Prognostic and predictive significance of GITR in metastatic renal cell carcinoma.

OBJECTIVE: Renal cell carcinoma (RCC) has gradually increased in recent years. There have been significant developments in metastatic RCC in recent years with the introduction of immune control point inhibitors. Glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein (GITR) is a co-stimulatory molecule and is seen in the highest amounts in activated CD4+ T lymphocytes and CD8+ T lymphocytes, forkhead box protein 3 (FOXP3) positive regulatory T cells (Treg). GITR leads to an increase in interleukin (IL)-2 and CD25 and Interferon Gamma. It shows an anti-tumoural effect by inhibiting the suppressive functions of FOXP3+ regulatory cells (Treg). Therefore, we aimed to evaluate the prognostic and predictive effect of GITR, tumor-infiltrating lymphocytes (CD4+CD8) (TIL), and FOXP3 in patients with metastatic RCC. PATIENTS AND METHODS: Patients diagnosed with pathologically confirmed metastatic renal cancer between 2016 and 2021 were included in our study. Clinicopathological features and some laboratory tests were recorded. GITR, CD4, CD8, and FOXP3 were evaluated by immunohistochemistry (IHC) from biopsies or nephrectomy material and recorded. RESULTS: The study included 41 patients. The median progression-free survival (PFS) was 10.5 months, and the median overall survival (OS) was 13.9 months. Median PFS was 7.9 months for the GITR-low group and 18.9 months for the GITR-high group. Median PFS was statistically significant and longer for the GITR-high group than the GITR-low group (p=0.003). When patients who received nivolumab in the 2nd line were evaluated, median PFS was found to be 5.7 months in the GITR-low group and 15.7 months in the GITR-high group. Median PFS was statistically significantly higher in the GITR-high group than in the GITR-low group (p=0.026). CONCLUSIONS: In patients with metastatic RCC, higher GITR was associated with better PFS. At the same time, in patients using nivolumab, better PFS was seen in the GITR high group. If supported by prospective studies, GITR can be used as both a prognostic and predictive marker.

PUBERTAL VIRILIZATION IN AN ADOLESCENT WITH 46, XY DISORDER OF SEXUAL DEVELOPMENT: A NOVEL MUTATION IN NR5A1 GENE.

Background: NR5A1 [Steroidogenic factor 1 (SF1)] is a nuclear receptor that is essential for the development of gonads and adrenal glands as well as the establishment of steroidogenesis in these organs. The clinical findings of the mutations of NR5A1 gene in 46, XY individuals are variable. Virilization at puberty can be seen in some of the 46, XY children who have a female phenotype and are raised as female.A girl aged 13 years and 10 months old was brought by the family for deepening of her voice. On physical examination, her breast development was Tanner stage 2, axillary hair (+) and pubic hair was Tanner stage 4. She had labioscrotal fusion and 4.4 cm phallus (External Masculinisation Score was 6). Hypergonadotropic hypogonadism, low AMH and high testosterone levels were detected in laboratory tests. Uterus was not visualized in pelvic ultrasonography. Karyotype analysis was reported as 46, XY. Sequence analysis of the NR5A1 gene revealed a novel heterozygote c.1075_1089del (p.Leu359_Leu363del) variant. The patient was raised as a female and oestrogen replacement was started following gonadectomy. Conclusion: It should be kept in mind that virilization may develop at puberty in individuals with 46, XY disorder of sexual development due to NR5A1 mutation.

Rectal cancer in pregnancy: a case report.

Rectal cancer in pregnancy is a rare but a life-threatening disease. This paper presents a case of rectal cancer in pregnancy, discussed in light of the literature.

Protective effects of silymarin against doxorubicin-induced toxicity.

OBJECTIVES: The aim of the present study was to investigate the effect of silymarin on doxorubicin-induced toxicity to the rat kidney, heart, and liver. MATERIALS AND METHODS: A single dose of 10 mg/kg doxorubicin was injected intraperitoneally (ip) in the doxorubicin group. The silymarin group received silymarin (100mg/kg) every other day. In the doxorubicin + silymarin group, silymarin was injected ip at 100 mg/kg dose for 5 days before doxorubicin administration (10 mg/kg, single ip injection) and then continued daily thereafter until euthanization. On the seventh day after doxorubicin injection, eight animals from each group were decapitated and liver and heart samples were obtained. The remaining eight animals of each group continued to receive silymarin every other day, till euthanized on the twenty first day. Serum was separated for determination of superoxide dismutase (SOD), glutathione peroxidase (GSHPx), catalase (CAT), malondialdehyde (MDA), nitric oxide (NO), creatinine, urea, AST, ALT, lactate dehydrogenase (LDH) and creatinine phosphokinase (CPK) activities. Histopathological and electron microscopic examinations of heart, kidney and liver sections were also performed. RESULTS: Doxorubicin caused a significant increase in serum NO levels compared to controls. Silymarin pretreatment group lowered these. Histopathological and electron microscopic examinations of kidney, heart, and liver sections showed doxorubicin to cause myocardial and renal injury which was levv evident in silymarin treated rats. CONCLUSION(S): Results of the present study indicate that silymarin significantly protected doxorubicin-induced toxicities to the rat kidney, heart, and liver, thus suggesting its administration as a supportive care agent during anti-cancer treatment featuring doxorubicin.

A prospective randomized comparative study of the effects of intranasal and transdermal 17 beta-estradiol on postmenopausal symptoms and vaginal cytology.

CONTEXT: Investigating the adverse effects of oral hormone replacement therapy (HRT), the clinical effectiveness of alternative combinations and route of administrations. AIM: To compare the effects of intranasal and transdermal 17 beta-estradiol combined with vaginal progesterone on vasomotor symptoms and vaginal cytology. SETTINGS AND DESIGN: A 12-week, prospective, randomized comparative study was conducted between July 2005 and September 2006. MATERIALS AND METHODS: Eighty postmenopausal women aged between 42-57 years, who had scores of > or =1.7 on the menopause rating scale-I (MRS-I) items "1-6", were randomly assigned to receive intranasal (300 microg/day, n =40) or transdermal (50 microg/day, n =40) 17 beta-estradiol continuously. All patients also received a vaginal progesterone gel twice weekly. Vasomotor symptoms were evaluated at weeks 0, 4, 8 and 12. Vaginal maturation index (VMI) was evaluated at weeks 0 and 12 of the study. STATISTICAL ANALYSES: The Mann-Whitney U and the Wilcoxon tests were used. P < 0.05 was regarded as significant. RESULTS: Thirty-two women in the intranasal and 29 women in the transdermal group completed the study. The total score of the MRS, the sum-scores of Factor 1 "HOT FLUSHES" and Factor 2 "PSYCHE" significantly decreased in both groups at week 4. Factor 3 "ATROPHY" scores significantly decreased only in the transdermal group at week 12. The VMI showed no changes within and between the two groups at the end of the study. CONCLUSION: Intranasal and transdermal 17beta-estradiol combined with vaginal progesterone gel as a continuous HRT caused a similar decrease in vasomotor symptoms but did not have any significant effect on VMI after 12 weeks of treatment in this study population.

The right method for midline laparotomy: what is the best choice for wound healing?

BACKGROUND: The techniques used for midline laparotomy affect healing in surgical wounds, but the relationship between cold scalpel and haemostatic methods (harmonic scalpel, diathermy) regarding wound healing remains unclear. There are also limited studies concerning the effects of harmonic scalpel on abdominal fascia. This study was aimed at comparing myofascial wound healing following laparotomy incision on fascia by cold scalpel (CS), harmonic scalpel (HS), and diathermy in terms of hydroxyproline content, inflammatory changes and tensile strength. MATERIALS AND METHODS: Twenty-seven male Wistar albino rats underwent midline laparotomy either with cold scalpel (CS), harmonic scalpel (HS) or diathermy. Fascia incisions were closed with continuous 4/0 polypropylene and skin incisions were closed with interrupted 4/0 polypropylene stitches. On the 7th postoperative day, the abdominal walls of the rats were tested for tensile strength. In addition, each abdominal fascia was evaluated for inflammation scores and hydroxyproline levels. RESULTS: HS caused less inflammation and necrosis in abdominal fascia compared to the diathermy group (p < 0.01 and p < 0.05, respectively), whereas the CS group showed no difference in inflammation scores, but had significantly lower necrosis scores than the HS and diathermy groups (p < 0.05 and p < 0.001, respectively). Hydroxyproline content of the fascia did not differ among groups, while the tensile strength of the wound was obviously higher in the CS group (p < 0.001). CONCLUSION: HS causes less inflammatory reaction and necrosis than diathermy, but more necrosis than CS. Fascia incisions with CS gains tensile strength faster than in other groups. HS appears to cause less tissue injury than diathermy and also has comparable results for wound healing. Further clinical studies on the impact of HS in fascia incisions are needed.

The effects of nitric oxide supplementation and inhibition on bacterial translocation in bile duct ligated rats.

Obstructive jaundice promotes bacterial translocation from the gut, but the role of nitric oxide is controversial in this process. We studied the effects of nitric oxide synthase substrate, L-arginine, and nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, on bacterial translocation in bile duct ligated rats. The animals were randomized into five groups; control, sham, common bile duct ligation alone, nitric oxide inhibition, and nitric oxide supplementation. Obstructive jaundice was performed with common bile duct ligation. L-arginine or N(G)-nitro-L-arginine methyl ester was injected once daily for 14 days. Blood bilirubin level, liver histology, and bacterial translocation to the mesenteric lymph nodes as well as to the liver were assessed. The L-arginine supplemented group had the lowest bacterial translocation rate, but the most prominent hepatic fibrosis. Nitric oxide inhibition increased bacterial translocation to the mesenteric lymph nodes. Therefore, the administration of nitric oxide donor or inhibitor acts as a significant regulatory factor for bacterial translocation in obstructive jaundice.

Is synchronous bowel anastomosis safe?

In this study, we investigated the effects of synchronous anastomosis on intestinal healing in experimental colonic resection. Sprague-Dawley rats were randomized into 3 groups; control (group I), single anastomosis (group II) and synchronous (double) anastomosis (group III). Single and proximal anastomoses were located 3 cm distal to caecum, and distal anastomoses were done 3 cm distal to them. On the 7th postoperative day, bursting pressure, hydroxyproline level and histology of the anastomotic site were assessed. Bursting pressures and hydroxyproline levels indicated that impaired healing of proximal anastomoses in group III was evident. Proximal anastomoses in group III had the lowest hydroxyproline value and bursting pressure level. Significant fibrosis was observed in the histological examination of distal anastomoses in group III. Double colonic anastomoses is not as safe as single anastomoses and involves additional risk. The healing of proximal anastomosis is significantly altered after experimental synchronous resection.

The interdomal fat pad of the nose: a new anatomical structure.

The nose is one of the most operated organs in the body and its anatomy has been well defined by plastic and ENT surgeons. Although rhinoplasty is the most commonly performed operation in plastic surgery, some unexpected results and complications may be related to unknown or unclarified anatomical structures in the nose. We aimed to evaluate the interdomal region in four fresh cadavers and 24 patients who underwent open rhinoplasty, since the nasal tip area is the most difficult part of the rhinoplasty. Detailed cartilage and soft tissue interactions were studied in fresh cadavers. The existence of the interdomal fat pad as a separate anatomical structure was proven in necropsy specimens from cadavers using various histochemical dyes. Nasal tip ultrasonography was performed preoperatively in patients who underwent rhinoplasty. All patients had a fat pad in the interdomal space, of varying sizes, but fatty (bulbous) noses had larger fat pads. Interdomal fat pad tissue, which occupies the interdomal space, was demonstrated by ultrasonography. The size of the fat pads varied from 1.2 mm x 2.4 mm to 3.6 mm x 5.2 mm. Anatomical observation and biopsies were performed during surgery. Finally, surgical and radiological anatomy of the interdomal fat pad was demonstrated in all cadavers and patients. We speculate that the interdomal fat pad is an important anatomical structure and may contribute to unexpected postoperative results in rhinoplasty. This newly defined fat pad can be assessed by ultrasonography, a safe and inexpensive technique. The surgical approach to the interdomal fat pad is solely through open rhinoplasty technique. Thus, a consideration of the interdomal fat pad and detection of its size preoperatively may play a key role in choice of technique and success of rhinoplasty.

Immunohistochemical findings in notalgia paresthetica.

BACKGROUND: Notalgia paresthetica (NP) is a sensory neuropathy the pathogenesis of which is not yet completely elucidated. OBJECTIVE: The aim of this study was to investigate the histopathological changes in NP with special emphasis on cutaneous innervation. METHODS: Along with site-matched biopsies from 5 healthy individuals, lesional skin biopsies from 14 cases of NP and biopsies from contralateral nonlesional skin in 9 of these cases were stained with hematoxylin-eosin and Congo red. For immunohistochemical analysis, all samples were stained with two general neural markers (S-100 protein and protein gene product 9.5) and two neuropeptides (vasoactive intestinal polypeptide and substance P). RESULTS: Light microscopy was compatible with postinflammatory hyperpigmentation. Immunohistochemistry did not reveal a significant difference in the staining pattern of lesional skin and control tissue (p > 0.05). Although not reaching statistical significance, the percentage of cases which showed no staining was higher in the group of patients with more chronic NP. CONCLUSION: The finding of less immunohistochemical staining in cases with more chronicity could be of clinical importance and is worth investigating further.

Epididymal changes associated with cryptorchidism in rats.

AIM: To investigate the effect of a new mechanically induced cryptorchidism model on rat epididymal histology. METHODS: Eighteen 21-day-old Sprague Dawley rats were randomly divided into 3 groups of 6 animals each. Animals of Groups 1 and 2 were made unilaterally cryptorchid by closing the left inguinal canal, while Group 3 (controls), sham operated. At Day 60 (Group 1) and Day 90 (Group 2 and 3), the rats were sacrificed. The epididymides of both sides were weighed, and the diameter of the epididymal tubules, the height of the tubular epithelium and the presence of fibrosis of the caput epididymides were examined under a light-microscope. RESULTS: The cryptorchid epididymis had a significantly lower weight increase than the contralateral ones and the controls, but the epithelial height and diameter of caput epididymal tubules were not significantly different. Fibrosis was not observed. CONCLUSION: The authors proposed that this new model is a convenient method to evaluate the epididymal changes associated with experimental cryptorchidism.

A new experimental model for cryptorchidism: inguinoscrotal approach.

We investigated the effect of inguinal canal closure as a new mechanically induced cryptorchid rat model. The effectiveness of this new model was evaluated by histopathological examination. Thirty-one 21-day-old Wistar rats were divided into four groups. In groups 1 (n = 6), 2 (n = 6) and 3 (n = 7), unilateral undescended testis was created by performing inguinal canal closure with inguinoscrotal approach. Sham-operated rats were used as controls in group 4 (n = 12). The rats were killed on day 30 after surgery in group 1, day 45 in group 2 and day 60 in group 3. The seminiferous tubular diameter, number of tubules with mature germ cell and Leydig cell clusters were evaluated. None of the rats were lost during the study period. Signs of infection were not detected in operation site although antibiotics were not used. Overall only three (16%) testes descended into scrotum in study groups. The operation time was 3-4 min for each rat. Histopathological examination revealed detrimental effects of cryptorchidism on testicular growth in study groups. In all groups, except the sham group, the mean tubular diameter and the number of tubules with mature germ cells in the left testicle were significantly decreased compared to the right ones. Our findings were in correlation with other experimental studies using different rat models of cryptorchidism. This new model of cryptorchidism is considered to provide a simple and effective technique for investigating the impaired development of the testes in cryptorchidism.

Quantification of tumor cellularity and mitotic index in invasive ductal carcinoma of the breast.

OBJECTIVE: To evaluate the use of stereologically estimated tumor cell counts in the mitotic index as well as to investigate its correlation with the currently used method and test the reproducibility of the method. STUDY DESIGN: The stereologic method described by Simpson et al was used to estimate tumor cellularity in 50 invasive ductal carcinomas. Mitotic counts were also performed, and the mitotic index was calculated by the use of estimated tumor cell counts. Estimated cell counts and the mitotic index calculated were compared statistically with the actual cell counts and the traditional mitotic grades, respectively. Interobserver reproducibility of the method was also tested. RESULTS: Stereologically estimated tumor cell counts had a good correlation with actual cell counts (r = .891, P < .001). Besides, the mitotic indices calculated with tumor cell counts (calculated with both estimated and actual cell counts) in the denominator of the fraction of the mitotic index were in agreement with the currently used method (P < .01 for both). There was no statistically significant difference between the counts of two observers (P = .068). CONCLUSION: The suggested method, considering tumor cellularity as an influencing factor, was practical, reproducible and in agreement with the traditional method. This method should be studied in a large group of patients with follow-up data to determine the threshold values for different grades and determine its prognostic value during the disease course.

Notalgia paresthetica: a study on pathogenesis.

BACKGROUND: Notalgia paresthetica is a sensory neuropathy involving the dorsal spinal nerves. The characteristic symptom is pruritus on the back, occasionally accompanied by pain, paresthesia, and/or hyperesthesia, which results in a well-circumscribed hyperpigmented patch in the symptomatic area. The etiology of this condition has not yet been completely defined. OBJECTIVE: Possible mechanisms that could explain the pathogenesis of notalgia paresthetica were investigated through clinical examination and various diagnostic tests. METHODS: Ten cases of notalgia paresthetica underwent dermatologic, neurologic, and orthopedic examination. This was followed by skin biopsy, electrodiagnostic investigation, and radiography of the spine. RESULTS: All patients had a typical symptomatology and dermatologic picture. Neurologic examination and standard electrodiagnostic investigation results were normal in all cases. Histopathology was compatible with postinflammatory hyperpigmentation; there were no amyloid deposits. In seven cases, degenerative changes in the vertebrae were observed and, in all of these cases, these changes were most prominent in the vertebrae which corresponded to the dermatome of the cutaneous lesion. CONCLUSIONS: The striking correlation of notalgia paresthetica localization with degenerative changes in the spine suggests that spinal nerve impingement may contribute to the pathogenesis of this entity.