PTEN, Akt, MAPK, p53 and p95 expression to predict trastuzumab resistance in HER2 positive breast cancer.

PURPOSE: Mutations that activate the PIK3CA oncogene and inhibit the tumor suppressor gene PTEN action are commonly found in breast tumors. Akt is a key activator of cell survival. p53 is frequently found mutated in human tumors, and mutant p53 protein actively contributes to tumorigenesis. In selected cases of breast cancer, trastuzumab (TZMB) is incorporated in the primary treatment in the adjuvant and metastatic settings. Many studies have reported that selected patients are resistant to TZMB due to the presence of p95 HER2 fragments. To address this, we analysed PTEN, Akt, MAPK, p53 and p95 expression in breast cancer patients treated with TZMB. METHODS: Out of 90 patients histologically diagnosed with breast cancer between 2004 and 2011, analysed were 25 patients with HER2 positive, and estrogen (ER) and progesterone receptors (PR) negative, metastatic or locally advanced disease. All 25 patients were treated with TZMB and resistance to TZMB was assessed. All patients were on anthracycline-and taxane-containing regimens. Tissue samples were obtained from paraffin blocks and evaluated immunohistochemically for PTEN, Akt, MAPK, p53, and p95 expression. RESULTS: TZMB resistance was detected in 5 (20%) patients. Akt expression was positive in 2 patients (8%) and MAPK, p95, and p53 expression was positive in 1 patient (4%); PTEN expression was negative in 3 patients (12%). No significant differences were found between TZMB resistance and PTEN, Akt, MAPK, p53, and p95 expression. Subgroup analysis was carried out in the neoadjuvant treatment group. Complete pathologic response was detected in 3 patients (21.4%). Statistically significant differences were not found between the complete response rate and PTEN, Akt, MAPK, and p95 expression. There was a statistically significant correlation between p53 expression and complete pathologic response (p=0.02). CONCLUSION: No statistically significant correlation between TZMB resistance and the expression of these biomarkers was noted. In patients with HER2-positive breast cancer that were treated with 4 dose-dense sequential cycles of doxorubicin and cyclophosphamide, followed by TZMB and paclitaxel combination therapy in the neodjuvant setting, p53 expression could predict complete response to chemotherapy.

Sepsis induces early phrenic nerve neuropathy in rats.

The aim of the present study was to investigate the electrophysiology of the phrenic nerve and the diaphragm muscle during sepsis. In total, 26 rats underwent either sham laparotomy or caecal ligation and puncture (CLP). Electrophysiology was evaluated via a phrenic nerve conduction study and needle electromyography of the diaphragm, prior to CLP, 6 and 24 h post-CLP and on day 7. The histopathology of the diaphragm muscle and phrenic nerve was also examined on day 7. In the sepsis group, the phrenic nerve conduction study showed decreased amplitude of compound action potential (CMAP), and prolongation in the duration and the latency of CMAP. The diaphragmatic needle electromyography showed decreased amplitude and frequency of the motor unit action potential (MUP), and prolongation in the duration of MUP, at all time points, compared with the pre-CLP values. The electrophysiological abnormalities were consistent with axonal and demyelinating phrenic nerve neuropathy. Electrophysiological abnormalities were present at 6 h with worsening at 24 h and on day 7. Histopathological examination showed normal muscular fibres and focally slight myelin degenerations of the phrenic nerve fibres. In conclusion, sepsis induced phrenic nerve neuropathy as early as the 6th h in rats.

Giant axonal neuropathy in two siblings: clinical histopathological findings.

OBJECTIVE: Giant axonal neuropathy is a rare, severe autosomal-recessive neurologic disease affecting both the peripheral and the central nervous system. In this article, we describe a detailed clinicopathological report of two affected sibs from a consanguineous Turkish family. PATIENTS: The index patient was a 6.5-year-old girl. Her intellectual development was normal. At the age of 3, her parents noticed progressive lack of balance and deterioration of motor skills. On examination, she had paresis and sensory loss more marked distally. Her mental status was normal. Her older brother had similar findings. RESULTS: Electrophysiological studies of young patients showed decreased median and ulnar nerve conduction velocities, absent peroneal motor potential, absent sensory nerve potentials and an EMG suggesting a neurogenic pattern. MRI showed mild cerebral and cerebellar atrophy. The nerve biopsy showed moderate myelinated nerve fibres loss, several regenerative clusters and multiple giant axons. Focal demyelination, hypertrophic "onion pulp" changes and endoneural fibrosis were also seen. Immunohistochemically, neurofilament protein accumulation was detectable in giant axons. CONCLUSIONS: This consanguineous family with two affected siblings and healthy parents complies with autosomal-recessive inheritance in GAN. In the majority of reported GAN cases, CNS involvement is described early in the course of the disease, but these patients did not present any sign of CNS involvement. GAN is a rare genetic disease of childhood involving the central and peripheral nervous systems. The diagnosis is easy with clinical, electrophysiological, and histopathological features, if it has been done. Early diagnosis is important, because of possible prenatal diagnosis.

Lipidized or lipomatous meningioma, which is more appropriate? A case report.

Lipoblastic, lipomatous or lipidized meningioma is an unusual extra-axial benign tumor. It shows benign clinical features and has a good prognosis after surgical excision. We present a 54-year-old woman with intracranial lipidized meningioma in the right temporal fossa, discuss the importance of the differential diagnosis among similar tumors and discuss the term 'Lipidized meningioma' in the light of the literature.

Choroid plexus papilloma of bilateral lateral ventricle.

BACKGROUND: Choroid plexus papillomas are rare, accounting for less than 1% of all intracranial tumours in adults. However, they are relatively more common in childhood and constitute 1.5 to 4% of intracranial tumours. They are most often located in the lateral ventricle, followed by the fourth and third ventricles and, rarely, in the cerebellopontine angle. Bilateral lateral ventricle choroid plexus papilloma is very rare and only a few cases has been reported. CLINICAL PRESENTATION: A 3-year-old boy was admitted to our hospital with a history of irritability and vomiting. Neurological examination on admission was normal. A head computed tomographic scan and magnetic resonance imaging showed tumours in both lateral ventricles, hydrocephalus and a left temporal arachnoid cyst. The bilateral intraventricular mass enhanced densely and homogeneously. A presumptive diagnosis of choroid plexus papillomas was made. INTERPRETATION: The initial surgery was performed for removal of the lesion in the right lateral ventricle, and 20 days later removal of the left lateral ventricle tumour was carried out. Bilateral temporoparietal craniotomy and total removal of tumours was performed. Hydrocephalus was controlled by total tumour resection from both sides. The histology of these tumours was the same and revealed choroid plexus papilloma. Interpretation: Bilateral choroid plexus papilloma is extremely rare and distinct from diffuse villous hypertrophy and their surgical approaches are different from each other. Differential diagnosis should be made by MRI preoperatively. If bilateral choroid plexus papilloma is detected, total surgical resection should be performed. Total surgical removal of the neoplasm not only cures the tumour but also may lead to complete resolution of the hydrocephalus.

99mTc-tetrofosmin scintigraphy in musculoskeletal tumours: the relationship between P-glycoprotein expression and tetrofosmin uptake in malignant lesions.

The aims of this study were to assess the role of (99m)Tc-tetrofosmin scintigraphy in the diagnosis of malignant vs. benign musculoskeletal tumours and to determine the relationship between P-glycoprotein expression and tetrofosmin uptake in malignant lesions. Forty-six patients (32 malignant, 14 benign) with various musculoskeletal lesions were studied. Each patient underwent (99m)Tc-methylene diphosphonate three-phase bone scanning initially. At least 2 days later, dynamic and static (99m)Tc-tetrofosmin scans were obtained. The tetrofosmin scans were evaluated by visual and quantitative analysis. The count ratio of the lesion to the contralateral normal area (uptake ratio, UR) was calculated from the region of interest drawn on the tetrofosmin scan. The lesions were then resected by open biopsy to obtain a histopathological diagnosis. P-glycoprotein levels were determined immunohistochemically in 22 of 32 malignant lesions. A significant difference between the mean UR values of benign and malignant lesions was found (1.36 +/- 0.47 vs. 3.35 +/- 2.08, P = 0.000). Visual analysis showed an accuracy of 85%, and the accuracy of the quantitative analysis was 87% with the threshold level of UR as 1.76. When perfusion findings were added to the evaluation criteria, the accuracies of visual and quantitative analysis were increased to 87% and 89%, respectively. The relationship between the levels of P-glycoprotein and the UR values of tetrofosmin was not statistically significant (r = -0.235, P = 0.2). In addition, the mean UR value of the patients with P-glycoprotein expression was not statistically different from that of the patients without P-glycoprotein expression (3.01 +/- 1.48 vs. 4.27 +/- 2.90, P = 0.297). In conclusion, visually significant tetrofosmin uptake and increased perfusion in a musculoskeletal lesion strongly suggest that the lesion is malignant (positive predictive value, 96%). P-glycoprotein expression was not found to be a major factor interfering with 30 min tetrofosmin uptake in a malignant musculoskeletal lesion. However, the relatively high false-negative rate among negative results (28%) limits the value of (99m)Tc-tetrofosmin scintigraphy as a single diagnostic tool in differentiating between benign and malignant musculoskeletal tumours.

MUC1 expression in plasmacytoma.

Plasmacytoma (Pm) is a plasma cell (PC) neoplasia consisting of PCs and some of them show progression to multiple myeloma. But there is no clear indicators predicting this progression. In this study, MUC1 expression was evaluated in Pm cases to determine the predictive value and was compared with histopathologic grade which is known to be a prognostic indicator in Pm. Nine of 31 cases with Pm showed MUC1 expression. Only two of the 18 cases with mature morphology showed MUC1 expression while seven of 13 cases with immature morphology showed MUC1 expression and this was statistically significant (P<0.006). Additionally, four of 11 cases with BM involvement showed MUC1 expression while five of 20 cases without BM involvement showed MUC1 expression. There was a trend MUC1 expression with BM involvement but there was not statistically significant association between MUC1 expression and BM involvement. We found that MUC1 expression is associated with immature morphology which is an important prognostic indicator in Pm and by analogy MUC1 expression may be an additional prognostic indicator in patients with Pm.

Postoperative radicular neuroma. Case report.

Lumbar discectomy is the most common surgical procedure performed in neurosurgery clinics. Such a large number of procedures underscore not only the prevalence of conditions such as intervertebral disc herniation, but also the strong belief of surgeons that the operation does provide benefits to patients suffering from sciatica. In spite of this belief, sciatic pain may continue after the surgery. The recurrence of sciatic and/or back pain after primary discectomy is called the "failed back surgery syndrome." The rate of the complications involved in standard lumbar discectomy ranges from 5.4 to 14%. One of the complications of the lumbar disc surgery is nerve root injury. The complication rate of this injury ranges from 0.7 to 2.2%. Postoperative radicular neuroma must be considered in differential diagnosis for the patient who has failed back surgery syndrome. In this study the authors evaluate a patient who had undergone surgery for lumbar disc herniation and suffered intractable pain. A traumatic radicular neuroma is demonstrated and the pertinent literature is presented.

Early ultrastructural findings and superoxide dismutase levels in experimental ischemic optic neuropathy: effect of hypertension and hypotension on ischemic changes.

We induced ischemia, hypertension and hypotension in 15 rabbits in order to evaluate the ischemic changes in the optic nerve and the effect of hypertension and hypotension on ischemia. We cauterized the right internal and external carotid arteries of 15 rabbits and applied dopamine hydrochloride and glycerol trinitrate to 5 each of these rabbits. Two rabbits were used as controls. We enucleated both eyes of all animals at the 24th hour. All of the optic nerves underwent biochemical, histopathological and ultrastructural examination. Histopathological and transmission electron-microscopic changes were found to be more prominent in the hypotensive group. We observed decreased superoxide dismutase levels in all groups, but it was more evident in the third group. In comparison to hypertension, hypotension is found to be a more important factor in the development of early degenerative changes.

Environmental malignant mesothelioma in southern Anatolia: a study of fifty cases.

Malignant mesothelioma is a highly aggressive tumor of the serous membranes, which in humans results from exposure to asbestos and asbestiform fibers. Although occupational malignant mesothelioma is still the most common form of this lesion, naturally contaminated soil can play an important role in the development of environmental malignant mesothelioma in some parts of the world. Fifty cases of malignant mesothelioma (MM) from southern Turkey with no occupational history of asbestos exposure were reviewed regarding pathologic and clinical features. A case of hyaline fibrous plaque of the pleura was also included in this series. Histologically the cases were classified as epithelial (36 cases); sarcomatous (7 cases); and biphasic (7 cases). One of the sarcomatous cases was desmoplastic. Ultrastructural examination of the tumor tissue in three cases revealed long-surface microvilli in epithelial cells. Interstitial cells of the lung in one case showed electron-dense asbestos fibers in the cytoplasm. Mineralogical analyses of the lung tissue in three cases of MM and the case of pleural plaque showed high amounts of asbestos fibers most consistent with tremolite and actinolite. The clinical and pathologic features of our cases support that the environmental inhalation of asbestos is still a major health problem in some parts of Turkey.

Leukaemia cutis and leukaemic vasculitis.

BACKGROUND: Leukaemia cutis (LC) and leukaemic vasculitis (LV) are uncommon but important features of haematological malignancy. OBJECTIVES: We aimed to evaluate clinicopathological features of a series of such cases. METHODS: Thirty-four patients with LC were studied. Nineteen had acute myeloblastic leukaemia, six had acute lymphoblastic leukaemia, three had myelodysplastic syndrome-refractory anaemia with excess blast in transformation, three had non-Hodgkin's lymphoma in leukaemic phase, two had chronic lymphocytic leukaemia and one had multiple myeloma. RESULTS: Cutaneous lesions were widely dispersed in 15 patients, but were restricted to the extremities in eight patients. In other patients lesions were localized on the face, hands and feet. Cutaneous lesions were generally erythematous, maculopapular, squamous, nodular, haemorrhagic or necrotic. Two localizations were very interesting: in one case, lesions were confined to the site of previous varicella zoster virus infection; in the other case, leukaemic infiltration occurred within a lesion of cutaneous leishmaniasis. All of the patients had high white blood cell count and/or other findings of high tumour burden. Vasculitis with leukaemic cell infiltration (LV) was detected in 24 patients, and was high-grade LV in 16 patients. Patients with high-grade LV tended to have a higher white blood cell count and other findings associated with an aggressive clinical course compared with patients not having LV. Thirteen patients with LV died within 1 month but five patients lived more than 1 year. CONCLUSIONS: LC, and especially LV, is generally an indicator of poor prognosis. Its pathogenesis must be evaluated further with additional studies, including adhesion molecules, angiogenic factors and other biological parameters.

Sweet's syndrome accompanying leukaemia: seven cases and review of the literature.

Seven patients with Sweet's Syndrome (SS) accompanying leukaemia are presented. Six had acute myeloid leukaemia and one chronic myeloid leukaemia. SS developed during G-CSF therapy in two patients and following long periods of chemotherapy-associated neutropenia in two. This finding may suggest a possible role of G-CSF in the pathogenesis of SS. SS was diagnosed during the first presentation of three patients with leukaemia. Skin lesions on the lower extremities in two patients, widespread distribution in one, a local infiltration at the inguinal region and pleural effusion in one were interesting findings in our patients which are not usual for classical SS.

Vasculitis and leukemia.

Vasculitis may accompany neoplasias and be of paraneoplastic type or associated with drugs used in patient treatment. We evaluated skin biopsies of twenty-eight cases with vasculitis accompanying leukemias reviewed and clinical outcome was evaluated. Eleven of the 28 cases had paraneoplastic vasculitis and 17 had vasculitis associated with various drugs including chemotherapy, cytokines and antibacterial agents. Paraneoplastic vasculitis was seen in 3 cases with chronic myelocytic leukemia in blastic phase, 5 patients with acute myeloblastic leukemia, and 3 with myelodysplastic syndrome. Drugs responsible for the 17 cases of vasculitis included hydroxyurea, vincristine, cytosine-arabinoside, methotrexate, all-trans retinoic acid, granulocyte-colony stimulating factor, interferon and antibiotics. Paraneoplastic vasculitis is not rare in leukemias and may be a manifestation of the blastic phase of chronic myeloid leukemia. Furthermore paraneoplastic vasculitis can be fatal in myelodysplastic syndromes and may be present clinically before the specific diagnosis is made. Drugs used in routine therapy may be the cause of the vasculitis, thus skin biopsy should be performed in all cutaneous lesions in patients with hemopoietic neoplasias.

The effect of collagen, interleukin-1 alpha and glicosaminoglycan on the neovascularization of central nervous system.

Neovascularization, the development of a new microvasculature, has an important role in physiological and pathological processes. The vascular changes in the brain can be easily detected because the proliferation of endothelial cells in its vascular structure is quite small, and so constitutes a good model for neovascularization studies. In the present investigation, to induce intracerebral neovascularization, we implanted collagen, Interleukin-1 alpha (IL-1 alpha) and glicosaminoglycan into the brain of pigs, in order to test the hypothesis that IL-1 alpha, collagen and glicosaminoglycan play a pivotal role in the process of neovascularization. Both pure collagen and collagen combined with IL-1 alpha induced neovascularization according to light-electron microscopic findings and values of enzymes' activities. In particular, collagen combined with IL-1 alpha synergically affected the increase of neovascularization. However, glicosaminoglycan did not affect it significantly. Although the results of this study provided us with some interesting data indicating the beneficial effects of collagen combined with IL-1 alpha on neovascularization, further studies should be done to study the short term effect of these biochemical substances.

All trans retinoic acid as the possible cause of necrotizing vasculitis.

All trans retinoic acid (ATRA) is the drug of choice in the treatment of acute promyelocytic leukemia (APL). Generally, it is well tolerated but it has some side-effects, some of which may be fatal. The most severe side-effect of ATRA is ATRA syndrome; the other side-effects are rather dermatologic. Among these vasculitis has not been reported so far. We detected fever and skin lesions in two patients treated with ATRA where histopathologic examination revealed necrotizing vasculitis. With cessation of ATRA and corticosteroid administration, the lesions healed and fever quickly disappeared.

Rhinocerebral zygomycosis treated with liposomal amphotericin B and surgery.

We report three cases with rhinocerebral zygomycosis in two diabetic persons and one otherwise healthy person. The diagnosis was established by histopathological appearance and computerized tomography (CT) and/or magnetic resonance imaging (MRI) scans. These cases were successfully treated by a combination of surgery and liposomal amphotericin B.

A giant dissecting aneurysm mimicking serpentine aneurysm angiographically. Case report and review of the literature.

Intracranial dissecting and giant serpentine aneurysms are rare vascular anomalies. Their precise cause has not yet been completely clarified, and the radiological appearance of such lesions can be different in each case according to the effect of hemodynamic stress on a pathologic vessel wall. For berry aneurysms, available evidence overwhelmingly favors their causation by hemodynamically induced degenerative vascular disease and there is an obvious need to determine the hemodynamic parameters most likely to induce the precursor atrophic lesions. In this study, a case of a giant dissecting aneurysm angiographically mimicking serpentine aneurysm of the right ophthalmic artery is reported and the relevant literature is reviewed to investigate the pathological characteristics and pathogenesis of this lesion. In the present case, radiological investigation of the lesion suggested a serpentine aneurysm, but the diagnosis was corrected to dissecting aneurysm subsequent to the pathological examination of the resected aneurysm. A giant dissecting aneurysm angiographically mimicking serpentine aneurysm and developing as the result of a circumferential dissection located between the internal elastic lamina and media is of particular interest when the etiology of these aneurysms is considered. To our knowledge this is the first report on intracranial dissecting aneurysm mimicking serpentine aneurysm angiographically. Our case illustrates the importance of careful serial section studies for a better understanding of the vascular pathology underlying the processes involved in intracranial serpentine aneurysms. We conclude that serpentine, dissecting and berry aneurysms may all arise by way of similar pathophysiological mechanisms.

Relationship of Helicobacter pylori infection to several malignant and non-malignant gastrointestinal diseases.

The importance of the Helicobacter pylori infection was investigated as a risk factor for several gastrointestinal diseases. In this study 203 patients with gastric cancer, 61 with peptic ulcus, 60 with gastritis and 100 asymptomatic control subjects were investigated. Serum samples were examined for IgC antibodies to H. pylori by enzyme linked immunoassay - tissue samples were stained for H. pylori by Wartin-Stary technique and by Giemsa for routine histopathology. H. pylori seropositivity was 58.1% in gastric cancer, 54% in peptic ulcus, 63.3% in gastritis and 27% in asymptomatic control group. There was a 10.1% discordance between the serum and tumor determinants in the seropositive group and 11.3% of discordance in the seronegative group. The frequency of H. pylori seropositivity was lowest in cardia tumors (22.7%) and highest in antral tumors (65.5%, p=0.00002). H. pylori seropositivity was 29% in diffuse type of histology, 35% in mixed type and 79% in the intestinal type (p=0.00000). In the gastric cancer patients the frequent use of salty food (p=0.00001, OR=6.4), excessive salt, pickled food (p=0.0000, OR=24.92) and proteins (p=0.003, OR=0.45) were more significant than asymptomatic volunteers. In gastric cancer patients the frequent use of salty and pickled food were relevantly associated with H. pylori infection (p=0.001). It was concluded that H. pylori infection could play a role in the pathogenesis of non-malignant gastrointestinal diseases which may be the precursor of carcinoma. However, other contributing factors to carcinogenesis must be investigated.

Bone marrow necrosis in antiphospholipid syndrome.

Bone marrow necrosis (BMN) is a relatively rare entity and has been associated with a poor prognosis. It is most commonly found in patients with neoplastic disorders, severe infections and sickle cell anemia. An unusual case of antiphospholipid syndrome (APS) with extensive bone marrow necrosis is described in a 27 year old woman. The patient presented with severe pancytopenia, some cognitive impairment resulting from a previous cerebrovascular accident, fever, hypertension, dyspnoea, tachycardia, hepatosplenomegaly, and vaginal bleeding. Her laboratory findings included a strongly positive Coombs' test (anti-IgG and anti-C3d), a prothrombin time of 23 seconds and an activated partial thromboplastin time of 45 seconds. Anticardiolipin antibody tests were positive. Antinuclear and anti-DNA antibodies were negative but the anti-SM test was positive. A bone marrow biopsy specimen was reported as showing extensive necrosis. The patient was treated with steroids, transfusion, and plasma exchange with some clinical improvement but her pancytopenia did not respond and necessitated frequent transfusions. This case lends further support to the association between APS and BMN.