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Acute leukemias of childhood: pathologic features.

Major advances have been made in the diagnosis and therapy of childhood leukemia over the last two decades (Zuelzer and Flatz, 1960; Miller, 1980; Steinhorn and Myers, 1981; Kobrinsky et al., 1980). Sophisticated phenotypic analysis of these leukemias has partially revealed their complexity; there are at least three to five distinct clinical pathological entities in the childhood leukemia groups. Improved therapy has resulted in marked increases in survival and cures. Less attention has been given to the pathology of childhood leukemia, although the frequency and complexity of tissue examinations have greatly increased. In particular, the pathologic manifestation of relapses, detection of focal leukemia after treatment and the pathology of complications have not been systematically reviewed. Our goal was to look at all of the pathologic manifestations of leukemia and to relate these manifestations to homogeneous patient populations grouped by their type of leukemia. Therefore all of the cytologic, hematologic, histopathologic, ultrastructural and immunologic materials on a consecutive group of leukemic children seen at Vanderbilt from 1970 to 1981 were reviewed; pathologic manifestations of leukemia were then analysed in relationship to diagnostic categories.

B-Lymphocytes↗

Clinical correlates of the pathology underlying parkinsonism: a population perspective.

We correlated the clinical features with pathological findings in an autopsy series of cases of incident parkinsonism. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of parkinsonism in Olmsted County, MN, for the years 1976 to 1990. Medical histories were abstracted in a standardized manner. Included in this study were those incident cases who died and underwent autopsy. Brain sections were studied with routine histology and special stainings. A neuropathologist blinded to any clinical information assigned cases to neuropathological categories. We found 364 incident cases of parkinsonism of which 235 were deceased at the time of this study; there were 39 autopsied brains available for analysis (17% of deceased cases). Of the 16 patients diagnosed pathologically with Lewy body disease, documentation indicated that 8 had an early dementia, 3 had prominent dysautonomia, and 2 had prominent ataxia. Of the 7 patients diagnosed pathologically with progressive supranuclear palsy, 4 had no documentation of supranuclear gaze palsy, and 3 had no documentation of early falls. Of the 3 patients diagnosed pathologically with multiple system atrophy, none had prominent ataxia or dysautonomia documented. Of the 5 patients with vascular disease at pathology, none had been given the clinical diagnosis of vascular parkinsonism. Of the 8 cases given the clinical diagnosis of drug-induced parkinsonism, 6 were found to have basal ganglia pathology. The autopsied cases in this study were not representative of all patients with parkinsonism, because atypical cases are more likely to come to autopsy than typical ones. Despite this selection bias, the retrospective data collection, and the small sample size, we made several observations that illustrate the difficulty in achieving an accurate antemortem diagnosis of parkinsonism.

Alzheimer Disease↗

Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease.

The cause and mechanism of neuronal cell death in the substantia nigra of patients with Parkinson's disease (PD) are unknown. There is also controversy about whether the cell death results from a single event followed by cell loss consistent with aging or whether there is an ongoing pathologic process. Using postmortem tissue obtained from the Parkinson's Disease Society Brain Tissue Bank in London, we have sought to establish whether apoptosis, or more specifically DNA fragmentation of neurons, is a prominent feature of nigral pathology. In addition, we have studied microglial activation in the substantia nigra as an indicator of ongoing pathology using the highly sensitive markers CR3/43 and EBM11. Reactive astrocytes have been assessed using immunostaining for glial fibrillary acidic protein (GFAP). Ten patients with pathologically proven PD were studied. In all cases, regardless of disease duration, severity, drug treatment, or age of the patient, there was no evidence of apoptosis in the substantia nigra as assessed by in situ end-labeling of DNA fragments using biotinylated dUTP and terminal deoxynucleotidyl transferase (TdT). In contrast, a case of multiple system atrophy (MSA) served as a positive control for the technique. In this case, positive DNA end-labeling could be found in neurons and non-neuronal cells in the brain stem. In the PD cases, there was, however, localized pathology in the substantia nigra as revealed by the CR3/ 43 and EBM11 markers for activated microglia. This process seemed independent of disease duration and was florid even in patients with severe neuronal loss. It remains to be determined to what extent the activation of glial cells reflects progressive nigral pathology, and whether those factors which are classically associated with prominent apoptotic neuronal cell death in vivo, such as neurotrophic factor deprivation, are prime causes of nigral neuronal loss in PD. Future studies should focus on recent-onset PD or incidental Lewy body disease to further address these questions.

Aged↗

Unique characteristics of ubiquitin-bonded complex play a pathological role in dentatorubral-pallidoluysian atrophy.

Abnormal complex formation of dentatorubral-pallidoluysian atrophy (DRPLA) protein and pathological ubiquitination of abnormal complex are two pathological processes involved in DRPLA neurodegeneration. Pathological ubiquitination and solubility in SDS and reducing agent are two unique characteristics of the DRPLA protein complex. Ubiquitination of abnormal DRPLA protein complex in DRPLA brain tissue is heat-resistant and stronger than that in control brain tissue. Pathological ubiquitination of DRPLA protein complex correlates with the onset of symptoms and the size of an expanded glutamine repeat in brain tissue of patients with DRPLA. Pathological ubiquitination plays an important role in DRPLA pathology. DRPLA protein complex is water-insoluble but soluble in SDS and reducing agent, and displays no difference in water insolubility between control and DRPLA brain tissue. Abnormal insoluble complex formation is not developed by a qualitative change in water insolubility of DRPLA protein complex but is developed by a spontaneous accumulation of an abnormally large amount of the DRPLA protein complex.

Adult↗

Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia.

Abnormal phosphorylation of the tau-protein is regarded as a crucial step in the formation of neurofibrillary tangles in the neuronal cell body and neuropil threads in dendrites. We studied the effects of tau-pathology on the clinical expression of dementia in 106 autopsy cases in the entorhinal region, the hippocampal stratum oriens, the stratum radiatum, and the perforant path target zone. The first cytoskeletal lesions were located in the perikarya and dendrites of the pre-alpha cells of the transentorhinal and entorhinal region. Next, abnormally phosphorylated tau-protein (PHF-tau) was found in the neuropil of the CA1-subiculum region. Thereafter, the stratum radiatum and stratum oriens began to be involved in PHF-tau pathology in Braak stage II. In the Braak stages IV and V, the stratum radiatum was completely involved, the stratum oriens increasingly so. Beginning in Braak stage III, we noted cases having PHF-tau pathology in the perforant path target zone of the outer molecular layer of the dentate gyrus. The increase of this pathology with ever greater involvement on the part of the entorhinohippocampal circuit correlated significantly not only with the Braak stages and with the neurochemically determined hippocampal content of PHF-tau but also with the degree of dementia as defined by the clinical dementia rating (CDR) scale. The affection of the stratum oriens in combination with PHF-tau pathology in the stratum radiatum and in the outer molecular layer of the dentate gyrus was encountered almost exclusively in demented individuals (CDR 1-3). These results indicate that axonal PHF-tau pathology in hippocampal pathways presumably is critical for the clinical expression of dementia and may constitute an anatomical substrate of clinically verifiable memory dysfunction in Alzheimer's disease.

Aged↗

Pathological and biochemical characterization of microcystin-induced hepatopancreas and kidney damage in carp (Cyprinus carpio).

Mass occurrences of cyanobacteria, due to their inherent capacity for toxin production, specifically of microcystins (MC), have been associated with fish kills worldwide. The uptake of MC-LR and the sequence of pathological and associated biochemical changes was investigated in carp (Cyprinus carpio) in vivo over 72 h. Carp were gavaged with a single sublethal bolus dose of toxic Microcystis aeruginosa (PCC 7806) amounting to an equivalent of 400 microg MC-LR/kg body wt. Damage of renal proximal tubular cells and hepatocytes was observed as early as 1 h, followed by pathological changes in the intestinal mucosa at approximately 12 h postdosing. These alterations were characterized in hepatopancreas by a dissociation of hepatocytes, an early onset of apoptotic cell death, and delayed cell lysis. In the renal proximal tubules (P2) observations included increased vacuolation of individual tubular epithelial cells, apoptosis, cell shedding, and finally proteinaceous casts at the cortico-medullary junction. Concurrently with the pathological alterations, MC-immunopositive staining was observed in hepatocytes and the proximal tubular cells; the staining increasing in the hepatopancreas in intensity with increasing time postdosing. The presence of apoptotic cell death was determined using in situ fragment end labeling (ISEL) of the respective tissue sections and agarose gel electrophoresis for detection of DNA-laddering. The analysis of carp tissue extracts (hepatopancreas, kidney, GI tract, skeletal muscle, brain, heart, spleen, and gills) demonstrated MC-LR adducts having molecular weights of 38 kDa (putatively catalytic subunit of protein phosphatases-1 and -2A) and 28 kDa, respectively. An additional band was found to be present at 23 kDa in both hepatopancreas and kidney. The present data demonstrate that, in comparison to the pathological events in salmonids exposed to MC, where a slower development of pathology and primarily necrotic cell death prevails, the pathology in carp develops rapidly and at lower toxin concentrations. This is most likely due to a more efficient uptake of toxin, while the mechanism of cell death is primarily apoptosis.

Animals↗

Studies of tissue PO2 in normal and pathological human brain cortex.

Brain cortex PO2 was measured after craniotomy and opening of the dura mater in 26 patients. We determined the brain tissue PO2 under standard narcotic conditions and after changing arterial PO2 and PCO2. Patients were divided into two groups (normal and pathological), depending on the aspect of their cortex on Ct/MRI and intraoperative appearance of the cortex. No statistical significantly difference was seen between tissue PO2 of the normal and the pathological group. A significant difference was seen only between the normal group and a subgroup with brain swelling (p = 0.0344). In the normal group no correlation was seen between tissue PO2 and arterial PO2 (r = 0.1541, p = 0.3076), whereas in the pathological group and especially in the oedema subgroup there was a highly significant correlation between tissue PO2 and PaO2 (r = 0.754, p = 0.0015 and r = 0.888, p = 0.0007). Breathing 100% oxygen changed tissue PO2 to 137.8 or 352 mmHg in the normal or the pathological group, respectively. Again, there was no correlation between tissue PO2 and PaO2 in the normal group (r = 0.1071, p = 0.392), whereas this correlation was significant in the pathological and the oedema subgroup (r = 0.6291, p = 0.0473 and r = 0.8385, p = 0.0185). This is evidence for regulatory mechanisms of tissue PO2. During hyperventilation no significant difference in tissue PO2 between the normal and the pathological group was seen. Low tissue PO2 values, however, indicate a risk for inducing ischemia.

Adult↗

[Pathologic fractures: diagnostic and therapeutic considerations and results of treatment].

Compared with bone fractures caused by trauma, pathologic fractures due to diseased bone are rare events. A pathologic fracture is one that occurs without adequate trauma and is caused by a benign or malignant bone lesion. Diagnosis of the basic disease is important for the subsequent therapy. In cases of benign bone lesions the aim of treatment is total osseus healing with complete restoration of function. In malignant pathologic fractures surgery is an essential part of the overall oncologic treatment design. In most cases it is combined with adjuvant therapy. Various surgical procedures are available for fractures at different sites and depending on whether the operation is performed with curative or palliative intent. In cases of progressive neoplastic disease stabilization is necessary to attenuate pain and to maintain mobility. Between 1983 and 1993 we treated 131 patients with 143 pathologic fractures. Conservative therapy was possible in 10 cases, while 133 fractures had to be treated surgically. Most fractures were caused by skeletal metastasis (61), solitary bone cysts (19), osteoporosis (17) and plasmocytoma (16). The most frequent localizations of pathologic fractures were humerus and femur. The favoured methods of surgical stabilization were endoprosthesis and reinforced osteosynthesis. Most fractures appeared in adolescent patients up to the age of 19 and in adults between the 5th and the 7th decade, and 57.3% of the fractures were caused by a primary or secondary malignant tumour lesion. Surgical treatment was performed in all but 1 case of malignant pathologic fractures. Of 74 patients, with malignant bone lesions 6 (8.1%), are still alive. For 68 patients who died after stabilization, the average survival time was 11.6 months; individual survival time depended on the kind of the tumour present. In 55 patients with fractures in the area of benign bone lesions complete healing was achieved, in 9 cases with conservative therapy. The rate of recurrence for solitary bone cysts treated by curettage or segment resection was 23.5%. Compared with the recurrence rates published by other authors this is a very good result.

Adolescent↗

Feasibility study of a statewide pathology-based cancer surveillance system in Minnesota. I. Information characteristics.

The Minnesota Department of Health has completed a 2-year feasibility study comparing the completeness and accuracy of information from pathology-based cancer ascertainment with that of the traditional surveillance method based on hospital discharge records. Overall, for incident cancers, the primary site designation of the pathology-based system was correct for 94.5% of the cancers, and the histologic designation was correct for 97.0% of the cancers. For prevalent cancers the accuracy of both site and histology designation was inadequate at 81.0 and 76.8% respectively. Pathology-based ascertainment was more complete than discharge-based surveillance (98.4% vs. 96.6%), which reflected the growing number of cancers diagnosed in hospital outpatient departments and medical clinics. The major limitation of the pathology-based system was the inability to determine from written pathology reports whether the cancer was newly diagnosed. However, when asked, pathologists correctly determined the incidence status for approximately 75% of the cancers. In light of the results of the feasibility study, Minnesota is implementing a pathology-based system as a cost-effective, scientifically valid method to meet the state's current and future needs for cancer surveillance.

Data Collection↗

Comparison of pathologic characteristics of T1c and non-T1c cancers detected in a population-based screening study, the European Randomized Study of Screening for Prostate Cancer.

In recent years the introduction of serum prostate-specific antigen (PSA) determination as a screening tool for early detection of prostate cancer in asymptomatic men has led to a markedly increased detection of prostate cancers that are neither palpable nor visible with transrectal ultrasonography (stage T1c). In this preliminary study we assessed pathologic features and aspects that are indicative of clinical significance in T1c tumors and tumors with palpable or visible lesions (non-T1c tumors). Between June 1994 and December 1995, 51 consecutive radical prostatectomies were performed on screened participants in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). After determination of pathologic stage and Gleason score, morphometric analysis was performed to determine tumor volume. Radical prostatectomy specimens were divided into three mutually exclusive subsets: T1c tumors, non-T1c tumors with preoperative PSA levels below 4 ng/ml, and non-T1c tumors with PSA levels equal to or greater than 4 ng/ml. These subsets were compared for differences in the distribution of tumor volume, pathologic stage, and Gleason score. An arbitrarily constructed categorization model was used to assess clinical significance. In all, 17 (33%) of the patients had clinical stage T1c disease. In our categorization mode, 88% of the T1c tumors fit the criteria for clinically significant tumors. T1c tumors, however, were significantly smaller (P < 0.01) and were more likely to be organ-confined (P = 0.01) as compared with non-T1c tumors in patients with an elevated preoperative serum PSA level. In contrast, tumors detected at preoperative PSA levels of < 4 ng/ml had comparably the lowest pathologic stages and tumor volumes in our series. In our categorization model, 42% of these tumors fit the criteria for minimal tumor. This group of radical prostatectomies was therefore most likely to harbor clinically insignificant cancer, a finding that was consistent in two other categorization models derived from earlier reports. T1c tumors comprise a large fraction of the tumors found in population-based screening. As judged by their pathologic characteristics. T1c tumors are clinically significant tumors. The overall low pathologic stage and Gleason score of these tumors make these patients excellent candidates for curative treatment by radical prostatectomy or radiotherapy. In contrast, some concern should be raised on the detection of tumors at low serum PSA levels by means of digital rectal examination and transrectal ultrasound alone, since a substantial proportion of these tumors could be considered clinically insignificant. Long-term follow-up, however, is necessary to substantiate this view.

Aged↗

Preoperative chemoradiotherapy and radical surgery for locally advanced distal rectal adenocarcinoma: pathologic findings and clinical implications.

PURPOSE: Preoperative chemoradiotherapy followed by radical surgical resection has been the preferred treatment for patients presenting with locally advanced distal rectal carcinoma at our institutions. We postulated that chemoradiotherapy-induced pathologic response of the primary tumor would identify which patients would be candidates for local excision as definitive surgical therapy. METHODS: A retrospective analysis of 60 patients with palpable, locally advanced, distal rectal adenocarcinomas treated from 1995 to 2000 was performed. All patients received preoperative chemoradiotherapy consisting of 5-fluorouracil (325 mg/m(2)) and leucovorin (20 mg/m(2)) by bolus infusion on Days 1 through 5 and 29 through 33 delivered concurrently with at least 45.0 to 50.4 Gy of pelvic radiation, followed six to eight weeks later by radical surgery and then adjuvant chemotherapy. RESULTS: Among 60 patients (20 females) there was a mean age of 58.7 (28-84) years. Clinical staging was as follows: Stage II, 14 patients (23 percent); Stage III, 35 patients (58 percent); and Stage IV, 11 patients (18 percent). Pathologic examination revealed that negative margins were obtained in 58 patients (97 percent). Downstaging to T0-2N0 was achieved in 17 patients (28 percent), with five (8 percent) achieving a pathologically complete response. Lymph nodes were positive in 24 patients (40 percent) despite chemoradiotherapy. Pathologic node positivity was found in 0 of 5 pT0 patients, 9 (41 percent) of 22 pT1 or pT2, and 15 (45 percent) of 33 pT3. Clinical stage, tumor size, pathologic stage, and adverse histologic features could not reliably predict pN0 status, except pT0 (5 patients only). CONCLUSIONS: Preoperative chemoradiotherapy often downsizes and downstages locally advanced rectal carcinoma. Neither pretreatment clinical characteristics, response to preoperative chemoradiotherapy, or pathologic features reliably predict pN0 status. Therefore, local excision is not recommended as an alternative to radical surgery for locally advanced adenocarcinoma of the distal rectum regardless of the response of the primary tumor to preoperative chemoradiotherapy.

Adenocarcinoma↗

Concordance in pathological response to neoadjuvant chemotherapy between invasive and noninvasive components of primary breast carcinomas.

BACKGROUND: Invasive breast carcinomas are composed of invasive and noninvasive components in varying proportions and sometimes the two components show different histopathological responses to chemotherapy, however there has been no study as yet comparing the pathological response to chemotherapy of invasive and noninvasive components. PATIENTS AND METHODS: A consecutive series of 100 women neoadjuvant chemotherapy with doxorubicin and docetaxel every three weeks before surgery. After the chemotherapy, surgically resected specimens were studied histologically according to the criteria of the Japanese Breast Cancer Society. RESULTS: Five cases (5/100; 5%) were determined to show Grade 3 pathological response, and 28 cases (28/100; 28%) showed Grade 2 response. There were 6 Grade 3 (6/96; 6%) and 18 Grade 2 (18/96; 19%) invasive component cases. There were 7 Grade 3 (7/82; 9%) and 18 Grade 2 (18/82; 22%) cases showing pathological response in the noninvasive component. With regard to pathological response, there was a strong correlation between the invasive and noninvasive components (p<0.001). There was also a correlation in pathological response between the invasive component and axillary lymph nodes in individual cases (p=0.02). There was no correlation between the response of the noninvasive component and axillary lymph nodes. By multivariate analysis, the overall primary tumor response was reflected by the histological response of the invasive component in the primary breast carcinoma. CONCLUSION: We suggest that the pathological response of the invasive component of breast carcinoma should be evaluated, which might provide more accurate information for prognosis and treatment decisions.

Antineoplastic Combined Chemotherapy Protocols↗

Large-scale pathology-based cancer data--a reflection of population-based cancer data.

Pathology-based cancer data is a high quality reflection of the patterns of cancer in the population it represents, provided the demographic details of the patients are carefully recorded. Relative frequency data is neither a replacement for population-based data nor a suggested alternative; it simply enhances the quality of population data and in very large data sets reflects the cancer patterns observed in the representative populations. Aware of the standard shortfalls of pathology-based data, the department of pathology, The Aga Khan University Hospital (AKUH) standardized its data, representing 53.4% of the cancer data of Karachi Division (Pakistan) and also reflecting the cancer pattern of other provinces of Pakistan. This data was compared with 4 different population and institutional-based data sets. The findings substantiate the observation that despite the problems of interpretation of data from pathology laboratories, they are an invaluable source of information on cancer patterns in much of the world where incidence data are unavailable . If developing countries, unable to organize National Population- Based Registry should as an alternate develop National Pathology-based Registers a well targeted and monitored, a Cancer Control Program would be possible. A good quality, large-scale pathology data with demographic details of the patient recorded can also be extended to give coverage to the population.

Female↗

["Pathological intoxication."Diagnostic artefact or a reliable psychiatric diagnosis?].

"Pathological intoxication" has been a matter of controversial discussions during the last years. On one hand diagnosis of "pathological intoxication" in forensic expertise often is associated with the assumption of legal insanity. On the other hand it has been suggested that the term "pathological intoxication" should be abandoned in favor of more accurate clinical diagnosis, and recently "alcoholic idiosyncratic intoxication" was canceled as a separate diagnosis in DSM-IV. In order to register the diagnostic habits connected with "pathological intoxication" we had sent a questionnaire to all psychiatric institutes (n = 541) in Germany. We were then able to evaluate 338 questionnaires (62.5%) relating to number of diagnoses and diagnostic criteria. In synopsis diagnostic habits turned out to be very inhomogeneous. Nearly two third of psychiatric institutes reported not to have used the diagnostic category between 1991 and 1993, whereas nearly 50% of diagnoses (210 out of 456) were reported by only 13 (3.9%) institutes. Diagnosis of "pathological intoxication" is based predominantly on vague and non-distinct criteria, such as "violent excitation" or "strange unusual behavior". In accordance to DSM-IV we therefore suggest that the diagnostic term "pathological intoxication" should be abandoned, especially in the context of forensic psychiatric expertise. Instead, assessment of intoxication must be based on individual somatic and psychopathological symptoms.

Academies and Institutes↗

The role of meniscal root pathology and radial meniscal tear in medial meniscal extrusion.

OBJECTIVE: The purpose of our study was twofold: to better understand the relationship between medial meniscal extrusion (MME) and degenerative joint disease (DJD), and to determine whether a relationship exists between MME and medial meniscal root (MMR) pathology, radial tear and joint effusion. DESIGN AND PATIENTS: Two hundred and five consecutive MR imaging examinations of the knee were prospectively evaluated, regardless of indication, for the presence and degree of MME, medial compartment marginal osteophytes, medial compartment articular cartilage loss, joint effusion, medial meniscal tear and MMR pathology. MME >or=3 mm was considered abnormal. All studies were performed using a 1.5 T GE Signa MR unit with a quadrature knee coil. The standard protocol included oblique sagittal, coronal and axial imaging. RESULTS: We found a strong association ( P<0.0001) between >or=3 mm MME and medial joint line osteophytosis (77%), medial compartment articular cartilage loss (69%), MMR pathology (64%) and radial tear (58%) when compared with knees without these findings. Fifty-one percent of cases with a moderate/large joint effusion had <3 mm MME. We found that 20% (31/155) of patients with minimal or no evidence of DJD had >or=3 mm MME. Of this group, 62% (19/31) had either MMR pathology and/or radial tear, 13% (4/31) had joint effusion as their only abnormality and 6% (2/31) had a normal examination (other than the presence of MME). The remaining 19% consisted of three cases of different types of meniscal tear and three cases of small joint effusions but no other detectable pathology. CONCLUSION: MME >or=3 mm is strongly associated with DJD, MMR pathology and radial tear. A significant number of cases with no or minimal evidence of DJD (20%) had >or=3 mm MME, suggesting that MME precedes, rather than follows, the development of DJD. We also found that joint effusion was not strongly associated with >or=3 mm MME.

Adolescent↗

Instrumental clinical restaging, pathological evaluation, and tumor regression grading: how to assess the response to neoadjuvant chemoradiotherapy for rectal cancer.

INTRODUCTION: The object of neoadjuvant chemoradiotherapy regimens is a downstaging or downsizing of advanced rectal tumor to increase the rate of curative resection and reduce loco-regional failure. A reliable method of assessing response to adjuvant therapies is required to help standardize the assessments of new multimodality therapies. The purpose of this study was to evaluate the role played by tumor regression grading on the evaluation of pathological response to chemoradiotherapy, compared with both the predicting value of the clinical response to neoadjuvant therapy and pathologic response evaluation. METHODS: From 1994 to 2003, 58 patients with a primary diagnosis of rectal cancer were studied at our department and enrolled in a single center, not randomized study based on 5-week sessions of radiotherapy associated with a 30-day 5-fluorouracil (FU) infusion, followed by surgical resection. Instrumental restaging and routine histological examination, including tumor regression grading, were performed to asses the response to neoadjuvant therapy. RESULTS: The cCR rate corresponds to pCR rate, while a 3.5% of cPR and a 3.4% of cSD corresponded to a pPD. cPR and cSD show a PPV of 92.8% and 90.9% respectively, while cPD NPV is 20%. No case was found with no regression (grade 0). Tumor regression was defined grade 1 in 24.5% of cases, grade 2 was found in 58.5% of cases, 7.5% were grade 3, and 9.5% showed complete regression (grade 4). Pathologic response resulted to be associated with regression grade (p=0.006). Tumor regression grading is an independent variable for pT (p=0.0002), pN status (p=0.00004), pathologic staging (p=0.000001) and local recurrence (p=0.003). CONCLUSION: Our results lead us to consider only pathologic evaluation to determine the response to neoadjuvant treatment: the application of tumor regression grading on the specimens obtained after combined neoadjuvant chemoradiotherapy and surgery is useful to plan a better therapeutic strategy on the ground of a quantitative evaluation of the response to neoadjuvant treatment; it shows it is an important comparable pathological feature, useful in comparing different protocols' results and differences between patient's response as well as prognostic factors.

Adult↗

Alzheimer's disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is defined by beta-amyloid peptide (Abeta) depositions in cerebral vessels and is associated with Alzheimer's disease (AD). The relationship between sporadic CAA and AD, and the origin of Abeta in CAA are poorly understood. The aim of our study was to investigate the relationship between CAA and AD. Autopsy brains (n=113, 61.1% female, 55.8% clinically demented, age range 54-102 years, mean +/- SE 83.5+/-0.93 years) underwent standardized neuropathological assessment. CAA was evaluated in frontal, frontobasal, hippocampal, and occipital regions. Using immunohistochemistry, the severity of Abeta deposition in vessels was assessed semiquantitatively for each region separately. Evaluation of APOE genotype in 53 cases using real-time PCR showed significant correlations with severe AD pathology and CAA. CAA was present in 77 cases (68.1%), with the occipital region being affected significantly more often and more severely than other regions (P<0.01). Of brains without AD pathology 23.5% revealed CAA, whereas 24% with AD pathology showed no CAA. In concordance with other studies, the severity of both AD pathology and CAA showed a low, but significant correlation. This correlation, however, was only caused by the significant increase of occipital CAA with increasing AD pathology (P<0.01), and was independent of APOE genotype. Our results suggest that progressing AD pathology not only increases the severity of CAA, but also shifts its topographical distribution towards the occipital cortex.

Aged↗

Tau and alpha-synuclein brainstem pathology in Alzheimer disease: relation with extrapyramidal signs.

Extrapyramidal symptoms (EPS) in Alzheimer disease (AD) often increase with disease severity. Their neuropathological substrate is a matter of discussion. We investigated tau and alpha-synuclein (AS) pathologies in brainstem in AD patients with and without EPS. Among 160 elderly subjects with autopsy-proven AD (110 female, 50 male, aged 61-102, mean 84.1 +/- 8.3 SD years), 151 (94.4%) being demented, 35 (21.9%) had clinically reported EPS (rigidity, bradykinesia, gait impairment). Neuropathological examination included standardized classification of AD according to current criteria, and semiquantitative assessment of neuronal loss in substantia nigra (SN), locus coeruleus (LC), and of tau and AS lesions in brainstem, and, in addition, of cerebrovascular lesions. The prevalence of EPS was only slightly more frequent in higher Braak stages. Tau pathology in brainstem significantly increased with increasing Braak stages, while AS lesions did not. EPS correlated best with SN cell loss (P < 0.001) and much less with AS pathology in several brain areas (P < 0.05), except in medulla oblongata (P < 0.001). Although both pathologies in substantia nigra correlated with neuron loss (P < 0.001), nigral tau lesions, present in 88.5% of EPS positive cases (without AS lesions in 55.6%), did not correlate with EPS. Additional cerebrovascular changes apparently did not influence the development of EPS symptoms in fully developed AD. With other recent data, these results suggest that neuronal loss in SN, partly related to tau lesions, is a major pathological substrate of EPS in AD, but some cases with and without EPS may show no or only minimal nigral changes. However, often associated with nigral tau lesions and higher Braak stages, EPS in elderly patients may be a surrogate marker for severe neuritic AD pathology.

Aged↗