds of the chest

Stab wounds of the chest may be associated with a spectrum of injuries ranging from the lethal to the insignificant. The management of asymptomatic patients with stab wounds of the chest is controversial. The results of previous reports have asserted that asymptomatic patients with stab wounds of the chest do not have delayed complications develop if roentgenograms of the chest taken six hours after the injury are normal. This "rule" has not been validated. A three year, prospective study of patients with stab wounds of the chest was done. Patients were excluded from the study if they had symptoms on arrival, evidence of physiologic derangement caused by intrathoracic injury, wounds near the subclavian vessels or precordial wounds. Patients with lower thoracic stab wounds were evaluated by diagnostic peritoneal lavage. If findings from lavage were negative, the patients were included in the study. One hundred and five patients met the criteria for inclusion in the study group. All of the patients were hospitalized and examined serially. All had roentgenograms of the chest performed at admission, at six hours and at 24 hours. Four patients had a pneumothorax or hemothorax develop between the time of admission and six hours of hospitalization. In the remaining 101 patients, none had a pneumothorax or hemothorax between six and 24 hours. No patient asymptomatic on admission had a tension pneumothorax develop later. No patient had delayed evidence of abdominal injury. An asymptomatic patient with a stab wound of the chest that is not precordial, not in proximity to the subclavian artery and not suspected of diaphragmatic penetration should be serially examined and have a follow-up roentgenogram of the chest at six hours. If the patient remains asymptomatic and the six hour film is normal, delayed complications are rarely, if ever, encountered and the patient does not require further studies or hospitalization. The six hour rule for stab wounds of the chest is valid.