EuGMS Task and Finish group on Fall-Risk-Increasing Drugs (FRIDs): Position on Knowledge Dissemination, Management, and Future Research.

Falls are a major public health concern in the older population, and certain medication classes are a significant risk factor for falls. However, knowledge is lacking among both physicians and older people, including caregivers, concerning the role of medication as a risk factor. In the present statement, the European Geriatric Medicine Society (EuGMS) Task and Finish group on fall-risk-increasing drugs (FRIDs), in collaboration with the EuGMS Special Interest group on Pharmacology and the European Union of Medical Specialists (UEMS) Geriatric Medicine Section, outlines its position regarding knowledge dissemination on medication-related falls in older people across Europe. The EuGMS Task and Finish group is developing educational materials to facilitate knowledge dissemination for healthcare professionals and older people. In addition, steps in primary prevention through judicious prescribing, deprescribing of FRIDs (withdrawal and dose reduction), and gaps in current research are outlined in this position paper.

Immediate and delayed neuroendocrine responses to social exclusion in males and females.

Social exclusion is a complex phenomenon, with wide-ranging immediate and delayed effects on well-being, hormone levels, brain activation and motivational behavior. Building upon previous work, the current fMRI study investigated affective, endocrine and neural responses to social exclusion in a more naturalistic Cyberball task in 40 males and 40 females. As expected, social exclusion elicited well-documented affective and neural responses, i.e., increased anger and distress, as well as increased exclusion-related activation of the anterior insula, the posterior-medial frontal cortex and the orbitofrontal cortex. Cortisol and testosterone decreased over the course of the experiment, whereas progesterone showed no changes. Hormone levels were not correlated with subjective affect, but they were related to exclusion-induced neural responses. Exclusion-related activation in frontal areas was associated with decreases in cortisol and increases in testosterone until recovery. Given that results were largely independent of sex, the current findings have important implications regarding between-sex vs. within-sex variations and the conceptualization of state vs. trait neuroendocrine functions in social neuroscience.

Prospective assessment of white matter integrity in adult stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) is often used in the treatment of hematologic disorders. Although it can be curative, the pre-transplant conditioning regimen can be associated with neurotoxicity. In this prospective study, we examined white matter (WM) integrity with diffusion tensor imaging (DTI) and neuropsychological functioning before and one year after HSCT in twenty-two patients with hematologic disorders and ten healthy controls evaluated at similar intervals. Eighteen patients received conditioning treatment with high-dose (HD) chemotherapy, and four had full dose total body irradiation (fTBI) and HD chemotherapy prior to undergoing an allogeneic or autologous HSCT. The results showed a significant decrease in mean diffusivity (MD) and axial diffusivity (AD) in diffuse WM regions one year after HSCT (p-corrected <0.05) in the patient group compared to healthy controls. At baseline, patients treated with allogeneic HSCT had higher MD and AD in the left hemisphere WM than autologous HSCT patients (p-corrected <0.05). One year post-transplant, patients treated with allogeneic HSCT had lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the right hemisphere and left frontal WM compared to patients treated with autologous HSCT (p-corrected <0.05).There were modest but significant correlations between MD values and cognitive test scores, and these were greatest for timed tests and in projection tracts. Patients showed a trend toward a decline in working memory, and had lower cognitive test scores than healthy controls at the one-year assessment. The findings suggest a relatively diffuse pattern of alterations in WM integrity in adult survivors of HSCT.

The impact of social exclusion vs. inclusion on subjective and hormonal reactions in females and males.

BACKGROUND: The experience of social exclusion represents an extremely aversive and threatening situation in daily life. The present study examined the impact of social exclusion compared to inclusion on steroid hormone concentrations as well as on subjective affect ratings. METHODS: Eighty subjects (40 females) participated in two independent behavioral experiments. They engaged in a computerized ball tossing game in which they ostensibly played with two other players who deliberately excluded or included them, respectively. Hormone samples as well as mood ratings were taken before and after the game. RESULTS: Social exclusion led to a decrease in positive mood ratings and increased anger ratings. In contrast, social inclusion did not affect positive mood ratings, but decreased sadness ratings. Both conditions did not affect cortisol levels. Testosterone significantly decreased after being excluded in both genders, and increased after inclusion, but only in males. Interestingly, progesterone showed an increase after both conditions only in females. DISCUSSION: Our results suggest that social exclusion does not trigger a classical stress response but gender-specific changes in sex hormone levels. The testosterone decrease after being excluded in both genders, as well as the increase after inclusion in males can be interpreted within the framework of the biosocial status hypothesis. The progesterone increase might reflect a generalized affiliative response during social interaction in females.

A prospective evaluation of changes in brain structure and cognitive functions in adult stem cell transplant recipients.

Hematopoietic stem cell transplantation (HSCT) is an efficacious treatment for many hematologic malignancies. However, the conditioning regimen of high-dose (HD) chemotherapy with or without total body irradiation (TBI) can be associated with neurotoxicity. In this prospective study, we used quantitative neuroimaging techniques to examine regional gray matter and ventricular volumes, and standardized neuropsychological tests to assess cognitive function before and 1 year after HSCT in 28 patients with hematologic malignancies and in ten healthy controls evaluated at similar intervals. Nineteen patients received conditioning treatment with HD chemotherapy alone and nine had both TBI and HD chemotherapy. There was a significant reduction in gray matter volume in the middle frontal gyrus bilaterally and in the left caudate nucleus in the patient group (all patients combined) but not among healthy controls over the 1-year follow-up period. There was a significant increase in left lateral ventricle volume and in total ventricle volume in the patient group, relative to healthy controls. Similar brain structural changes were seen for patients treated with HD chemotherapy alone. The neuropsychological results showed that 21% of patients could be classified as impaired at baseline. The Reliable Change Index suggested no significantly different rates of cognitive decline between patients and healthy controls. The findings suggest that HSCT patients may be at an increased risk for developing regional brain volume loss, and that subgroups may experience cognitive dysfunction prior to and 1 year following the transplant.

Lactate MRSI and DCE MRI as surrogate markers of prostate tumor aggressiveness.

Longitudinal studies of lactate MRSI and dynamic contrast-enhanced MRI were performed at 4.7 T in two prostate tumor models grown in rats, Dunning R3327-AT (AT) and Dunning R3327-H (H), to determine the potential of lactate and the perfusion/permeability parameter Ak(ep) as markers of tumor aggressiveness. Subcutaneous AT (n = 12) and H (n = 6) tumors were studied at different volumes between 100 and 2900 mm(3) (Groups 1-5). Lactate concentration was determined using selective multiple quantum coherence MRSI with the phantom substitution method. Tumor enhancement after the administration of gadolinium diethylenetriaminepenta-acetic acid was analyzed using the Brix-Hoffmann model and the Ak(ep) parameter was used as a measure of tumor perfusion/permeability. Lactate was not detected in the smallest AT tumors (Group 1; 100-270 mm(3) ). In larger AT tumors, the lactate concentration increased from 2.8 ± 1.0 mm (Group 2; 290-700 mm(3)) to 8.4 ± 2.9 mm (Group 3; 1000-1340 mm(3)) and 8.2 ± 2.2 mm (Group 4; 1380-1750 mm(3) ), and then decreased to 5.0 ± 1.7 mm (Group 5; 1900-2500 mm(3)), and was consistently higher in the tumor core than in the rim. Lactate was not detected in any of the H tumors. The mean tumor Ak(ep) values decreased with increasing volume in both tumor types, but were significantly higher in H tumors. In AT tumors, the Ak(ep) values were significantly higher in the rim than in the core. Histological hypoxic and necrotic fractions in AT tumors increased with volume from 0% in Group 1 to about 20% and 30%, respectively, in Group 5. Minimal amounts of hypoxia and necrosis were found in H tumors of all sizes. Thus, the presence of lactate and heterogeneous perfusion/permeability are signatures of aggressive, metabolically deprived tumors.

Bone matrix quality and plasma homocysteine levels.

It has recently been reported in the clinical literature that blood homocysteine levels correlate well with fracture risk, although a couple of reports exist to the opposite. Bone strength depends on both bone quantity and quality. The purpose of the present study was to investigate possible correlations between plasma homocysteine levels and bone material properties (Bone Mineral Density Distribution; BMDD, and collagen cross-link ratio). In the present study, femoral heads from subjects (N=19, females, age range 70-95 years old) with known homocysteine plasma levels were investigated. The bone material was collected during hemiarthroplasty surgery. We have determined collagen cross-link ratio and bone mineralization density distribution (BMDD) in bone tissue from patients with acute femoral neck fractures, by Fourier Transform Infrared Imaging (FTIRI) and quantitative Backscattered Electron Imaging (qBEI), respectively. The collagen cross-link ratio that was spectroscopically determined was pyridinoline/divalent cross-links (pyr/divalent). The BMDD variables quantified were: CaMean: the weighted mean calcium concentration; CaPeak: the most frequent Ca concentration; CaWidth: the width of the distribution, a measure of the mineralization homogeneity; CaLow: the percentage of bone area that is mineralized below the 5th percentile in the reference range; CaHigh: the percentage of bone area that is mineralized above the 95th percentile in the reference range. There was a significant correlation between plasma homocysteine levels and collagen cross-link ratio in areas of primary mineralized bone (p<0.0001), unlike the case of trabecular bone surfaces undergoing resorption (p>0.05). On the other hand there was no correlation in any of the BMDD parameters and plasma homocysteine levels (p>0.05). The results are consistent with the known effect of homocysteine on collagen post-translational modifications. These changes were independent of bone mineral characteristics. The results of the present study offer a mechanism by which homocysteine affects bone quality, but caution should be exercised since all patients examined had sustained fracture.

Early CA-125 fluctuations in patients with recurrent ovarian cancer receiving chemotherapy.

The objective of this study was to analyze retrospective populations with recurrent ovarian cancer to assess differences in CA-125 patterns during chemotherapy. The populations included all patients treated between January 1994 and January 2004, who received liposomal doxorubicin and topotecan, and all patients treated between July 1997 and June 2001, who received carboplatin. Prognostic variables were abstracted from the medical records. Eighty-nine patients received liposomal doxorubicin and topotecan therapy and 21 received carboplatin; of these, 59 (liposomal doxorubicin), 60 (topotecan), and 17 (carboplatin) patients had evaluable CA-125 patterns. Patients given liposomal doxorubicin were more likely to have received only one or two cycles of therapy (37/89 [42%]) than patients receiving either carboplatin (5/21 [24%]) or topotecan (20/89[22%]). In cycle 1, CA-125 increases in patients were carboplatin, 4/17 (24%); liposomal doxorubicin, 41/59 (69%); and topotecan, 11/60 (18%). In cycle 2, CA-125 increases were carboplatin, 2/16 (13%); liposomal doxorubicin, 19/37 (51%); and topotecan, 9/50 (18%). In cycle 3, CA-125 increases were carboplatin, 0/12 (0%); liposomal doxorubicin, 7/23 (30%); and topotecan, 6/38 (16%). Of patients having any CA-125 decrease and given two or more cycles, fewer declines were seen in those given liposomal doxorubicin precycle 2 (18/35[51%]) than in those given carboplatin (13/16[81%]) or topotecan (49/56[88%]). The most prominent delay in CA-125 decline was in patients given liposomal doxorubicin compared with those given topotecan or carboplatin. In the entire population, only 3 of 107 (2.8%) patients demonstrated first CA-125 decline precycle 4. Discontinuation of therapy solely on the basis of early CA-125 increase (precycle 3), particularly with liposomal doxorubicin chemotherapy, may exclude some patients who will benefit from continued therapy.

Neuroendocrine carcinomas of the colon and rectum.

PURPOSE: This study was designed to review experience with neuroendocrine carcinomas of the colon and rectum at a single institution, with emphasis on the pathology and clinical characteristics of this uncommon malignancy. METHODS: A study group of patients was identified from a prospective colorectal service database. Pathology was reviewed and neuroendocrine tumors were classified by a single pathologist. Medical records were retrospectively reviewed. RESULTS: From March 1975 to September 1998, 38 patients with neuroendocrine carcinomas were identified from the colorectal service database comprising 6495 patients (0.6 percent). These neuroendocrine carcinomas did not include carcinoid tumors. Average patient age was 57 years (range, 29-86 years). There were 17 males (44.7 percent) and 21 females (55.3 percent). Tumors were located as follows: 17 colon, 14 rectum, 6 anal canal, and 1 appendix. The diagnosis of neuroendocrine carcinoma was suggested preoperatively from tissue biopsy in 59.3 percent (16/27) of patients evaluable. Pathology was reviewed and tumors were categorized as small cell carcinoma (n = 22) or large cell neuroendocrine carcinoma (n = 16). Most tumors (20/25 evaluable, 80 percent) stained positive by means of immunohistochemistry for neuroendocrine markers, including chromogranin (18/19), synaptophysin (10/15), and/or neuron-specific enolase (14/15). Metastatic disease was detected at the time of diagnosis in 69.4 percent of the patients (25/36). Tumors were advanced at the time of diagnosis, with American Joint Committee on Cancer (AJCC) Stage I (n = 6), Stage III (n = 7), and Stage IV (n = 25) tumors. As a group, these tumors had a poor prognosis, with a median survival of 10.4 months. One-year, two-year, and three-year survival was 46 percent, 26 percent, and 13 percent, respectively. There was no significant difference in survival based on pathologic subtypes. Median follow-up time was 9.4 months (range, 0.6-263.7 months). CONCLUSIONS: Neuroendocrine carcinomas of the colon and rectum are uncommon, comprising less than 1 percent of colon and rectal cancers. Pathologically, these tumors are poorly differentiated carcinomas with distinctive cytoarchitectural features and are often immunoreactive for markers of neuroendocrine differentiation. The prognosis for high-grade neuroendocrine carcinomas is poor, as most patients have metastatic disease at the time of diagnosis.

Cognitive functions in survivors of primary central nervous system lymphoma.

BACKGROUND: The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based (MTX) chemotherapy and whole brain radiotherapy (WBRT). This combined regimen prolongs patient survival, but also carries a substantial risk for delayed neurotoxicity particularly in the elderly. However, cognitive outcome evaluations have not been included in most clinical trials. OBJECTIVE: To assess cognitive functioning and quality of life in PCNSL survivors treated either with WBRT +/- MTX-based chemotherapy or chemotherapy alone. METHODS: Twenty-eight PCNSL patients in disease remission received a post-treatment baseline neuropsychological evaluation, and a subset of patients were available for an 8-month follow-up evaluation. Assessment of quality of life and extent of white matter disease on MRI were also performed. RESULTS: Patients displayed mild to moderate impairments across several cognitive domains. These were of sufficient severity to reduce quality of life in half of the patient sample. Comparisons according to treatment type revealed more pronounced cognitive impairment, particularly in the memory and attention/executive domains, among patients treated with WBRT +/- chemotherapy. Extent of white matter disease correlated with attention/executive, memory, and language impairment. CONCLUSIONS: PCNSL survivors treated with WBRT +/- chemotherapy displayed more pronounced cognitive dysfunction than patients treated with MTX-based chemotherapy alone.

Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of a haematopoietic stem cell clone with a PIG-A mutation (the PNH clone) in an environment in which normal stem cells are lost or failing: it has been hypothesized that this abnormal marrow environment provides a relative advantage to the PNH clone. In patients with PNH, generally, the karyotype of bone marrow cells has been reported to be normal, unlike in myelodysplastic syndrome (MDS), another clonal condition in which cytogenetic abnormalities are regarded as diagnostic. In a retrospective review of 46 patients with a PNH clone, we found a karyotypic abnormality in 11 (24%). Upon follow-up, the proportion of cells with abnormal karyotype decreased significantly in seven of these 11 patients. Abnormal morphological bone marrow features reminiscent of MDS were common in PNH, regardless of the karyotype. However, none of our patients developed excess blasts or leukaemia. We conclude that in patients with PNH cytogenetically abnormal clones are not necessarily malignant and may not be predictive of evolution to leukaemia.

Impact of a surgeon-trained observer on accuracy of colorectal surgical site infection rates.

PURPOSE: The aims of this study were 1) to establish accurate and reproducible baseline surgical site infection rates for our department and 2) to identify risk factors associated with surgical site infection in patients undergoing surgery on a colorectal service. METHODS: Phase I--Surgical site infection grading between the surgeon-trainer and the observer-trainee was validated using a four-point scale for wound evaluation previously used by our institution. Phase II--Patients undergoing colorectal surgery were prospectively monitored. The observed surgical site infection rate was compared with morbidity and mortality reports. Patient and perioperative variables were analyzed for their effect on surgical site infection using the chi-squared test. Risk factors approaching significance on univariate analysis (P < 0.2) were entered into a multivariate stepwise logistic regression model. RESULTS: Concordance on surgical site infection grading between the surgeon-trainer and the observer-trainee improved from an initial 79 percent to 96 percent during the validation period. The surgeon-trained observer reported a surgical site infection rate of 7.2 percent vs. a morbidity and mortality reported rate of 3.3 percent. Among the variables examined, obesity and surgical procedure category were significantly associated with surgical site infection rates. The effect of prophylactic antibiotics and prior chemotherapy, radiation, or steroid therapy on surgical site infection rates approached significance. A logistic regression analysis incorporating these risk factors for surgical site infection accurately predicted infection status 93 percent of the time. CONCLUSION: Use of a surgeon-trained observer doubles the detection rate of postoperative surgical site infection. Accurate, prospective assessment identifies risk factors significantly associated with increased surgical site infection rates in colorectal surgical patients.

Thromboprophylaxis with 60 mg enoxaparin is safe in hip trauma surgery.

BACKGROUND: Little information is available concerning dosage and optimal initiation of thromboprophylactic therapy with low-molecular-weight heparin (enoxaparin) in nonelective hip surgery. The aim of our prospective study was to evaluate the incidence of clinically apparent deep vein thrombosis (DVT), pulmonary embolism (PE), and major hemorrhage in patients receiving thromboprophylaxis with enoxaparin undergoing hip surgery after hip fracture. METHOD: From 946 consecutive patients admitted with hip fractures, 897 were operated on and received enoxaparin according to the following regimen: Preoperative heparinization from time of admission onwards. Administration of 60 mg enoxaparin, in two doses (20 and 40 mg subcutaneously), during the first 5 days postoperatively. Prophylaxis for a minimum of 5 weeks (40 mg daily). RESULTS: Clinical signs of DVT were present in 37 patients (4.2%), who all underwent venography. In five patients, DVT was confirmed (0.6%). None of these patients suffered from PE. Another four patients (0.4%) developed clinical signs of PE, and suspected diagnosis was confirmed by computed tomographic scan in two (0.2%). No deaths because of PE were observed. Major hemorrhage occurred in 42 patients (4.7%), there was one death from hemorrhage caused by an intracerebral event. No case of heparin-induced thrombocytopenia type II was observed. CONCLUSION: Thromboprophylaxis with 60 mg enoxaparin daily, in split doses, starting before surgery, is safe and appropriate in patients with hip fractures. Clinically apparent DVT and PE are rarely observed, and bleeding complications are comparable to those occurring with a conventional thromboprophylactic regimen.

Pap smears in women with endometrial carcinoma.

OBJECTIVE: To correlate Pap smear findings with the histology of endometrial carcinoma and stage of the disease. STUDY DESIGN: Between 1995 and 1998, 76 women with endometrial carcinoma, having had Pap smears done within two to three months of hysterectomy at Memorial Sloan-Kettering Cancer Center, formed the basis for this study. All Pap smears and histologic sections were reviewed. RESULTS: Thirty-four patients had normal Pap smears (45%), and 42 had abnormal ones (55%). The mean age of the two groups was 65.1 and 65.2 years, respectively. Histologic subtypes included 44 International Federation of Gynecology and Obstetrics (FIGO) grade 1 endometrioid adenocarcinoma (low grade) and 32 high grade carcinomas, including 19 FIGO grade 2 or 3 endometrioid adenocarcinomas, 5 papillary serous carcinomas (PSC), 2 clear cell carcinomas (CC), 1 adenosquamous carcinoma, 3 endometrioid adenocarcinomas mixed with PSC and 2 endometrioid adenocarcinomas mixed with CC. The proportions of patients with low and high grade tumors with abnormal Pap smears were 43% (19/44) and 72% (23/32), respectively (P=.01). The proportions of patients with abnormal Pap smears and no myometrial invasion, invasion of <50% and >50% myometrial thickness were 40% (8/20), 62% (26/42) and 57% (8/14), respectively (P =.27). Vascular invasion was identified in 56% (9/16) of patients with abnormal Pap smears and in 55% (33/60) of patients with normal ones (P = .93). The proportions of patients having abnormal Pap smears with stage I and stages II, III or IV disease were 48% (30/62) and 86% (12/14), respectively (P =.01). CONCLUSION: Although the Pap smear is not a sensitive screening test for endometrial cancer and a negative Pap smear does not rule it out, this study revealed that abnormal Pap smears are significantly associated with high grade of tumor and stage II-IV endometrial carcinoma. However, they are not associated with patient age, depth of myometrial invasion or vascular invasion.

Testicular microlithiasis: what is its association with testicular cancer?

PURPOSE: To determine the prevalence of testicular microlithiasis in patients who were referred for scrotal ultrasonography (US) at a tertiary care cancer center and to evaluate the association between microlithiasis and cancer. MATERIALS AND METHODS: Testicular sonograms obtained in 528 men were retrospectively reviewed to identify patients with US findings suggestive of microlithiasis, intratesticular masses, and intratesticular heterogeneous changes. The association of US findings with medical records and with histopathologic findings that were available in 95 patients was evaluated. Statistical analysis was performed to determine the relationship of testicular cancer, intratesticular mass, and microlithiasis. RESULTS: Forty-eight (9%) of the 528 patients had microlithiasis; 13 of these (27%) had testicular cancers. Of the 480 patients without microlithiasis, 38 (8%) had testicular cancer. Ninety patients had an intratesticular mass, of whom 23 (26%) had microlithiasis. Forty-three (12 with microlithiasis) patients with a mass had testicular cancer, 43 (10 with microlithiasis) had benign findings or nontesticular malignant histopathologic findings, and four (one with microlithiasis) had no pathologic findings. CONCLUSION: Intratesticular microlithiasis is highly associated with confirmed testicular cancer, as well as with US evidence of testicular mass.

Effects of Motexafin gadolinium on tumor metabolism and radiation sensitivity.

PURPOSE: Experiments were undertaken to determine if metabolic changes induced by Motexafin gadolinium (Gd-Tex(+2), XCYTRIN) predict time intervals between drug and radiation wherein there is enhancement of radiation efficacy. METHODS AND MATERIALS: We evaluated the effect of Gd-Tex(+2) on tumor metabolism and on tumor growth using a mouse mammary carcinoma model and (31)P nuclear magnetic resonance (NMR) experiments. Response to therapy was evaluated based on time for the tumor to regrow to pretreatment size and also tumor doubling time. RESULTS: (31)P NMR experiments indicated that Gd-Tex(+2) effected tumor energy metabolism during the first 24 hours postadministration. A decrease in phosphocreatine was noted at 2 (p < 0.04), 6 (p < 0.006), and 24 (p < 0.001) hours post Gd-Tex(+2). A decrease in nucleoside triphosphates was noted only at 2 hours (p < 0.02), with subsequent recovery at 6 hours. Phosphocreatine in control (saline treated) tumors showed a significant decrease only at 24 hours (p < 0.01). Irradiation at 2 and 6 hours post Gd-Tex(+2) induced an enhanced effect compared to radiation alone as measured by analyzing the growth curves, maximum tumor volumes, and the time for the tumors to regrow to their initial volumes. Irradiation at 24 hours post Gd-Tex(+2) induced a modest enhancement in tumor growth delay compared to radiation alone. DISCUSSION: NMR spectroscopy may be useful for monitoring tumor metabolism after treatment with Gd-Tex(+2) and administering radiation during the time of maximal efficacy of Gd-Tex(+2).

Limitations of family cancer history assessment at initial surgical consultation.

PURPOSE: Although important for the diagnosis of familial clustering of colorectal cancer and hereditary nonpolyposis colorectal cancer, the accuracy of familial cancer history assessment in the office setting has been questioned. Furthermore, there are few publications describing the optimal method for accurately capturing a family cancer history. The purpose of this study was to determine how well family cancer history is assessed in patients with early age-of-onset colorectal cancer at initial surgical consultation compared with a telephone interview and mailed questionnaire. METHODS: Medical records of patients 40 years old or younger at the time of colorectal cancer surgery were reviewed for documentation of family cancer history at initial surgical consultation. In addition, family cancer history was solicited from surviving patients or their next of kin by telephone and a mailed questionnaire. The kappa coefficient was used to measure degree of correlation between family cancer history obtained at initial surgical consultation and subsequent telephone interview and questionnaire. RESULTS: One hundred twenty-five patients were available for analysis. Family cancer history was documented on the initial surgical consultation report in 78 percent of cases. Although 31.2 percent were identified as having no family cancer history at initial surgical consultation, this proportion decreased to 13.5 percent after telephone interviews and questionnaires. Family history assessment at initial surgical consultation also failed to identify 7 of 11 individuals meeting Amsterdam criteria for hereditary nonpolyposis colorectal cancer and 10 of 16 individuals meeting modified clinical criteria for hereditary nonpolyposis colorectal cancer. CONCLUSIONS: Although family cancer history was commonly obtained during the initial surgical consultation of patients with colorectal cancer, there was a tendency to underestimate the extent of familial cancer. A telephone interview and questionnaire conducted at a later date may reveal a more comprehensive family cancer history. This is an important observation, because individuals identified as high-risk for hereditary nonpolyposis colorectal cancer or familial clustering of colorectal cancer require special consideration with respect to screening, surveillance, and surgical management.

Selective loss of KGDHC-enriched neurons in Alzheimer temporal cortex: does mitochondrial variation contribute to selective vulnerability?

THE RESEARCH OBJECTIVE: of this study was to test whether variation in mitochondrial composition is associated with "selective vulnerability" in Alzheimer brain. The term "selective vulnerability" refers to the loss of relatively vulnerable brain cells and the sparing of relatively resistant brain cells in disorders in which a genetic defect or environmental agent acts on both types of cells. The mechanisms underlying selective vulnerability are largely unknown, but mitochondria may be involved; the composition of mitochondria varies among different types of neurons, and mitochondria have an important role in cell death. Alzheimer's Disease (AD) is one of a number of neurodegenerative disorders in which both selective vulnerability and abnormalities of mitochondria occur. METHODS: We examined by immunohistochemistry the cellular distribution of a mitochondrial constituent (the alpha-ketoglutarate dehydrogenase complex, KGDHC) known to be deficient in AD, in relation to the known selective vulnerability of neurons in areas 21 and 22 of the temporal lobe in this neurodegenerative disorder. RESULTS: In normal human brain, cortical layers III and V contain neurons intensely immunoreactive for KGDHC, compared to other cells in these areas. The KGDHC-enriched cells are lost in AD (p < 0.001). In layer III, the loss of KGDHC-enriched cells is proportional to total loss of neurons, as determined by immunoreactivity to neuron specific enolase (NSE). In layer V, a higher proportion of the KGDHC-enriched neurons are lost than of other (NSE positive) neurons (p < 0.001). SIGNIFICANCE: Variations in mitochondrial composition may be one of the factors determining which cells die first when different types of cells are exposed to the same stress.

Peritoneal washings in endometrial carcinoma. A study of 298 patients with histopathologic correlation.

OBJECTIVE: To correlate findings of peritoneal washings in patients with endometrial carcinoma with histologic parameters. STUDY DESIGN: Between 1995 and 1998, 298 women with endometrial carcinoma were treated by hysterectomy with intraoperative peritoneal washings (PW) at Memorial Sloan-Kettering Cancer Center. All cytology and pathology slides were available for review. Pathologic parameters of hysterectomy specimens were evaluated and correlated with the findings of PW. RESULTS: Thirty-two patients (10.7%) had abnormal PW. Two hundred sixty-two had endometrioid adenocarcinoma; 26 of them had abnormal PW (10.0%). Thirty-six patients had other histologic subtypes (papillary serous carcinoma, clear cell carcinoma and adenosquamous carcinoma), and six of them had abnormal PW (16.7%). The incidence of abnormal PW in the two groups was not significantly different (P = .78). Among 26 patients with endometrioid adenocarcinoma and abnormal PW, there were 17 cases (9.9%) of International Federation of Gynecology and Obstetrics (FIGO) grade 1, 7 (12.7%) of grade 2 and 2 (5.7%) of grade 3 (P = .56). Ten cases (14.9%) had no myometrial invasion, 10 (7.0%) had myometrial invasion of < or = 50% of myometrial thickness, and 6 (11.5%) had invasion of > 50% of myometrial thickness (P = .18). Vascular invasion was present in 8 cases (14.8%) and absent from 17 (8.2%) (P = .14). Eighteen patients (7.6%) had stage I/II disease, and eight patients (30.8%) had stage III/IV disease (P = .001). Among 298 patients, cervicovaginal smears performed before surgery were available for review in 76. Five of the 7 patients (71.4%) with abnormal PW and 37 of the 69 patients (53.6%) with normal PW had abnormal Pap smears (P = .45). CONCLUSION: Abnormal PW did not correlate with histologic subtypes, FIGO grade, depth of myometrial invasion, vascular invasion or abnormal Pap smears. A significantly higher incidence of abnormal PW was associated with stage III/IV disease.

Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo.

Suberoylanilide hydroxamic acid (SAHA) is the prototype of a family of hybrid polar compounds that induce growth arrest in transformed cells and show promise for the treatment of cancer. SAHA induces differentiation and/or apoptosis in certain transformed cells in culture and is a potent inhibitor of histone deacetylases. In this study, we examined the effects of SAHA on the growth of human prostate cancer cells in culture and on the growth of the CWR22 human prostate xenograft in nude mice. SAHA suppressed the growth of the LNCaP, PC-3, and TSU-Pr1 cell lines at micromolar concentrations (2.5-7.5 microM). SAHA induced dose-dependent cell death in the LNCaP cells. In mice with transplanted CWR222 human prostate tumors, SAHA (25, 50, and 100 mg/kg/day) caused significant suppression of tumor growth compared with mice receiving vehicle alone; treatment with 50 mg/kg/day resulted in a 97% reduction in the mean final tumor volume compared with controls. At this dose, there was no detectable toxicity as evaluated by weight gain and necropsy examination. Increased accumulation of acetylated core histones was detected in the CWR22 tumors within 6 h of SAHA administration. SAHA induced prostate-specific antigen mRNA expression in CWR22 prostate cancer cells, resulting in higher levels of serum prostate-specific antigen than predicted from tumor volume alone. The results suggest that hydroxamic acid-based hybrid polar compounds inhibit prostate cancer cell growth and may be useful, relatively nontoxic agents for the treatment of prostate carcinoma.