Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Expression of Fas protein (CD95) and Fas ligand in liver tissue of patients with HCV-induced chronic liver disease and its correlation with the disease progression.

This study evaluated hepatic expression of both Fas and Fas ligand (FasL) in patients with hepatitis c virus (HCV)-induced chronic liver disease and its correlation with the histopathological activity and laboratory parameters as an early predictor of advancement of the disease. The selected patients were (39) males and (21) females, their ages ranged from (20-67years) with a mean of 43.5 +/- 4.5 years, as well as (10) subjects (normal individuals) serving as a control group. They were (7) males and (3) females, their age ranged from (26-53 years) with a mean of 39.5 +/- 7.3 years. Patients were grouped as (1) Chronic hepatitis (CH) group including (30) patients with chronic viral hepatitis C. (2) Liver cirrhosis (LC) group including (30) patients with post hepatitis C cirrhosis. Liver biopsy was done for all subjects using an automated 18-gauge true cut needle. Sections were stained with Haematoxylin and Eosin for histopathological diagnosis and with Maisson and Trichrome for assessment of fibrosis. Unstained paraffin sections from each case were subjected for immuno-histochemical procedures using indirect immunoflourescence technique for detection of apoptotic hepatic and lymphocytic cells using monoclonal antibodies. Semiquantitative analysis of the pattern and distribution of the Fas antigen and Fas Ligand as indicators for hepatic apoptosis was studied and assessed.

Role of natural killer cell subsets in cardiac allograft rejection.

To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4(+) T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8(+) T cells and NK1.1(+) cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2(+) NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function.

Pet ownership: its effect on allergy and respiratory symptoms.

BACKGROUND: Studies have shown that pets are very important sensitizing agents in patients with asthma. Respiratory disorders such as asthma and allergic rhinitis are common in the State of Qatar. OBJECTIVE: The aim of the present study was to determine whether exposure to pets and domestic animals plays a significant role in the development of asthma and allergic rhinitis among Qatari population. DESIGN: A hospital-based prospective descriptive study conducted. SETTING: Allergy Laboratory at the Hamad General Hospital and Hamad Medical Corporation, State of Qatar. PATIENTS: Adult patients over 12 years of age diagnosed with bronchial asthma and/or allergic rhintis who were referred for allergy skin prick test. 1106 adult patients recruited with respiratory diseases of suspected allergic origin who attended Allergy Clinic at the Hamad General Hospital, during three years from January 2001 to April 2003. Total of 1106 whom 607 were females (54.9 %) and 499 were males (45.1%) and their mean was age 30 years (12-48). METHODS: Skin Prick Test (SPT) was performed on 1106 patients for common allergens whom the blood sample was taken for measuring total IgE concentration. RESULTS: There were 1106 patients studied and 496 patients (44.9%) had positive and 610 (55.1%) had negative skin prick tests. Out of 1106 patients, 311 patients (28.1%) had asthma; 503 patients had allergic rhinitis (45.5%) and 87 patients (7.8%) had skin allerg. Three hundred and forty (340/1106=30.7%) of the 1006 subjects studied had at least one animal at home, and the remaining 69.3% had never had pets in the home. A further 12% reported having had pets in the past, but not anymore. Cats (26.7%), goats (15%) and birds (14.7%), animals were the most common present within the house and was the most frequently seen pet types when compared to other pet types. The risk of having asthma (RR: 1.29; 95% CI: 1.07-1.55; p=0.008), allergic rhinitis (RR: 1.48; 95% CI: 1.24-1.77; p<0.0001) and eczema (RR: 3.56; 95% CI:1.24-1.77; p<0.0001) was significantly higher in subjects with animals than in patients without. CONCLUSION: In the present study, the prevalence of asthma, rhinitis, and skin allergy was significantly more common in families with animals than in those without.

Comparison of PCR method with the culture method for identification of gonococci from endocervical swabs.

Gonococcal infection remains still a major cause of morbidity among sexually active individuals. Diagnosis of the infection in a female case is more difficult than that in a male. This was a prospective study among 269 female commercial sex workers (CSWs) to screen them for gonococcal infection, comparing the rapid method of identification of gonococci by polymerase chain reaction (PCR) with the selective culture method. A total of 92 (34.2%) CSWs were identified positive for Neisseria gonorrhoeae by combination of the two methods. The PCR method identified 87 of the specimens to harbour cppB gene of N. gonorrhoeae, whereas culture method identified 83 specimens showing colonies of gonococci. Taking into consideration of the total positive cases (92), the PCR method showed a sensitivity of 94.57%, whereas sensitivity of culture method was 90.22%. The selective culture method appears to be the most applicable in the identification of gonococci from clinical specimens, particularly in the less resourceful countries like Bangladesh.

Primary drug resistance pattern of mycobacterium tuberculosis in Dhaka, Bangladesh.

One thousand two hundred and eighty one clinically suspected untreated patients with pulmonary tuberculosis were studied from an urban tuberculosis clinic in Dhaka. Majority of the 1281 patients (77.6%) were from the age group of 14 to 44 years. Sputum, 106 (8.3%) were found positive for mycobacteria (both by Ziehl-Neelsen smear staining and culture to consider those as confirmed cases of mycobacterial infection. Out of these 106 cases, 101 (95.3%) were identified as M. tuberculosis and the rest 5 (4.7%) as Non-tuberculous Mycobacteria (NTM). Among the 101 M. tuberculosis strains, 30 (29.7%) were resistant to at least one drug; 16 (15.8%); to isoniazid, 11 (10.9%) to rifampicin, 07 (6.9%) to streptomycin, 03 (2.9%) to ethambutol and 04 (3.9%) to pyrazinamide. Multi-drug resistant tuberculosis (MDR-TB) was found in 5 (4.95%) cases. 5 (4.95%) cases were resistant to two drugs and 3 (2.97%) cases to three drugs. Ciprofloxacin was tested against 30 strains of M. tuberculosis; 2 (6.67%) of which were resistant. This is the first report of ciprofloxacin resistant Mycobacterium tuberculosis from Bangladesh. All the 5 strains of NTM tested for said 5 anti-tuberculous drugs, were found resistant to more than one.

Sero-epidemiological study of hepatitis B virus infection in a village.

A cross-sectional study was conducted in a randomly selected village of Rangpur district from June '94 to May '95. Serum from 1000 human subjects irrespective of age and sex were screened for hepatitis B surface antigen (HBsAg). Among the respondents 661 were male and 339 female. The overall seroprevalence of HBsAg was 6.4%. It was 6.66% in male and 5.89% in female. Age, sex, religion, income, occupation, education and marital status did not show any relationship with HBsAg status. Among 64 sero-positive cases, 16 (25%) had no history of exposure to known risk factors and 48 (75%) had one or more exposure to known risk factors (p < 0.05). This study did not depict the national scenario. Well designed studies with more sensitive serological methods are recommended to get the epidemiological information of hepatitis B virus (HBV) infection in our community.

Hepatitis B virus markers among the prostitutes of Dhaka.

The objective of this study was to estimate the prevalence of hepatitis B virus (HBV) carrier states among prostitutes in Dhaka. Enzyme linked immunosorbent assay (ELISA) was used to detect HBV markers in a group of 164 prostitutes. Serological evidence of current or past HBV infection was present in 129(78.7%) prostitutes. HBsAg was detected in 16(9.7%) of whom 7(43.7%) were positive for e-antigen and e-antibody was present in another 7 (43.7%). Anti-HBs was detected in 94 (57.3%) of the specimens while anti-HBc in 108(73%) of HBsAg negative sera. Prevalence of HBV markers was 87% and 52.6% in VDRL reactive and non reactive sera respectively. The study indicates that the prevalence of HBV infection is high among the prostitutes in Dhaka city. Infection with Treponema pallidum is associated with increased risk of infection with HBV.

An anti-murine CD3 monoclonal antibody with a low affinity for Fc gamma receptors suppresses transplantation responses while minimizing acute toxicity and immunogenicity.

145-2C11, a hamster mAb directed against the mouse CD3 complex, is a potent immunosuppressive agent. Upon initial treatment, 145-2C11 triggers a systemic release of multiple cytokines that is responsible for the acute toxicity of the mAb. This cellular activation is a consequence of the cross-linking between T lymphocytes and Fc gamma R-bearing cells, mediated by the high affinity of the hamster mAb for murine Fc gamma Rs. Repeated mAb injections result in the onset of a neutralizing humoral response. Therefore, there has been an increased interest in developing nonmitogenic forms of anti-CD3 mAbs, although it is not clear whether these Abs will retain immunosuppressive properties. To determine whether the initial cytokine production is necessary for the immunosuppressive properties and the immunogenicity of anti-CD3 mAbs in vivo, we have generated chimeric (hamster 145-2C11 F(ab')2 region/mouse Fc gamma portion) mAbs using murine isotypes with different affinities for Fc gamma Rs. The 145-2C11 and a chimeric IgG2a isotype, both of which bind murine Fc gamma Rs avidly, had similar activating, immunogenic, and immunosuppressive properties in mice. The administration of a chimeric IgG3 isotype with a very low affinity for murine Fc gamma Rs did not result in cytokine production, a humoral response against the mAb, or TCR desensitization. Nevertheless, prolongation of skin graft survival was similar in the IgG3, IgG2a, and 145-2C11-treated mice, indicating that Fc gamma R nonbinding anti-CD3 mAbs retain potent immunosuppressive properties in vivo while not being immunogenic. This enhanced therapeutic to toxic profile may be beneficial in clinical transplantation.

Development and evaluation of co-agglutination test to detect rotavirus antigens in stools of patients with diarrhoea.

Rotavirus is the most common cause of acute diarrhoea in infants and children in both the developed and developing countries including Bangladesh. Information about rotavirus diarrhoea in Bangladesh is insufficient primarily due to the lack of diagnostic facilities due to the high cost of reagents and equipment and lack of skilled personnel. A simple, suitable and less costly technique of co-agglutination test using protein-A secreting staphylococci was developed and evaluated against a commercially available ELISA kit to detect rotavirus antigen in stools of patients with diarrhoea. Staphylococcus cowan strain 1 was grown and coated with rabbit antisera raised against RV5 and SA11 rotavirus strains. The antibody-coated staphylococci were agglutinated specifically by rotavirus present in faecal samples within one or two minutes. A total of 1332 stool specimens were tested by co-agglutination and ELISA, of which 210 (15.77%) were positive by ELISA and 276 (20.72%) by co-agglutination test. Compared to ELISA, sensitivity of co-agglutination test was 76.19%, specificity 89.66% and predictive values of a positive and a negative test were 57.97% and 95.26% respectively. The results indicate that the co-agglutination test is a simple and suitable technique for rapid screening of rotavirus infection which could be adopted in clinical practice.

Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse.

Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies demonstrate that costimulatory signals play an important role in the autoimmune process, and that different members of the B7 family have distinct regulatory functions during the development of autoimmune diabetes.

A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo.

OKT3, a mouse anti-human CD3 mAb, is a potent immunosuppressive agent used in clinical transplantation to prevent or treat allograft rejection. Associated with this therapy is the systemic release of several cytokines that result in a series of adverse side effects. This release of cytokines is dependent on the cross-linking mediated by OKT3 between T cells and the Fc gamma R-bearing cells. To generate an anti-human CD3 mAb with reduced activating properties as compared with OKT3, we have transferred the complementary determining regions of OKT3 onto human IgG frameworks and then performed point mutations that reduce the affinity of the "humanized" anti-CD3 mAbs for Fc gamma Rs. Initial, in vitro, studies showed that whereas OKT3 and the parental humanized anti-CD3 mAbs activated T cells similarly, a humanized Fc variant failed to do so. Both the Fc variant and the activating anti-CD3 mAbs induced comparable modulation of the TCR and suppression of cytolytic T cell activity, in vitro. In the current study, we exploited an experimental model in which human splenocytes from cadaveric organ donors were inoculated into severe combined immunodeficient mice (hu-SPL-SCID mice) to test the activating and immunosuppressive properties of these anti-human CD3 mAbs in vivo. Unlike injection of OKT3 or of the parental humanized mAb, administration of the Fc variant did not result in T cell activation in vivo, as evidenced by the lack of induction of surface markers of activation, and of systemic human cytokines, including IL-2. Importantly, similar prolongation of human allograft survival was achieved with all anti-CD3 mAbs, indicating that the nonactivating anti-CD3 mAbs retained significant immunosuppressive properties in vivo. Thus, the use of an Fc variant in clinical transplantation should result in fewer side effects than observed with OKT3, while maintaining its clinical efficacy.

Prevention of the humoral response induced by an anti-CD3 monoclonal antibody by deoxyspergualin in a murine model.

Multiple treatments with the potent immunosuppressant murine antihuman CD3 mAb OKT3 is sometimes precluded by the onset of a neutralizing humoral response mostly consisting of anti-idiotypic antibodies. A hamster antimurine CD3 monoclonal Ab, 145-2C11, shares many properties with OKT3, in particular the ability to induce a strong Ab response in mice. Deoxyspergulain (DSG), a metabolite of the antibiotic spergualin, has been shown to reduce Ab production triggered by pathogens in a variety of infectious models and against common antigens. In this study, we examined the ability of DSG to inhibit the humoral response induced by 145-2C11. DSG prevented the Ab production triggered by the anti-CD3 mAb in an Ag-specific manner and significantly reduced the Ab production in mice previously primed with 145-2C11. We showed that DSG had a long-term effect on B cells and a transient effect on T cells. In effect, DSG was found to induce a prolonged Ag-specific unresponsiveness of B lymphocytes, and to transiently reduce the capacity of T lymphocytes to deliver help to B cells, in part by reducing IL-4 production. DSG did not reduce the immunosuppressive properties of the anti-CD3 mAb. In fact, the combination of DSG with 145-2C11 prolonged the survival of allogeneic skin grafts when compared with the administration of 145-2C11 or DSG alone. Thus, the coadministration of DSG with OKT3 may be of clinical interest to reduce the humoral response triggered by the mAb.

Prevalence of hepatitis B surface antigen (HBsAg) among prostitutes at Dhaka.

One hundred prostitutes were studied with an aim to acquire more insight on the role of sexual transmission of HBsAg and to detect carrier state among them. All subjects were interviewed and their serum samples were tested for HBsAg by reverse passive haemagglutination method (RPHA). Eleven (11%) of the prostitutes were found to be positive for HBsAg. Their mean age was 19.3 +/- 4.9 years. The mean duration in the profession was 2.5 +/- 1.6 years. Mean number of clients for each woman per 24 hours was 10.7 +/- 1.2. Most of the prostitutes (84%) were lacking knowledge about spread and contact of the disease.

Forensic toxicology of some orphenadrine-related deaths.

Toxicological data for orphenadrine in ten cases of fatal poisoning are presented together with results for a further eight cases in which orphenadrine was present in combination with alcohol or another drug. Collapse and convulsions occur within an hour of ingestion of an overdose and death supervenes soon after. Autopsy blood concentrations of orphenadrine in such acute fatal poisonings range from 5.5-37 mug/ml. The unchanged drug was found in the bile and urine and the concentrations in the liver, lung and kidney, though differing between cases, were of the same order in any one case.

The relationship of transepidermal water loss to skin temperature in psoriasis and eczema.

Transepidermal water losses (TEWL) from psoriatic and eczematous skin were measured while skin temperature was varied between 29 degrees C and 37 degrees C. The relationship of TEWL to skin temperature in these diseases is different from that obtaining in normal skin. These differences are thought to be due to the altered filtration properties of diseased stratum corneum. Formulae were devised to allow TEWL rates in psoriasis and eczema to be expressed at a standard temperature for comparative purposes.

An evaluation of Na+, C1- and pH ion-specific electrodes in the study of the electrolyte contents of epidermal transudate and sweat.

Ion-specific electrode detectors have been used to measure electrolytes in various biological fluids, including sweat. As part of a study of skin barrier function, we have used such electrodes to detect the presence of sodium, chloride and hydrogen (pH) in the transepidermal water loss. This paper describes the effects of cellophane tape stripping (of human forearm epidermis in vivo) on surface electrolyte concentrations, in parallel with observations on transepidermal water loss and galvanic skin resistance.