Effect of Extending the Original Eligibility Criteria for the CROSS Neoadjuvant Chemoradiotherapy on Toxicity and Survival in Esophageal Cancer.

BACKGROUND: Patients with curable esophageal cancer (EC) who proceed beyond the original Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) eligibility criteria are also treated with neoadjuvant chemoradiotherapy (nCRT). This study assessed the effect that extending the CROSS eligibility criteria for nCRT has on treatment-related toxicity and overall survival (OS) in EC. METHODS: The study enrolled 161 patients with locally advanced EC (T1N1-3/T2-4aN0-3/M0) treated with the CROSS schedule followed by esophagectomy. Group 1 consisted of 89 patients who met the CROSS criteria, and group 2 consisted of 72 patients who met the extended eligibility criteria, i.e. a tumor length greater than 8 cm (n = 24), more than 10% weight loss (n = 35), more than 2-4 cm extension in the stomach (n = 21), celiac lymph node metastasis (n = 13), and/or age over 75 years (n = 2). The study assessed the differences in nCRT-associated toxicity [National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3] and 90-day postoperative mortality. Moreover, the prognostic value for OS was assessed with multivariate Cox regression analysis. RESULTS: No difference was found in nCRT-associated toxicity (P = 0.117), postoperative complications (P = 0.783), and 90-day mortality (P = 0.492). The OS differed significantly (P = 0.004), with a median of 37.3 months [95% confidence interval (CI), 10.4-64.2 months] for group 1 and 17.2 months (95% CI 13.8-20.7 months) for group 2. Pathologic N stage (P = 0.023), pathologic T stage (P = 0.043), and group 2 (P = 0.008) were independent prognostic factors for OS. CONCLUSIONS: Extension of the CROSS study eligibility criteria for nCRT did not affect nCRT-associated toxicity, postoperative complications, and postoperative mortality, but was prognostic for OS.

Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne.

Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients.

Co-transmission of the non-transmissible South African Babesia bovis S24 vaccine strain during mixed infection with a field isolate.

The South African Babesia bovis live blood vaccine, originating from a field isolate attenuated by 23 serial syringe passages in splenectomized calves, has lost the ability to infect the natural vector Rhipicephalus (Boophilus) microplus. In this study, infection with mixed parasites from the vaccine strain and a field isolate, resulted in transmission of both genotype populations. Comparing the field isolate and transmitted combination indicated no significant difference in their virulence, while challenge of vaccinated cattle with these isolates showed the ability of the vaccine to protect against both. Limiting dilution of the transmitted combination, followed by infection of splenectomized cattle (n=34) yielded no single infections for the vaccine strain genotype, seven clonal lines of the field isolate and one mixture of vaccine strain and field isolate. Only one of two field isolate clonal lines selected for vector transmission study was transmitted. Showing that B. bovis isolates can contain both tick transmissible and non-transmissible subpopulations. The findings of this study also indicate the probability of vaccine co-infection transmission occurring in the field, which may result in new genotype populations of B. bovis. However, the impact of this recombination with field isolates is considered negligible since a genotypically diverse population of B. bovis is already present in South Africa.

Adenomatoid tumors (mesothelioma) of testicular and paratesticular tissue.

Fourteen cases of adenomatoid tumor of the paratesticular tissues are presented. The clinical presentation and histopathologic aspects are discussed. Two hundred and three cases from the English literature are reviewed, and the clinical presentation, natural history, malignant changes, histopathologic aspects, and possible hormonal associations are discussed.

The dog prostate under defined hormonal influences: an approach to experimental induced prostatic growth.

The prostate of castrated dogs following treatment with testosterone, dihydrotestosterone and androstanediol combined with 17-beta-estradiol application was analyzed by light microscopic stereology. In all three groups there is a statistically significant increase of prostatic volume and weight. There is a statistically significant increase of the relative and absolute volume of the glandular as well as of the stromal part. Seen by the absolute data there is only a statistically significant increase of the volumetric amount of the smooth muscle cells in the dihydrotestosterone and 17-beta-estradiol treated animals. Regarding tissue distribution there is no difference between the controls and the castrated testosterone and 17-beta-estradiol treated animals. Regarding the stromal part, there is no statistically significant difference between the testosterone and 17-beta-estradiol treated group and the control animals. TIn the androstanediol and 17-beta-estradiol group there is a double and in the dihydrotestosterone and 17-beta-estradiol group a four-fold increase of the stromal part. The synergistic effect of estrogens and androgens on the growth of both parts of the dog prostate--the glandular and stromal compartment--is discussed.

Relationship of seminal volume to size and disease of the prostate in the beagle.

The seminal volume of young adult Beagles was correlated with the size of and disease in their prostates. The ejaculate volume of naturally collected semen increased in a linear manner with prostatic weight in dogs with normal or glandular hyperplastic prostates. This correlation was not observed in the dogs with cystic hyperplasia, in which there was a reduction in volume of 50% in the semen produced for each gram of prostate. There were no significant differences in other seminal characteristics regardless of prostatic size of disease.

Resistance of Nguni, Bonsmara and Hereford cattle to ticks in a Bushveld region of South Africa.

Counts of engorged female ticks on naturally infested cattle over a 2 year period, showed that indigenous Nguni cattle harboured significantly fewer Amblyomma hebraeum, Boophilus decoloratus and Hyalomma spp. during periods of peak abundance than either Bonsmara or Hereford cattle. Fewer abscesses, associated with tick bite, were also present in the Nguni cattle. Individual tick resistance indices, determined after artificial tick infestation in the field, could not be correlated with hair length, skin thickness or conglutinin titres. The consistently large percentage of Nguni cattle showing high tick resistance according to index determinations, indicates a superior level of natural immunity in this breed. The relative incidence of individuals in high, medium and low resistance classes reflected an increase in resistance with exposure to ticks and the potential for the selection for tick resistance within all 3 breeds.

Prostate carcinoma--the value of T stage and grade in predicting metastases and prognosis. A cost-effective approach to clinical staging.

In order to evaluate the initial T stage and tumour grade as predictors of metastatic disease and prognosis in adenocarcinoma of the prostate, 963 patients were reviewed. Of the patients, 41% presented with metastatic disease. Stage T4 tumours were associated with a consistently poor prognosis, and 70% of such patients had demonstrable distant metastases. No patient with TOf local disease had metastases or died of prostate cancer during follow-up. The incidence of metastases was also low in stages T1 and T2. High tumour grade correlated strongly with more advanced disease. Using this information a more cost-effective approach to the staging of prostate carcinoma is proposed.

Rectal examination in the detection of prostatic cancer.

Since the aetiology of prostatic cancer is unknown, and therapy for metastatic disease non-curative, a decrease in the mortality rate from this condition can only be achieved by early diagnosis and effective treatment of the primary tumour. For diagnosis of localised cancer no practical alternative exists to rectal palpation. Of 629 cases of prostatic cancer seen at Tygerberg Hospital, the disease had metastasised in 29% of white and 58% of coloured patients at initial diagnosis. Prostatism or urinary retention was the presenting complaint in 74.7% of patients. The letters of referral of 97 patients were examined to determine whether prostatic cancer had been diagnosed by the primary care physician before referral. Rectal examination by the referring physician was recorded or implied in 64.9% of patients, and in those patients who underwent rectal examination before referral prostatic cancer was diagnosed in 54%. These findings imply that the opportunity for early diagnosis of prostatic cancer may be missed in many patients in whom rectal examination by the primary physician is indicated.

The glycosaminoglycans of human bladder cancers of varying grade and stage.

The glycosaminoglycans of four normal human bladders and fourteen bladder cancers were characterized and quantitated (after proteolytic extraction) by specific enzyme digestion, cellulose acetate electrophoresis and densitometry. Hyaluronic acid, heparan sulfate, dermatan sulfate and chondroitin sulfate were identified in both normal and cancerous bladders. Hyaluronic acid and dermatan sulfate were the major glycosaminoglycans of the normal epithelium/submucosa while heparan sulfate and dermatan sulfate were predominant in normal bladder muscle. Bladder cancer glycosaminoglycan content was influenced by the stage and grade of the neoplasm. Hyaluronic acid and dermatan sulfate tended to decrease and chondroitin sulfate to increase in infiltrating cancers, whereas a decrease in the percentage of heparan sulfate correlated closely with higher grade tumors. The bladder cancer glycosaminoglycan profile may be indicative of the tumor's invasive potential.

The glycosaminoglycans of normal and hyperplastic prostate.

A study has been made of the glycosaminoglycans (GAG) of the fetus, normal adult, and benign hyperplastic prostate. In the adult normal prostate dermatan sulphate (DS) is the predominant GAG. The central zone has a slightly higher chondroitin sulphate (Ch AC) content than the peripheral zone. Fetal prostates (22-27 weeks gestation) contain no heparan sulphate (HS). Benign prostatic hyperplasia (BPH) has an increased content of Ch AC. On separation of BPH stroma and epithelium, the epithelial fraction contains only Ch AC and DS. HS and hyaluronic acid (HA) are confined to the prostatic stroma.

Fluctuations in prostatic glycosaminoglycans during fetal and pubertal growth.

Mesenchymal glycosaminoglycans have been shown to fluctuate during the development of various organs. Prostatic development is an interesting example of organogenesis as it is only at puberty, under androgen influence, that differentiation is completed. We have extracted and quantitated the glycosaminoglycans of human prostates obtained from fetuses, prepubertal, and adult males to determine the changes that occur during prostatic differentiation. The total glycosaminoglycan content per prostate followed the wet weight growth curve. The percentages of heparan sulfate and heparan sulfate sulfation seemed to correlate with prostatic epithelial differentiation. After 25 years of age prostatic glycosaminoglycan concentrations tend toward the glycosaminoglycan ratios typical of benign prostatic hyperplasia.

The gubernaculum during testicular descent in the pig fetus.

The role of the gubernaculum during testicular descent was investigated in a study of 119 male pig fetuses obtained at gestational ages ranging from 53 to 116 days. Histologically the gubernaculum was shown to consist of primitive mesenchymal cells with an abundant intercellular material containing glycosaminoglycans (mucopolysaccharides). Rapid descent of the testis through the inguinal canal occurred between 77 and 88 days' gestation, while sustained but slower descent occurred up to 109 days. There was a dramatic increase in the total wet mass of the gubernaculum at the commencement of rapid testicular descent from 77 to 81 days, and a further increase in wet mass during sustained descent from 91 to 95 days. In the period just prior to rapid testicular descent (day 74-81) the percentage increase in the water content of the gubernaculum was larger than the percentage increase in the dry mass. After descent of the testis (day 95-109) there was a decrease in the water content, but also an increase in the dry mass of the gubernaculum. No comparable increase in the water content of umbilical cord or striated muscle tissue occurred during the period of testicular descent. Thus, the marked swelling of the gubernaculum, which dilates the inguinal canal and scrotum and may possibly exert traction on the testis by the force of its expansion, is due largely to an accumulation of water by the gubernaculum. This process may be mediated by the intercellular glycosaminoglycans, since these poly-anionic macromolecules are known to have a large hydrodynamic volume and can act as a "water trap."

Anterior sacral meningoceles.

Three cases of the extremely rare lesion, anterior sacral meningocele, are reported. Its mode of presentation, pathology and possible methods of treatment are reviewed.

Giant haemangiomas of the scalp. A report of 2 cases.

Two cases of giant scalp haemangiomas are presented. In both patients a coagulation defect similar to that described by Kassabach and Merrit resulted, although not as severe. The possible mechanisms involved are discussed and a regimen for treatment is suggested.

Crystalluria and urolithiasis in a relatively stone-free population.

The occurrence of renal stone in South African blacks is extremely rare. Whites however are prone to calculi to the same extent as that reported in other Western communities. The nature of the particulate material and crystalluria in urine samples from the two population groups were investigated using a Coulter Counter and scanning electron microscope. In addition, 10 calculi obtained from black patients over a 5 year period were analysed. The particle size distribution curves obtained for normal black and white males were identical. The curves for normal black and white females were also identical but different from those for males. Black male stone formers had larger particles than their controls while the single black female stone former investigated had particles of the same size as female controls, but in greater numbers. Scanning electron microscopy revealed profuse amounts of crystalline NaCl, KCl and other salts in the urinary sediments of blacks. These were not observed in the specimens from whites nor in the black stone formers' urines. Analysis of the calculi identified chemical and ultrastructural features similar to those observed in stones from whites. The hypothesis that the lower incidence of stone disease in blacks may be due to a high Na/Ca ratio is supported by our findings. It is suggested that various salts play a role in lowering the stone forming potential of such urines by a competitive substitution mechanism in which lattice calcium is displaced by sodium. It is also suggested that when urinary stone formation does occur in blacks, it does so via the same physicochemical mechanisms as in any other race group.

Stromal and epithelial growth of the prostate during puberty.

In 30 male Chacma baboons, prepubertal, pubertal, and adult animals have been identified by their testicular and prostatic weights. The volume of the stromal and epithelial components of caudal prostate were calculated from morphometric determination of the percentage volume of each component and the total caudal prostate volume. Both stromal and epithelial volumes increased at puberty and plateaued at maturity. These increases could be fitted to logistic curves that support the conclusion that stromal pubertal growth precedes epithelial pubertal growth. The stromal contribution to prostates of increasing size followed a model distinct to that of the epithelial contribution, thus suggesting that the factors (e.g., androgens) controlling stromal and epithelial growth are not identical. Stromal growth may be a prerequisite for pubertal epithelial development of the prostate.

DNATYPE--a personal computer program for HLA-DR typing based upon restriction fragment length polymorphisms.

The use of specific cDNA probes and selected combinations of restriction endonucleases makes it possible to characterize specific antigens by the molecular weights of the hybridized restriction enzyme digests of DNA. We have developed a simple program suitable for personal computers which utilizes such results to deduce HLA-DR phenotypes of any nucleated cell from which DNA may be extracted.

The glycosaminoglycans of the gubernaculum during testicular descent in the fetus.

Tissues were obtained from 387 male pig fetuses ranging from 60 to 120 days of gestation. The relative wet mass and water content of the gubernaculum increased during and decreased after the period of testicular descent. The extracellular glycosaminoglycans (GAG) were assayed to determine whether these polyanionic macromolecules are responsible for the increased water content of the gubernaculum. The total GAG/wet tissue mass in the gubernaculum decreased during and increased after descent, while the total GAG/dry mass decreased during and after descent, indicating an accumulation of water during descent, with a loss of water and an increase in less hydrated tissue components after descent. The major GAG fraction in the gubernaculum was dermatan sulfate, but the percentage hyaluronate in the gubernaculum was two times higher than in striated muscle or umbilical cord, indicating that this GAG fraction may be responsible for the increased water content of the gubernaculum, which probably serves to dilate the inguinal canal and scrotum, thus facilitating descent.

Stab wounds associated with hematuria--a review of 67 cases.

The clinical records of 67 patients who underwent surgical exploration for stab wounds associated with hematuria were reviewed in an attempt to evaluate the need for mandatory operation and to define criteria for possible nonoperative of such cases. Minor renal injuries without associated intra-abdominal lacerations were found in 61 per cent of the patients. Delayed renal hemorrhage occurred in 15 per cent of the patients despite early exploration, suture and drainage of the kidney, and antibiotic prophylaxis. Of 7 nephrectomies 5 were performed for secondary hemorrhage. Postoperative pulmonary complications arose in 28 per cent of the patients. A policy of mandatory operation on all patients with stab wounds and hematuria led to apparently needless surgery in 61 per cent of the patients in this series. Retrospective analysis revealed that the rate of probably unnecessary operations could have been reduced to 24 per cent by selecting for operation only those patients with signs of severe hemorrhage, associated intra-abdominal injury or major extravasation of contrast material on excretory urography.