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The feasibility, safety, and preliminary efficacy of a second-line combination therapy for oral topotecan and pegylated liposomal doxorubicin in patients with platinum-resistant or refractory epithelial ovarian, peritoneal, or tubal carcinoma were investigated in this phase I trial.A fixed dose of oral topotecan 2.3 or 1.53 mg/m(2) on days 1 through 5 and escalating doses of pegylated liposomal doxorubicin on day 1 of a 28-day cycle were administered. Dose-limiting toxicities and maximum tolerated doses were recorded. Safety was assessed by adverse event monitoring, and complete and partial responses were recorded.Twenty-two patients received a total of 61 courses of therapy. The maximum tolerated dose of combination therapy was 1.53 mg/m(2) of topotecan on days 1 through 5 and 40 mg/m(2) of pegylated liposomal doxorubicin on day 1 of a 28-day cycle. Because of cumulative thrombocytopenia, the dose of topotecan was decreased by one-third from 2.3 to 1.53 mg/m(2) in an effort to increase the dose of pegylated liposomal doxorubicin. Only 5 patients completed4 cycles of therapy. The most common grade 4 adverse events at dose level 4 were neutropenia (5/9 patients) and leukopenia (2/9 patients). Overall responses were observed in 2 of 22 patients.Oral topotecan and pegylated liposomal doxorubicin can be combined at doses that are active as monotherapies. However, the overall response rates after monotherapy in patients with platinum-resistant ovarian cancer are comparable to or higher than those observed in this phase I study of combination therapy.

Given the expected increase in the older population and driving in this age group, concerns have been raised about the safety of older drivers. People over 65 years are over-represented in motor vehicle fatalities when calculated by distance driven. They are also at risk of neurodegenerative diseases, such as Alzheimer's disease, that affect cognitive function. We have examined the brains of older drivers (15M:12F) who died as a result of a motor vehicle accident (MVA) to determine the extent of Alzheimer's disease-related neurofibrillary changes (neuritic plaques and neurofibrillary tangles), Lewy body pathology and cerebrovascular disease and compared them to a control group of older licenced drivers (23M:5F) who died of other causes. The prevalence of moderate or severe neuritic plaque pathology was less than expected for the general population of this age and there was no difference between the groups. However, mild neuritic plaque pathology was increased for MVA deaths compared to controls. There was no evidence of vascular dementia or dementia with Lewy bodies. The current mandatory age-related re-licencing procedures in NSW may contribute to the low percentage of drivers with severe pathology. Further research into the role of mild pathology in cognitive impairment and older drivers is warranted. © 2007 Elsevier Ltd. All rights reserved.

In a retrospective postmortem study, we examined the neuronal expression of active caspase-3, a specific apoptotic marker, in the brainstem of 67 infants dying from sudden infant death syndrome (SIDS), and 25 age-matched control infants (non-SIDS). Neuronal immunostaining for active caspase-3 was semi-quantitatively scored in nuclei from five brainstem levels: rostral, mid and caudal pons, and rostral and caudal medulla. Regardless of the cause of death (SIDS vs. non-SIDS), age-related differences in active caspase-3 expression were identified, predominantly in the medulla. No gender-related differences were identified. Comparing SIDS to non-SIDS cases, increased active caspase-3 expression was restricted to four nuclei in the caudal pons (abducens, facial, superior olivary, and pontine nuclei) and two nuclei in the rostral medulla (hypoglossal and dorsal motor nucleus of the vagus). We conclude that neuronal apoptosis is increased in the brainstem of SIDS compared to non-SIDS infants.

PurposeThe aim of this study was to identify patient and physician factors related to enrollment onto Gynecologic Oncology Group (GOG) trials.MethodsProspective study of women with primary or recurrent cancer of the uterus or cervix treated at a GOG institution from July 2010 to January 2012. Logistic regression examined probability of availability, eligibility and enrollment in a GOG trial. Odds ratios (OR) and 95% confidence intervals (CI) for significant (p4 comorbidities (OR 4.5; CI 1.7–11.8) had higher odds of trial ineligibility. Non-White patients (OR 7.9; CI 1.3–46.2) and patients of Black physicians had greater odds of enrolling (OR 56.5; CI 1.1–999.9) in a therapeutic trial. Significant patient therapeutic trial enrollment factors: belief trial may help (OR 76.9; CI 4.9–>1000), concern about care if not on trial (OR12.1; CI 2.1–71.4), pressure to enroll (OR .27; CI 0.12–.64), caregiving without pay (OR 0.13; CI .02–.84). Significant physician beliefs were: patients would not do well on standard therapy (OR 3.6; CI 1.6–8.4), and trial would not be time consuming (OR 3.3; CI 1.3–8.1).ConclusionsTrial availability, patient and physician beliefs were factors identified that if modified could improve enrollment in cancer cooperative group clinical trials.

Sir, Thank you for the opportunity to reply to the correspondence concerning our recent publication in Brain , ‘Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2’ (Rossor et al. , 2015). We read with great interest the letter from Bansagi et al. and thank the authors for providing further evidence that p.Ser107Leu in BICD2 is a mutation ‘hot spot’. Bansagi et al. (2015) describe two unrelated families with a typical Spinal Muscular Atrophy Lower Extremity Dominant (SMALED) phenotype. In both families, affected individuals presented at birth with either toe deformities …

Objective and background: The prevalence and characteristics of pleural effusions occurring in adults with the superior vena cava (SVC) syndrome are unknown. The purpose of the present study was to characterize these pleural effusions. Methods: Charts of patients diagnosed with SVC syndrome at a tertiary care referral centre were reviewed. Radiographs were evaluated for the presence and size of pleural effusions, presence and location of masses and mediastinal width. If a pleural effusion was present, the patient's chart and a pre-existing database on pleural effusions were searched to determine whether the effusion was sampled and the results of any laboratory investigations on the fluid. Results: The SVC syndrome occurred in 78 patients. Malignancy was the aetiology in 60% of the cases and bronchogenic carcinoma was the most common malignancy. An intravascular device was the aetiology in the majority of benign cases. Pleural effusion was found in 70% of patients with a malignant aetiology and 58% of those with a benign cause (P = 0.345). The mean size of the effusions was larger in malignant cases (P = 0.012). Of the 44 effusions 22 were sampled (17 in malignancy and five with benign processes); none was transudates, 20 (91%) were exudative (four of these were chylous) and the remaining two were reported as exudates but did not have pleural chemistries documented. Conclusions: More than half of patients with SVC syndrome have pleural effusions, regardless of the aetiology. However, the effusions are larger when associated with malignancy. The majority of these effusions are exudative and occasionally chylous. None was transudates.

Background/Aims: Older people are over-represented in pedestrian fatalities, and it has been suggested that the presence of cognitive impairment or dementia in these individuals may contribute to their accidents. Using neuropathological methods, we aimed to compare the prevalence of dementia pathology in fatally injured older pedestrians with similarly aged ambulatory subjects who died from other causes. Methods: The brains of 52 pedestrians (65–93 years) and 52 controls (65–92 years) were assessed for neurofibrillary tangles (NFT), neuritic plaques, Lewy bodies and vascular lesions using established neuropathological criteria. Results: The examination for Alzheimer’s disease (AD) pathology showed that 43% of the pedestrians had NFT scores of III–VI using Braak and Braak staging, compared with 23% of the controls (p < 0.05, Fisher’s exact test), indicating incipient, possible or probable AD. There were no differences in the prevalence of pathology for vascular dementia or dementia with Lewy bodies. Conclusion: These results suggest that cognitive decline associated with AD, even in the earliest stages of the disease, may be a factor in fatal traffic accidents for older pedestrians. Special measures for pedestrian safety are necessary in areas with high densities of older citizens and especially for those diagnosed as having a mild cognitive impairment or AD.

Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible hot spot mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.

Summary Study objective The purpose of this study was to determine if an oxygen prescription based on continuous oximetry monitoring, would result in an increased percentage of time spent within an S pO 2 level between 88% and 92%. Methods We conducted a prospective, cohort study in an outpatient, pulmonary setting in a tertiary care referral center, on 17 patients with stable chronic obstructive pulmonary disease (COPD) who had previously been prescribed long-term oxygen therapy. The patients were monitored for ∼24h with a portable oximeter that recorded S pO 2 and EKG readings. During the initial 24h of monitoring, the patients were on their previous oxygen prescription. Their oxygen prescription was then altered based on a predetermined protocol described below. The patients were then monitored for an additional 24h. Results Sixteen patients completed the study. Based on the initial continuous oximetry, the median oxygen prescription was reduced from 2.5 to 1.2L/min ( P 0.001 ). The oxygen prescription during exercise, rest, and sleep decreased from 3.0±0.9 to 1.8±1.3L/min ( P 0.001 ), 2.2±0.4 to 0.8±0.7L/min ( P 0.001 ), and 2.2±0.4 to 0.9±0.8L/min ( P 0.001 ) respectively. After the oxygen prescription was adjusted, the percentage of the time that the S pO 2 was between 88 and 92% increased from 24.8±21.7% to 52.8±25.0% ( P = 0.001 ), but the percentage of time that the S pO 2 was below 88% did not change significantly (2.8±6.1% to 4.3±8.1%). Conclusions This study demonstrates that an oxygen prescription based on continuous oximetry monitoring results in (1) a significant increase in the percentage of time that the S pO 2 is between 88% and 92%, (2) a significant decrease in the amount of oxygen prescribed, (3) a slight increase in the amount of time that the S pO 2 is below 88% that was not statistically significant.

Study objectives: The mechanisms responsible for the accumulation of eosinophils in pleural fluid are not fully understood. The objective of the present study was to examine the relationship between pleural fluid eosinophilia and the levels of vascular cell adhesion molecule (VCAM)-1, eotaxin, RANTES (regulated upon activation, normal T-cell expressed and secreted), and interleukin (IL)-4 in pleural effusions. Patients and methods: Thirty-one patients with eosinophilic pleural effusion (EPE) [eosinophil percentage > 10% of the pleural fluid nucleated cells] and 10 patients without EPE were evaluated. VCAM-1, eotaxin, RANTES, and IL-4 in all pleural fluids were measured using enzyme-linked immunosorbent assay kits. IL-5 levels of the same fluids were measured in a previous study. Results: VCAM-1, eotaxin, and RANTES but not IL-4 were detectable in the pleural fluids. The mean level of VCAM-1 in EPE (336 85 ng/mL) was significantly higher (p 0.011) than that in the noneosinophilic effusions (260 34 ng/mL) [mean SD]. VCAM-1 levels were significantly correlated with the eosinophil count and percentage in all pleural fluids (r 0.43, p 0.005, and r 0.37, p 0.019, respectively). Multiple linear regression analysis disclosed that both IL-5 (, 0.63; p < 0.001) and VCAM-1 (, 0.27, p 0.025) are independent predictors of the number of eosinophils in all pleural fluids. RANTES and eotaxin did not differ significantly between EPEs and non-EPEs, and were not correlated with the number of pleural fluid eosinophils. Conclusion: The levels of VCAM-1 are increased in EPE, suggesting that VCAM-1 is important in the pathogenesis of EPE. Neither eotaxin nor RANTES is associated with pleural fluid eosinophilia. (CHEST 2003; 124:159–166)

Study objectives To determine whether, in patients with bilateral pleural effusions, the main cellular and biochemical features of the pleural fluid on the right side differ from or correlate with those on the left side. We examined lactate dehydrogenase (LDH), glucose, and total protein (TP) levels, RBC count, nucleated cell count (NCC), and differential cell count. Patients and methods Twenty-seven patients with bilateral pleural effusions, including 13 patients with effusions after coronary artery bypass graft surgery, 12 patients with congestive heart failure, 1 patient with malignant pericarditis, and 1 patient with renal failure, were studied retrospectively. Results The right-sided and the left-sided pleural effusions did not differ in the mean TP (p = 0.38), glucose (p = 0.31), and LDH (p = 0.39) levels, RBC count (p = 0.31), NCC (p = 0.96), and the percentage of neutrophils (p = 0.22), lymphocytes (p = 0.73), mononuclear cells (MNCs) [p = 0.49], and eosinophils (p = 0.65). The bias ± precision was 0.1 ± 0.64 g/dL for TP, − 2.7 ± 23 mg/dL for glucose, 41 ± 362 IU/L for LDH, 6,100 ± 62,900 cells/μL for RBC count, − 36 ± 1,043 cells/μL for NCC, − 2.9 ± 11.6% for the percentage of neutrophils, 1.15 ± 17% for the percentage of lymphocytes, 2.3 ± 17% for the percentage of the MNCs, and − 0.15 ± 5.4% for the percentage of eosinophils. Moreover, there was a close correlation between the right-sided and the left-sided pleural effusions concerning TP level ( r = 0.85, p r = 0.78, p r = 0.71, p r = 0.66, p r = 0.60, p = 0.001), and the percentage of neutrophils ( r = 0.77, p r = 0.77, p r = 0.74, p r = 0.84, p Conclusion Since the pleural fluid findings tend to be similar in both sides of patients with bilateral pleural effusion, we suggest that diagnostic thoracentesis may not need to be performed on both sides, unless there is a specific clinical indication.

Study objectives: The objectives of this study are as follows: (1) to determine the incidence of complications from thoracentesis performed under ultrasound guidance by interventional radiologists in a tertiary referral teaching hospital; (2) to evaluate the incidence of vasovagal events without the use of atropine prior to thoracentesis; and (3) to evaluate patient or radiographic factors that may contribute to, or be predictive of, the development of re-expansion pulmonary edema after ultrasound-guided thoracentesis. Design: Prospective descriptive study. Setting: Saint Thomas Hospital, a tertiary referral teaching hospital in Nashville, TN. Patients: All patients referred to interventional radiology for diagnostic and/or therapeutic ultrasound-guided thoracentesis between August 1997 and September 2000. Results: A total of 941 thoracenteses in 605 patients were performed during the study period. The following complications were recorded: pain (n = 25; 2.7%), pneumothorax (n = 24; 2.5%), shortness of breath (n = 9; 1.0%), cough (n = 8; 0.8%), vasovagal reaction (n = 6; 0.6%), bleeding (n = 2; 0.2%), hematoma (n = 2; 0.2%), and re-expansion pulmonary edema (n = 2; 0.2%). Eight patients with pneumothorax received tube thoracostomies (0.8%). When > 1,100 mL of fluid were removed, the incidence of pneumothorax requiring tube thoracostomy and pain was increased (p 1,000 mL of pleural fluid were removed. Conclusions: The complication rate with thoracentesis performed by interventional radiologists under ultrasound guidance is lower than that reported for non–image-guided thoracentesis. Premedication with atropine is unnecessary given the low incidence of vasovagal reactions. Re-expansion pulmonary edema is uncommon even when > 1,000 mL of pleural fluid are removed, as long as the procedure is stopped when symptoms develop.

The present prospective study was designed to determine the prevalence of pleural effusion at approximately 28 days after cardiac surgery and their subsequent course. This consecutive case study included 389 patients; 312 had only coronary artery bypass graft surgery (CABG) surgery, 37 had both valve and CABG surgery, and 40 had only valve surgery. Chest radiographs were obtained approximately 28 days postoperatively. Patients were subsequently contacted by telephone 3, 6, and 12 months postoperatively and questioned about the presence of fluid in their chest and related symptoms. The prevalence of pleural effusions in the patients undergoing only CABG surgery (63%) or CABG surgery plus valve surgery (62%) was significantly (p = 0.05) higher than that in the patients undergoing valve surgery only (45%). The prevalence of effusions occupying more than 25% of the hemithorax was 9.7%. The primary symptom associated with these larger effusions was dyspnea. Chest pain and fever were uncommon. Over the 12-month follow-up, the effusions tended to resolve. In conclusion, the prevalence of pleural effusions occupying more than 25% of the hemithorax is approximately 10%, 28 days postoperatively. These larger pleural effusions produce dyspnea but not chest pain or fever, and most of the effusions disappear gradually over the subsequent months.

In an effort to explore second-line therapy in ovarian, peritoneal, and tubal carcinoma, a phase I trial combining prolonged oral etoposide and liposomal doxorubicin was conducted by the Gynecologic Oncology Group.Liposomal doxorubicin (20 mg/m(2)) was administered intravenously over 1 h followed by oral etoposide at 50 mg/m(2)/day beginning on day 2. In the first phase of accrual, the number of days of oral etoposide was increased until its maximum tolerated dose (MTD) was determined based on hematologic toxicity. In the second phase, etoposide was given at the MTD while the dose of liposomal doxorubicin was escalated until its maximum tolerated dose was reached based on hematologic or nonhematologic toxicity. Cycles were repeated every 28 days for a maximum of 12 courses. Dose-limiting toxicity was defined as neutropenic sepsis, grade 4 thrombocytopenia, absolute neutrophil count1000/microl or platelets50,000 during treatment with etoposide, oror =grade 3 mucositis/stomatitis, palmar-plantar erythrodyesthesia, or rash.Fifteen patients were accrued to the study's first phase, and 3 were accrued to the second phase. Dose-limiting hematologic toxicity occurred with 14 days of oral etoposide in combination with liposomal doxorubicin at 20 mg/m(2). Efforts to escalate the dose of liposomal doxorubicin to 30 mg/m(2) in combination with 12 days of oral etoposide at 50 mg/m(2) resulted in dose-limiting hematologic toxicity. Five of 17 (29%; 95% CI: 13-53%) evaluable patients experienced a response.The regimen of oral etoposide at 50 mg/m(2)/day for 12 days in combination with liposomal doxorubicin at a dose of 20 mg/m(2) is tolerable without supportive therapy. While this dose of oral etoposide has demonstrated activity as a single agent in ovarian cancer, liposomal doxorubicin has only been effective in ovarian cancer at higher doses. There are no immediate plans to study this combination further.

The aim of this study was to assess the variation between neuropathologists in the diagnosis of common dementia syndromes when multiple published protocols are applied. Fourteen out of 18 Australian neuropathologists participated in diagnosing 20 cases (16 cases of dementia, 4 age-matched controls) using consensus diagnostic methods. Diagnostic criteria, clinical synopses and slides from multiple brain regions were sent to participants who were asked for case diagnoses. Diagnostic sensitivity, specificity, predictive value, accuracy and variability were determined using percentage agreement and kappa statistics. Using CERAD criteria, there was a high inter-rater agreement for cases with probable and definite Alzheimer's disease but low agreement for cases with possible Alzheimer's disease. Braak staging and the application of criteria for dementia with Lewy bodies also resulted in high inter-rater agreement. There was poor agreement for the diagnosis of frontotemporal dementia and for identifying small vessel disease. Participants rarely diagnosed more than one disease in any case. To improve efficiency when applying multiple diagnostic criteria, several simplifications were proposed and tested on 5 of the original 20 cases. Inter-rater reliability for the diagnosis of Alzheimer's disease and dementia with Lewy bodies significantly improved. Further development of simple and accurate methods to identify small vessel lesions and diagnose frontotemporal dementia is warranted.

We report on an airborne demonstration of atmospheric oxygen (O2) optical depth measurements with an Integrated Path Differential Absorption (IPDA) lidar using a fiber-based laser transmitter and photon counting detectors. Accurate atmospheric temperature and pressure measurements are needed for NASA’s Active Sensing of CO2 Emissions over Nights, Days and Seasons (ASCENDS) mission. Since O2 is uniformly mixed in the atmosphere, its spectrum can be used to estimate the dry mixing ratio of CO2. In its airborne configuration, the IPDA lidar uses an Erbium Doped Fiber amplifier, a frequency doubler and single photon counting detectors to measure O2 absorption at multiple wavelengths near 765 nm. This instrument was deployed in 2013 and 2014 aboard NASA’s DC-8 airborne laboratory as part of two campaigns to measure CO2 mixing ratios over a wide range of topography and weather conditions from altitudes ranging between 3 km and 13 km. In this paper we will review a summary of the results from our flights, discuss the errors that limit the precision and accuracy of the measurement and identify possible areas of improvement.

OBJECTIVE To review the histologic findings in patients diagnosed with "atypical glandular cells of uncertain significance, endocervical cell type" (AGUS-EC) by ThinPrep Pap Test (TPPT) or conventional Pap smear (CPS) and to evaluate the clinical value of subclassifying AGUS-EC as "favor reactive" or "favor neoplastic." STUDY DESIGN All TPPT and CPS diagnosed as AGUS-EC (favor reactive, unspecified and favor neoplastic) from January 1998 through December 1999 and all available histologic follow-up (defined as endocervical curettage, cervical biopsy, cervical conization or hysterectomy obtained within six months of the time of an AGUS-EC diagnosis) were obtained from a computerized database. RESULTS AGUS-EC was diagnosed in 0.77% of CPS (683 of 88,825) and 0.59% of TPPT (183 of 30,968) (P = NS). There was no statistically significant difference in any of the follow-up histologic diagnoses between the CPS and TPPT groups. The majority of the follow-up biopsies demonstrated benign processes in both groups. Patients with a diagnosis of AGUS-EC "favor neoplastic" had a greater proportion of true glandular pathology as compared with AGUS-EC "unspecified" or "favor reactive" (P < .001). None of the patients with a diagnosis of AGUS-EC "favor reactive" were found to have true glandular pathology; however, a minority of them proved to have squamous pathology. CONCLUSION In this study there was no difference in CPS and TPPT in regard to the specificity of a diagnosis of AGUS-EC for true glandular pathology. Subclassifying AGUS-EC as "favor reactive" or "favor neoplastic" may provide valuable information for directing patient follow-up.

The importance of technology in managing relationships with customers has grown significantly, especially with the advent of innovations such as cloud computing and web-based technology. One of the more popular topics in both academic research and business discussions has been the use of Customer Relationship Management (CRM) technology to increase business and sales productivity through the ongoing development of relationships with buyers. A new phenomenon in understanding buyers’ needs and reaching new customers is social media. Organizations are capturing data from tools such as LinkedIn, Facebook and blogs, and attempting to integrate this information into their sales process. In order to extract value from technology, organizations need to build a framework and processes to deliver value to the customer.

In the last decade firms have implemented technology initiatives for sales professionals that provide access to customer data and enable them to increase workplace efficiency by communicating electronically with their clients and colleagues. Many salespersons work virtually outside the traditional office and technology, in the form of CRM, allows sales professionals to devote more flexible time to better serve their customers. By utilizing CRM technology, today’s sales professionals can communicate and collaborate with clients and internal managers anytime, anywhere. This study’s findings support the hypotheses that CRM utilization has positive impacts on sales performance, namely sales process effectiveness, performance with customers, and administrative efficiency. Among the three performance measures, CRM usage has the greatest impact on sales process effectiveness.

A loop graph $\mf G$ is a finite undirected graph that allows loops but does not allow multiple edges. The set $\sym(\lG)$ of real symmetric matrices associated with a loop graph $\lG$ of order $n$ is the set of symmetric matrices $A=[a_{ij}]\in\Rnn$ such that $a_{ij}\ne 0$ if and only if $ij\in E(\lG)$. The minimum (maximum) rank of a loop graph is the minimum (maximum) of the ranks of the matrices in $\sym(\lG)$. We characterize loop graphs having minimum rank at most two (by forbidden induced subgraphs and graph complements) and loop graphs having minimum rank equal to the order of the graph. A Schur complement reduction technique is used to determine the minimum ranks of cycles with various loop configurations; we also determine the minimum ranks of complete graphs and paths with various configurations of loops. Unlike simple graphs, loop graphs can have maximum rank less than the order of the graph. We present some results on maximum rank and which ranks between minimum and maximum can be realized. Interesting open questions remain.

Objective. Topotecan (1.5 mg/m 2 ) administered daily for 5 consecutive days of a 21-day cycle is an established chemotherapeutic regimen in recurrent ovarian cancer. However, noncumulative myelosuppression has limited its use by many clinicians. We sought to determine whether a lower dose of topotecan could provide comparable tumor activity and higher tolerability in pretreated ovarian cancer patients. Methods. A retrospective chart review was conducted on recurrent ovarian, peritoneal, or fallopian tube cancer patients with measurable disease or elevated cancer antigen 125 levels (evaluable disease). Patients were treated with topotecan (1.0 mg/m 2 ) given by 30-min intravenous infusion for 5 consecutive days every 21 days until disease progression or unacceptable toxicity. Results. Treatment records from 37 women who had been treated with a median of 3 courses (range, 1 to 17) of lower dose topotecan were evaluated; all were evaluable for tolerability and 36 were evaluable for response. Patients had received a median of 3 (range, 1 to 6) previous treatments. The overall response rate was 22% (8/36); the response rates for patients with evaluable disease and measurable disease were 35.7 (5/14) and 13.6% (3/22), respectively. An additional 8 patients (22%) achieved stable disease. Grade 4 neutropenia, thrombocytopenia, and anemia occurred in 48.6, 5.4, and 5.4% of patients, respectively. Granulocyte colony-stimulating factor support was used in 37% of patients, including 5 who experienced febrile neutropenia. Conclusion. Topotecan at 1.0 mg/m 2 × 5 days every 21 days is active in platinum- and paclitaxel-resistant ovarian cancer, with significant improvements in hematologic toxicity. In heavily pretreated patients-topotecan can be safely given at reduced doses without apparent loss of efficacy.

Background: Recently, pregnancies in patients after radical vaginal trachelectomy and laparoscopic pelvic lymphadenectomy have been reported. Radical abdominal trachelectomy and pelvic lymphadenectomy with uterine conservation has been previously described; however, subsequent outcome and pregnancy has not. Methods: Three patients with cervical carcinoma, 1 with stage IA1 with lymph-vascular space invasion and 2 with stage IA2, were treated with radical abdominal trachelectomy and pelvic lymphadenectomy with uterine conservation. Results: All patients underwent the planned procedure with no significant intraoperative or postoperative complications. All patients had return to normal menstrual function. One patient had a successful pregnancy delivered at 39 weeks by cesarean section and is now subsequently pregnant with a second pregnancy. Conclusion: Radical abdominal trachelectomy is a technically feasible operation that uses operative techniques familiar to the American-trained gynecologic oncologist and results in wider parametrial resection than radical vaginal trachelectomy. In young patients desiring to retain fertility, successful pregnancies after radical abdominal trachelectomy are possible. Intraoperative and postoperative complications are likely to be lower with an abdominal versus a vaginal approach. Long-term survival of patients treated with radical trachelectomy for early invasive cervical cancer are yet to be determined. (Am J Obstet Gynecol 2001;185:370-74.)

The aim of this study was to evaluate the relative activity and tolerance of liposomal doxorubicin in recurrent ovarian, peritoneal, and tubal carcinoma at an initial dose of 40 or 50 mg/m(2) every 4 weeks.A retrospective single-institution study was performed on patients who received liposomal doxorubicin from 1/97 to 12/00. Demographic data, liposomal doxorubicin dose, dose reductions, response, and progression-free and overall survival were recorded.Seventy-eight patients, 38 treated at 40 mg/m(2) and 40 treated at 50 mg/m(2), were identified. There was no difference with respect to patient age, performance status, percentage of patients who were platinum resistant or paclitaxel resistant, or tumor bulk. The response rate in this highly resistant population was 13.5 and 7.7% for liposomal doxorubicin at 40 and 50 mg/m(2) every 4 weeks, respectively. Stable disease was observed in 49 and 51% of patients treated with liposomal doxorubicin at a dose of 40 and 50 mg/m(2) every 4 weeks, respectively. The progression-free survival for patients with responding and stable disease was similar. Dose reductions were required in 27.5% of patients treated at 50 mg/m(2) versus no patients treated at 40 mg/m(2) (P0.001). Treatment delays due to toxicity were required in 32.5% of patients treated at 50 mg/m(2) versus 16% of patients treated at 40 mg/m(2) (P = 0.14).Liposomal doxorubicin at a dose of 40 mg/m(2) appears to be as active as liposomal doxorubicin at a dose of 50 mg/m(2) in ovarian, peritoneal, and tubal carcinoma and is better tolerated based on the frequency of dose reductions and treatment delays.

Recent studies have demonstrated high levels of vascular endothelial growth factor (VEGF) in exudative pleural effusions and a possible etiologic role. The factors regulating VEGF accumulation in the pleural space are unknown. Transforming growth factor (TGF)-beta is a potent stimulator of VEGF expression in vitro. We hypothesized that TGF-beta induces VEGF production in pleural tissues, and, hence, the pleural fluid VEGF levels should correlate with the levels of TGF-beta in pleural fluid of different etiologies.Seventy pleural fluid samples were analyzed. These included 20 malignant, 13 post-coronary artery bypass grafting (CABG), 8 parapneumonic, 11 miscellaneous exudative, and 18 congestive heart failure (CHF) pleural effusions.Pleural fluid VEGF levels showed good correlation with those of TGF-beta(1) (r = 0.58; p0. 0001), TGF-beta(2) (r = 0.43; p0.001), and lactate dehydrogenase (r = 0.65; p0.001). The levels of TGF-beta(1) and TGF-beta(2) also were correlated (r = 0.60; p0.0001). The median levels of TGF-beta(1) (2,480 pg/mL) and TGF-beta(2) (266 pg/mL) in the CHF group were significantly lower than those in the malignant (TGF-beta(1), 4,902 pg/mL; TGF-beta(2), 428 pg/mL), post-CABG (TGF-beta(1), 5,456 pg/mL; TGF-beta(2), 377 pg/mL), parapneumonic (TGF-beta(1), 5,024 pg/mL; TGF-beta(2), 464 pg/mL), and miscellaneous exudate groups (TGF-beta(1), 7,690 pg/mL; TGF-beta(2), 369 pg/mL). There was no significant difference in TGF-beta(1) and TGF-beta(2) levels among the four exudate groups.VEGF levels in pleural effusions are significantly correlated with the levels of TGF-beta(1) and beta(2) isoforms. VEGF, TGF-beta(1), and TGF-beta(2) levels were all higher in exudative effusions than in effusions secondary to CHF.

BACKGROUND The purpose of this study was to compare the effectiveness and safety of a chronic indwelling pleural catheter with doxycycline pleurodesis via tube thoracostomy in the treatment of patients with recurrent symptomatic malignant pleural effusions (MPE). METHODS In this multi-institutional study conducted between March 1994 and February 1997, 144 patients (61 men and 83 women) were randomized in a 2:1 distribution to either an indwelling pleural catheter or doxycycline pleurodesis. Patients receiving the indwelling catheter drained their effusions via vacuum bottles every other day or as needed for relief of dyspnea. RESULTS The median hospitalization time was 1.0 day for the catheter group and 6.5 days for the doxycycline group. The degree of symptomatic improvement in dyspnea and the quality of life was comparable in each group. Six of 28 patients who received doxycycline (21%) had a late recurrence of pleural effusion, whereas 12 of 91 patients who had an indwelling catheter (13%) had a late recurrence of their effusions or a blockage of their catheter after the initially successful treatment (P = 0.446). Of the 91 patients sent home with the pleural catheter, 42 (46%) achieved spontaneous pleurodesis at a median of 26.5 days. CONCLUSIONS A chronic indwelling pleural catheter is an effective treatment for the management of patients with symptomatic, recurrent, malignant pleural effusions. When compared with doxycycline pleurodesis via tube thoracostomy, the pleural catheter requires a shorter hospitalization and can be placed and managed on an outpatient basis. Cancer 1999;86:1992–9. © 1999 American Cancer Society.

The purpose of this study was to analyze the relationship of the pleural fluid vascular endothelial growth factor (VEGF) level with the diagnostic category and with the pleural fluid characteristics in a group of 70 patients.The VEGF levels of consecutive patients undergoing therapeutic thoracentesis were determined with an enzyme-linked immunosorbent assay.University-affiliated tertiary care center.The median level of pleural fluid VEGF in the patients with congestive heart failure (150 pg/mL) was significantly (p0.05) lower than the median level in the patients with coronary artery bypass grafting (357 pg/mL), which in turn was significantly lower (p0.05) than the median levels in the patients with malignancy (1,097 pg/mL). The overlap between groups, however, limits the diagnostic usefulness of pleural fluid VEGF levels. The VEGF level was most closely correlated with the lactate dehydrogenase level (r = 0.42, p0.001) and was also significantly correlated with the total pleural fluid protein level. The median VEGF levels in the pleural fluid of patients with breast cancer were significantly lower (p = 0.017) than in those with lung cancer. The VEGF level was very high (3,294 pg/mL) in the one patient with pulmonary embolism.We conclude that the VEGF levels in pleural fluid differ significantly from one diagnostic category to another with the highest median levels occurring in patients with malignant pleural effusions. We speculate that VEGF may be responsible for the pleural fluid accumulation in at least some situations.

OBJECTIVE: To determine the significance of atypical squamous cells of undetermined significance (ASCUS) in patients 55 years or older. STUDY DESIGN: From January 1994, to January 1997, 8,175 cervicovaginal smears were obtained from patients 55 years or older (mean age, 64.8; range, 56-84) at University Hospitals of Cleveland. Ninety-six of these patients were diagnosed with ASCUS only or ASCUS with a qualifying statement on the smear. Patient records, follow-up cervicovaginal smears and biopsies were reviewed for a period of one to four years following the diagnosis of ASCUS. RESULTS: The incidence of ASCUS only or ASCUS with a qualifying statement for patients 55 years or older was 1.8%. The ASCUS:SIL ratio was 2.6:1. An estrogen stimulation test was recommended in two cases. Women older than 55 with ASCUS were three times more likely to be receiving hormonal replacement therapy than similar-aged women with normal cervicovaginal smears. Follow-up cervicovaginal smears or biopsies were obtained on 93 (80 cervicovaginal smears, 13 biopsies). The results were the following : LSIL (13), squamous carcinoma in situ (1) and ASCUS (53); the remainder of the cases were normal. In the patients who received a second diagnosis of ASCUS, follow-up cervicovaginal smears or biopsies revealed low grade dysplasia in six. CONCLUSION: Although the incidence of ASCUS and the frequency of underlying dysplasia is lower in postmenopausal women than the general population, there is still a real risk that a postmenopausal woman with ASCUS has underlying intraepithelial neoplasia. Therefore, these patients should be managed as is the general population.

The purpose of this study was to compare the pleural fluid pH values obtained with a blood gas machine (pHbg), with a pH meter (pHmet), and with a pH indicator strip (pHstrip), to determine if the pleural fluid pH measured by a pH meter or a pH indicator strip was sufficiently accurate for clinical decisions.The pleural fluid pH was determined, within 20 min after being collected anaerobically, by a blood gas machine (CIBA-Corning model 288), pH meter (Corning pH meter 610A), and pH indicator strip (Baxter Diagnostic) following routine laboratory procedures in 50 pleural fluids. Pleural fluid pH was determined in seven additional samples with the blood gas machine and a pH meter at 25 and 37 degrees C respectively, initially, and after 30 min.The mean pHbg (7.42+/-0.01) was significantly less than the mean pHmet (7.58+/-0.02) or the mean pHstrip (8.23+/-0.06). There were significant differences between the pHbg and the pHmet (p0.001), and between the pHbg and the pHstrip (p0.001). Analysis of the additional seven samples demonstrated that when the blood gas machine was set at 25 degrees C, the pHbg (pHbg = 7.54+/-0.02) and the pHmet (7.53+/-0.01) were almost identical.When the pleural fluid pH is going to be used for decision making, only the pH values provided by the blood gas machine are sufficiently accurate.

PURPOSE The combination of paclitaxel and a platinum compound is the most active first-line regimen for advanced ovarian carcinoma. The current study was undertaken to evaluate this combination in the re-treatment of patients with ovarian or peritoneal carcinoma who had disease recurrence > or = 6 months following this combination. METHODS Twenty-five patients with recurrent ovarian or peritoneal carcinoma > or = 6 months after a complete clinical response with first-line paclitaxel and platinum chemotherapy were studied. Recurrent disease was documented by computed tomography (CT), elevated CA 125 level, or surgical findings. Second-line chemotherapy consisted of paclitaxel 135 mg/m2 as a 24 hour infusion and carboplatin at an area under the concentration-time curve (AUC) of 5 to 6 every 21 days. Response to therapy was classified as measurable or assessable. RESULTS The median time to recurrence after first-line therapy was 10 months (range, 6 to 30). Among 20 measurable and assessable patients, 14 (70%) demonstrated a complete clinical response and four (20%) a partial clinical response. The response rate with measurable disease was 91% and with assessable disease was 89%. The median progression-free interval for all patients was 9.0+ months (range, 2 to 15). The median progression-free interval for patients with measurable or assessable disease was 9.0+ months and for nonassessable disease was 7.0+ months. Fifteen patients (60%) have developed recurrence after secondary therapy at a median interval of 9.0 months (range, 2 to 15). Only two patients have died with a median survival after secondary therapy of 10.0+ months (range, 2.0 to 21.0+). CONCLUSION The use of this combination, in this sensitive population, has a high response rate and long progression-free interval. In a chemotherapy-sensitive population, the activity of alternative second-line agents must be interpreted with this perspective.

OBJECTIVE: To correlate the cytologic diagnoses of peritoneal washings (PWs) with histologic findings of ovarian tumors of low malignant potential (LMP). METHODS: PW cytology from 90 patients with histologically confirmed ovarian tumors of LMP were reviewed and correlated with histologic findings. RESULTS: In 90 LMP tumor patients who underwent PW, cytologic diagnoses were reported as positive in 30 (33%) cases, atypical in 5 (6%) cases and negative in 55 (61%) cases. On review of the five atypical cases, three were reclassified as negative and two as positive. Peritoneal washings were positive in 20 (33%) of 60 patients with serous LMP tumors, 12 (44%) of 27 patients with mucinous LMP tumors and none of 3 patients with mixed LMP tumors. The presence of positive cytology was highly indicative of surface ovarian involvement or peritoneal implants in completely staged or selectively biopsied patients (P

In a large-scale mutagenesis screen in the zebrafish, Danio rerio, we have identified a heterogeneous group of 30 recessive, embryonic lethal mutations characterized by degeneration in the developing central nervous system that is either transient or initially localized to one area of the brain. Transient degeneration is defined as abnormal cell death occurring during a restricted period of development. Following degeneration, the affected structures do not appear to regenerate. In each case degeneration is identified after somitogenesis is complete and is not associated with visually identified patterning defects. These 30 mutations, forming 21 complementation groups, have been classified into four phenotypic groups: group 1, transient degeneration (13 mutations); group 2, spreading degeneration, early onset, in which degeneration is initially confined to the optic tectum but subsequently spreads to other areas of the central nervous system (7 mutations); group 3, late-onset degeneration, initially identified after 4 days (6 mutations); and group 4, degeneration with abnormal pigmentation (4 mutations). Although apoptotic cells are seen in the retina and tectum of all mutants, the distribution, temporal progression, and severity of degeneration vary between mutations. Several mutations also show pleiotropic effects, with degeneration involving extraneural structures including the pharyngeal arches and pectoral fins. We discuss some of the pathways important for cell survival in the nervous system and suggest that these mutations will provide entry points for identifying genes that affect the survival of restricted neural populations.

We report on an airborne demonstration of atmospheric oxygen optical depth measurements with an IPDA lidar using a fiber-based laser system and a photon counting detector. Accurate knowledge of atmospheric temperature and pressure is required for NASA's Active Sensing of CO2 Emissions over Nights, Days, and Seasons (ASCENDS) space mission, and climate modeling studies. The lidar uses a doubled erbium-doped fiber amplifier and single photon-counting detector to measure oxygen absorption at 765 nm. Our results show good agreement between the experimentally derived differential optical depth measurements with the theoretical predictions for aircraft altitudes from 3 to 13 km.

A 73-year-old man with Parkinson's disease underwent thalamic stimulation for disabling tremor with excellent results only when stimulation on. Post-mortem neuropathology (7 years postoperatively) revealed 60% cell loss within 0.5 mm of the electrode tip. Tremor improvement was attributable to chronic stimulation, not microthalamotomy.

Importance Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines. Objective To further characterize EV71-related neurological disease and neurological outcome in children. Design, Setting, and Participants Prospective 2-hospital (The Sydney Children’s Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013. Main Outcomes and Measures Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed. Results Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P Conclusions and Relevance Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.