Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. @*Results@#CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.

Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. @*Results@#CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.

Epidemiological study of dementia after retirement

To determine prevalence of dementia and its subtypes among governmental retired employee [above 60 years old] attending Zagazig health insurance out patient clinic, Sharkia governorate, Egypt. A three phase study was carried out to screen 1800 subjects aged 60 years and above. During phase I all subjects were administrated standardized Mini-Mental state Examination [SMMSE]. In phase II, all screened positive subjects were subjected to: complete history taking, clinical examination, Neuropsychiatric scales [Blessed Dementia scale, Clinical Dementia Rating scale and geriatric depression scale]. We diagnosed dementia only in 66 subjects [depending on DSM IV diagnostic criteria] yielding a crude prevalence rate of dementia of 3.66%. From the remaining screened negative subjects we selected 30 age and sex matched controls. To complete and further diagnose dementia subtypes, patients were subjected to some laboratory tests, EEG and brain Imaging [phase III]. Prevalence rates for specific dementia subtypes were 1.4% for Alzheimer's disease [AD], 1.05% for vascular dementia [VaD], 0.5% for mixed dementia [MD], other dementias represented 0.44% and undetermined cases 0.22%. Age specific prevalence ratios for dementia increased steeply with increasing age. There was no gender difference in the prevalence rates of dementia or its subtype. This study proved that professional and administration occupations and higher levels of education had inverse relation with dementia prevalence. Some risk factors such as DM, hypertension and hypercholesterolemia were significantly more frequent in our patients than in controls, while positive family history of dementia was significantly higher among AD patients. Comparison with previous studies suggests that dementia is as frequent in Sharkia, Egypt as elsewhere

Micronized progesterone: a beneficial new modality of treatment for Egyptian patients with hyperemesis gravidarum

Hyperemesis gravidarum [HG] is a condition of intractable vomiting during pregnancy, leading to fluid, electrolyte and acid-base imbalance, nutrition deficiency and weight loss often severe enough to require hospital admission. Theories on how pregnancy hormones could cause HG assert that patients who develop HG may be exposed to higher levels of hormones during early pregnancy. Because HG is most prevalent in weeks when both the placenta and the corpus luteum produce hormones, progesterone and HCG in particular are thought to be associated with HG. Pregnancies with iatrogenic-elevated progesterone levels, such as pregnancies with multiple corpora lutea caused by controlled ovarian stimulation [COS], or pregnancies in which progesterone is administered for luteal phase support do not exhibit an increased incidence of HG, suggesting that high progesterone levels [endogenous or exogenous] alone do not cause HG. The aim of the present study was to evaluate the therapeutic role of progesterone therapy [Utrogestan] as a new modality in the management of hyperemesis gravidarum and to compare this new modality of treatment with the conventional methods used before. Forty Egyptian pregnant women below 40 years of age who are pregnant 20 weeks and had no preconception history of any other medical illnesses. They were suffering from pernicious vomiting: > 5 times per day with subjective weight loss, fluid and electrolyte imbalance and ketonuria. They were randomly divided into group I, which included 20 patients suffering from HG. These patients were managed by iv fluids [5-6 litres/day] and micronized progesterone [Utrogestan] 300-400 mg vaginally/day for two weeks. Group II included another 20 pregnant women suffering from HG who received the traditional lines of treatment of HG. A control group composed of 15 pregnant women not suffering from vomiting or weight loss was also included in the study. Routine investigations included midstream urine analysis, complete blood picture [CBC], fasting blood glucose, liver function tests [serum bilirubin, AST and ALT], kidney function tests [blood urea and serum creatinine], serum electrolytes [Na and K], and serum uric acid were also measured. Assessment of fasting serum progesterone and serum estradiol level was done. Transabdominal ultrasound examination was carried out in all patients to exclude vesicular mole and multiple pregnancies. It was also done for assessment of the gestational age using crown-rump length. No statistically significant difference was found in haemoglobin or haematocrit values. Blood urea was significantly higher in the group of HG treated conventionally both before and after treatment. Serum creatinine did not show any statistically significant difference in both groups of HG patients. The same could be said about serum electrolytes. Before treatment no statistically significant difference was found in serum uric acid levels of both groups of HG patients. Serum total bilirubin, ALT and AST were comparable in both groups. Although the mean serum estradiol level of both groups of HG patients was significantly higher than that of control subjects, yet before treatment, the mean value of serum estradiol in HG patients treated with micronized progesterone was found not to be significantly different from that of HG patients treated conventionally. Before treatment, the mean serum progesterone value of HG patients treated with micronized progesterone was found to be not significantly different from that of HG patients treated conventionally or that of control subjects. Before treatment, HG patients treated conventionally had a significantly higher E2/P ratio than normal controls. In HG patients treated with micronized progesterone, the E2/P ratio before treatment did not differ significantly from that of group II patients or normal control subjects. The E2/P ratio after treatment was significantly lower in HG patients treated with micronized progesterone when compared to those HG patients who were treated conventionally, but it was still significantly higher than that of control subjects. Estradiol is implicated in NVP. Serum levels of estradiol are significantly higher in hyperemetic patients compared to normal pregnant women. When balance is restored by increasing natural progesterone levels, these symptoms typically disappear. Therefore, micronized progesterone has a significant beneficial effect to treat Egyptian pregnant women suffering from hyperemesis gravidarum

New treatment of hyperemesis gravid arum a randomized study

A randomized study was undertaken to assess efficacy of micronizedprogesterone as a new treatment ofhyperemesis gravidarum compared with anti-emetics, anti-histaminics, liver support, vitamin B6 and intravenousfluids.The study was conducted on 40 pregnant ladies diagnosed as hyperemesis gravidarum. They wererandomized into 2 groups:Group [I] includes twenty cases where intravenous fluids [5-6 L], sodium bicarbonate, liver support, vitamin B6,anti-emetics and anti-histaminics were given.Group [II] includes twenty cases were treated with micronized progesterone, intravenous fluids and sodiumbicarbonate were given.Both groups were subjected to complete blood picture [CBP], liver and kidney function tests, serum sodium [Na] and potassium [K], serum estrogen and progesterone estimations.This study indicated that significant differences were found on both groups between CBP, liver and kidneyfunction tests, serum Na and K levels, serum estrogen and progesterone levels after treatment than before.Signiflcnt differences were found between the two groups after treatment as regard kidney and liver function testsand also, seum progesterone levels.Intavenous fluid hydration and electrolytes correction is essential in the management of hyperemesisgravidarum. Micronized progesterone is an effective therapy as anti-emetics, anti histaminics, vitamin B6 and liversupport in controlling hyperemesis gravidarum

Immunological aspects of recurrent vaginal candidiasis [RVC] in prgnant and non pregnant patient

A possible monocyte/macrophage defect and the effect of progesterone hormone were studied in 40 cases of recurrent vaginal candidiasis [RVC], 20 pregnant and 20 non pregnant versus 20 healthy control women. Mitogen [phytohemagglutinin] induced lymphocyte proliferation and blastogenic transformation were comparable in patient and control groups. In marked contrast, Candida induced lymphocyte responses were significantly [P < 0.001] reduced in patient groups than control [36.5 +/- 3.2, for pregnant, 45 +/- 4.2 for non pregnant and 87.5 +/- 4.3 for controls]. In vitro depletion of patients' monocytes [adherent cell population] from whole peripheral blood' mononuclear layer [PBML], improved the lymphocyte responses [P < 0.001] suggesting a down regulatory role of patients' macrophages on the immune response to Candida in cases of RVC. A trial was made to correct this macrophagal dysfunction by in vitro addition of prostaglandin inhibitors [indomethacin 4 umol/L] to cell cultures. Significant [P < 0.001] improvement in Iymphocyte responses were noticed suggesting that this macrophagal defect may be attributed to abnormal excess production of prostaglandins. When progesterone hormone was added in vitro to cell cultures with concentrations equivalent to its level observed in the menstrual cycle [0.15 ng/ml in proliferative phase and 25 ng/ml ID luteal phase] a significant [P < 0.001] inhibition in lymphocyte responses were obtained in the presence of luteal phase level. In vitro depletion of monocytes masked this inhibitory effect, suggesting that the progesterone hormone inhibits the immune response to Candida via monocyte ependent mechanism. We concluded that fluctuations in a woman's macrophagal activity in cases of RVC may account for the frequent recurrent attacks of such disease. This macrophagal defect may be predisposed by high levels of progesterone hormone, which may suggest a type of receptors for progesterone on monocytes, and corrected by incorporation of prostaglandin inhibitors in the treatment

Study of myelitis: epidemiology, clinical aspects and laboratory studies

Twenty patients with acute transverse myelitis appearing as the first neurological episode [13 males and 7 females] fulfilling the criteria of Berman and other 10 apparently healthy controls were selected for this study and subjected to detailed history taking, full neurological examination, plain X-ray, myelography and spinal CT examination, CSF examination for cells, protein, glucose and microbiological tests for any growth and estimation of some serum and CSF immunoglobulins using immunodiffusion plate technique. The results were given

Ultrasound assessment of uterine involution

Uterine involution was studied ultrasonographically in 130 patients. The patients included 4 groups: Group I of 40 patients, 20 of them were primiparas and 20 multiparas to study the effect of parity on the rate of involuation. Group II of 30 patients, 15 of them delivered vaginally and the other 15 delivered by cesarean section to study the effect of the mode of delivery on uterine involution. Group III of 20 patients, 10 of them were lactating and the other 10 non-lactating to study the effect of lactation on uterine involution. Group 1 V of 40 patients, 20 of them received ecbolics and the other 20 did not to study the effects of ecbolics. The results have shown that parity and ecbolics have no effects on the rate of uterine involution. The rate of uterine involution was faster in breast feeders and those delivered vaginally compared to non-breast feeders and those delivered by cesarean section [P < 0.05]. Ultrasonography proved to be a useful method for assessing uterine involution

Diagnostic problems in patients allergic to or chronically infected by Candida

The present work was carried out on 120 cases classified into 4 groups: Group I included 40 patients allergic to C and ida albicans, group II included 40 patients with current vaginal c and idiasis [RCV], group III included 20 nonallergic cases with one episode of vaginal c and idiasis and group IV included 20 nonallergic cases. All the cases were subjected to skin testing using 6 different antigenic extracts from C and ida albicans. Specific IgE was also determined using crude C and ida-allergen coupled to CNBr discs. All C and ida albicans extracts gave positive intradermal test [IDR] among patients allergic to C and ida albicans. Also, many female cases with RCV showed positive skin reactions with different extracts. The allergic patients [Group I] reacted more intensively to the polysaccharides extracts CCF and MAN-I-Ag. Enzyme Immune Assay [EIA] technique used to measure specific IgE to crude Ag was less sensitive than skin testing. This work confirmed the role of cell wall allergens of C and ida albicans in atopic patients and suggested the presence of specific allergens related to clinical allergy and others representative of infection with C and ida albicans

Genital chlamydia trachomatis infection and preterm labour

The genital carriage of Chlamydia trachomatis [C. trachomatis] was assessed in 50 women admitted to hospital in spontaneous preterm labor with premature rupture of the membrane [PROM] and 70 women in preterm labor without PROM. The incidence of C. trachomatis isolated from the endocervix by direct immunofluorescent was 4.41% among asymptomatic low risk group and 21.15% among the group presented with symptomatic endocervicitis [high risk group] with a total incidence 11.67%. C. trachomatis was found more associated with greater sexual activity, so its incidence was high among younger age group and early married. There was a significant [P < 0.05] association between endocervical carriage of chlamydia, spontaneous preterm PROM and perinatal death

Study on microbial causes of corneal ulcer and antibiotic sensitivity tests

A microbiological study of 120 patients with corneal ulcers due to bacterial and fungal infections was performed. Positive cultures were obtained in 67 percent of all samples. 20 patients with negative cultures had received antimicrobial treatment prior to sampling. Staphylococcus epidermis was the commonest bacteria isolated from central ulcers followed by streptococcus pneumonie while in marginal ulcers staphylococcus aureus predominated. Aspirgillus fumigatus was the most common fungus isolated from central ulcers while in marginal ulcers, aspirgillus Niger was more common. Antibiotic sensitivity tests revealed that most gram positive isolates were sensitive to bacitracin, clindamycin and fucidin. As concerns gram negative isolates, almost all pseudomonas aeruginosa strains [the commonest gram negative isolate] were susceptible to amikacin, gentamycin and polymyxin B