Radiation dose metrics in multidetector computed tomography examinations: A multicentre retrospective study from seven tertiary care hospitals in Kerala, South India.

BACKGROUND: Presently, computed tomography (CT) is the most important source of medical radiation exposure. CT radiation doses vary considerably across institutions depending on the protocol and make of equipment. India does not yet have national or region-specific CT diagnostic reference levels. AIM: To evaluate radiation doses of consecutive multidetector CT (MDCT) examinations based on anatomic region, performed in 1 month, collected simultaneously from seven tertiary care hospitals in Kerala. SETTINGS AND DESIGN: Descriptive study. MATERIALS AND METHODS: We collected the CT radiation dose data of examinations from the seven collaborating tertiary care hospitals in Kerala, performed with MDCT scanners of five different makes. The data included anatomic region, number of phases, CT dose index (CTDIvol), dose-length product (DLP), and effective dose (ED) of each examinations and patient demographic data. STATISTICAL ANALYSIS: We calculated the 25th, 50th, and 75th percentiles of the CTDIvol, DLP, and ED according to anatomic region. We made descriptive comparisons of these results with corresponding data from other countries. RESULTS: Of 3553 patients, head was the most frequently performed examination (60%), followed by abdomen (19%). For single-phase head examinations, 75th percentile of CTDIvol was 68.1 mGy, DLP 1120 mGy-cm, and ED 2.1 mSv. The 75th percentiles of CTDIvol, DLP, and ED for single-phase abdomen examinations were 10.6, 509.3, and 7.7, and multiphase examinations were 14.6, 2666.9, and 40.8; single-phase chest examinations were 23.4, 916.7, and 13.38, and multiphase examinations were 19.9, 1737.6, and 25.36; single-phase neck were 24.9, 733.6, and 3.814, and multiphase neck were 24.9, 2076, and 10.79, respectively. CONCLUSION: This summary CT radiation dose data of most frequently performed anatomical regions could provide a starting point for institutional analysis of CT radiation doses, which in turn leads to meaningful optimization of CT.

Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer.

The gene encoding phosphatidylinositol 3-kinase catalytic subunit α-isoform (PIK3CA, p110α) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110α (myristoylated-p110α, myr-p110α) along with p53fl/fl deletion and KrasG12D also regulated by Cre-recombinase. After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110α accelerated breast tumor initiation in a copy number-dependent manner. Breast tumors induced by p53fl/fl;KrasG12D with no or one copy of myr-p110α had predominantly sarcomatoid features, whereas two copies of myr-p110α resulted in tumors with a carcinoma phenotype. This novel model provides experimental support for importance of active p110α in breast tumor initiation, and shows that the amount of PI3K activity can affect the rate of tumor initiation and modify the histological phenotype of breast cancer.

In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer.

Nanotechnology has tremendous potential to contribute to cancer immunotherapy. The 'in situ vaccination' immunotherapy strategy directly manipulates identified tumours to overcome local tumour-mediated immunosuppression and subsequently stimulates systemic antitumour immunity to treat metastases. We show that inhalation of self-assembling virus-like nanoparticles from cowpea mosaic virus (CPMV) reduces established B16F10 lung melanoma and simultaneously generates potent systemic antitumour immunity against poorly immunogenic B16F10 in the skin. Full efficacy required Il-12, Ifn-γ, adaptive immunity and neutrophils. Inhaled CPMV nanoparticles were rapidly taken up by and activated neutrophils in the tumour microenvironment as an important part of the antitumour immune response. CPMV also exhibited clear treatment efficacy and systemic antitumour immunity in ovarian, colon, and breast tumour models in multiple anatomic locations. CPMV nanoparticles are stable, nontoxic, modifiable with drugs and antigens, and their nanomanufacture is highly scalable. These properties, combined with their inherent immunogenicity and demonstrated efficacy against a poorly immunogenic tumour, make CPMV an attractive and novel immunotherapy against metastatic cancer.

WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma.

Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressed WWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12-Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.

Efficacy of mirtazapine in preventing intrathecal morphine-induced nausea and vomiting after orthopaedic surgery*.

Nausea and vomiting are frequent complications of intrathecal morphine. In this randomised, double-blind trial, we tested the efficacy of mirtazapine, an antidepressant that blocks receptors associated with vomiting, on the incidence of nausea and vomiting after intrathecal morphine. One hundred patients receiving spinal anaesthesia for lower limb surgery were assigned equally to take either an orally disintegrating form of 30 mg mirtazapine or matching placebo 1 h before surgery. Spinal anaesthesia was performed by injection of 15 mg isobaric bupivacaine 0.5% along with 0.2 mg preservative-free morphine. Nausea and vomiting were evaluated 3, 6, 12, 18 and 24 h after intrathecal morphine administration. The incidence of nausea and vomiting was significantly lower in patients receiving mirtazapine compared with placebo (26.5% vs 56.3%, respectively; p = 0.005). The mean (SD) onset time of postoperative nausea and vomiting was significantly delayed in mirtazapine patients: 9.4 (2.5) vs 5.2 (1.8) h, respectively; p < 0.0001. The severity of nausea and vomiting was also decreased after mirtazapine at the 3-6 h and 6-12 h periods. Our data indicate that pre-operative mirtazapine decreases the incidence, delays the onset and reduces the severity of nausea and vomiting induced by intrathecal morphine in patients undergoing spinal anaesthesia.

Who will participate in acute stroke trials?

BACKGROUND: Despite the high incidence of acute stroke, only a minority of patients are enrolled in acute stroke treatment trials. We aimed to identify factors associated with participation in clinical trials of novel therapeutic agents for acute stroke. METHODS: Prospective survey of patients with acute stroke <72 hours from onset. A structured interview was administered to the patient or primary decision-maker. If offered participation in an actual acute treatment trial, questions focused on decisions about that trial; otherwise a similar mock trial was proposed. The primary outcome was whether the subject agreed to participate in the proposed trial. RESULTS: A total of 200 subjects (47% patients, 53% proxies) completed the survey: mean age 63 +/- 14 years, 47% women, 44% white, 50% black. A real acute trial was offered to 22%; others were offered a mock trial. Overall, 57% (95% confidence interval: 50%-64%) of respondents stated they would participate in the proposed acute treatment trial. There were no differences with respect to age, sex, race, educational level, self-assessed stroke severity or stroke type, vascular risk factors, or comorbidities. Misconceptions about key research concepts were found in 50% but did not impact participation. Participation was associated with the perceived risk of the proposed trial intervention (p < 0.001), prior general attitudes about research (p < 0.001), and influences attributed to family, religion, and other personal beliefs (p < 0.001). Patients were more likely to participate than proxy decision-makers (p = 0.04). CONCLUSIONS: Demographic factors, clinical factors, and prior knowledge about research have little impact on the decision to participate in acute stroke clinical trials. Preexisting negative attitudes and external influences about research strongly inhibit participation. Patients are more inclined to participate than their proxy decision-makers.

Prophylactic mirtazapine reduces intrathecal morphine-induced pruritus.

BACKGROUND: Activation of the serotonergic system is an important factor in the pathogenesis of intrathecal morphine-induced pruritus. Mirtazapine is a new antidepressant that selectively blocks 5-HT(2) and 5-HT(3) receptors. We therefore tested the hypothesis that preoperative mirtazapine would reduce the incidence of intrathecal morphine-induced pruritus. METHODS: One hundred and ten ASA I patients undergoing lower limb surgery under spinal anaesthesia were randomly allocated into two equal groups and received either mirtazapine 30 mg or an orally disintegrating placebo tablet 1 h before operation in a prospective, double-blinded trial. All patients received an intrathecal injection of 15 mg of 0.5% isobaric bupivacaine and 0.2 mg preservative-free morphine. The occurrence and the severity of pruritus were assessed at 3, 6, 9, 12, and 24 h after intrathecal morphine. RESULTS: Pruritus was significantly more frequent in the placebo group compared with the mirtazapine group (75% vs 52%, respectively; P=0.0245). The time to onset of pruritus in the two groups was also significantly different. The patients who experienced pruritus in the placebo group had a faster onset time than that in the mirtazapine group [mean (sd): 3.2 (0.8) vs 7.2 (4.1) h, P<0.0001]. CONCLUSIONS: Mirtazapine premedication prevents pruritus induced by intrathecal morphine in patients undergoing lower limb surgery with spinal anaesthesia.

Carcinoembryonic antigen in monitoring of response to cetuximab plus FOLFIRI or FOLFOX-4 in patients with metastatic colorectal cancer.

First-line treatment of metastatic colorectal cancer with combinations of cetuximab and irinotecan-based or oxaliplatin-based chemotherapy has shown promising efficacy. The clinical response to such treatment is generally assessed by tumor measurement through imaging. This study was performed to evaluate the correlation between serial changes in imaging results and carcinoembryonic antigen (CEA) levels. In 64 patients with metastatic colorectal cancer receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy we retrospectively analyzed the relationship between changes in serum CEA and changes in imaging results throughout the treatment course. Response in terms of serum CEA change was defined as a >/=50% drop in CEA level for more than 4 weeks. The sensitivity and specificity of serum CEA changes after targeted chemotherapy in relation to imaging results were 80.5% (33/41) and 73.9% (17/23), respectively, with a diagnostic accuracy of 78.1% (50/64). The progression-free survival time of responders assessed by serum CEA change was significantly longer than that of nonresponders (p=0.0091). Our results highlight the importance of serum CEA monitoring in assessing the response to targeted chemotherapy and in predicting the prognosis of patients with metastatic colorectal cancer.

Comparison of the effects of thoracic epidural analgesia and i.v. infusion with lidocaine on cytokine response, postoperative pain and bowel function in patients undergoing colonic surgery.

BACKGROUND: Both thoracic epidural analgesia (TEA) and i.v. lidocaine were able to decrease postoperative pain and duration of ileus. We compared TEA and i.v. lidocaine (IV) regarding their effects on cytokines, pain and bowel function after colonic surgery. METHODS: Sixty patients were randomly allocated to one of the three groups. TEA group had lidocaine 2 mg kg(-1) followed by 3 mg kg(-1) h(-1) epidurally and an equal volume of i.v. normal saline. The IV group received the same amount of lidocaine i.v. and normal saline epidurally. The control group received normal saline via both routes. These regimens were started 30 min before surgery and were continued throughout. Blood cytokines were measured at scheduled times within 72 h. RESULTS: Both TEA and IV groups had better pain relief. The total consumptions using patient-controlled epidural analgesia were 81.6 (6.5), 55.0 (5.3) and 45.6 (3.9) ml (P<0.01) and the times of flatus passage were 50.2 (4.9), 60.2 (5.8) and 71.7 (4.7) h (P<0.01) in the TEA, IV and control groups, respectively. The TEA group exhibited the best postoperative pain relief and the least cytokine surge. The IV group experienced better pain relief and less cytokine release than the control group. CONCLUSIONS: The TEA lidocaine had better pain relief, lower opioid consumption, earlier return of bowel function and lesser production of cytokines than IV lidocaine during 72 h after colonic surgery; IV group was better than the control group.

How tonicity regulates genes: story of TonEBP transcriptional activator.

TonEBP stimulates genes whose products drive cellular accumulation of organic osmolytes and HSP70, which protect cells from the deleterious effects of hypertonicity and urea, respectively. Mice deficient in the TonEBP gene display severe atrophy of the renal medulla because cells failed to adapt to the hyperosmolality. Emerging data suggest that TonEBP plays a key role in the urinary concentrating mechanism by stimulating the UT-A urea transporters and possibly AQP2 water channel. Thus, TonEBP is an essential regulator in the urinary concentrating mechanism. Studies on structural basis of TonEBP function have revealed the structure of the DNA binding domain, and defined the transactivation domains. Molecular mechanisms underlying the nucleocytoplasmic trafficking, transactivation, and phosphorylation in response to changes in tonicity need to be understood in molecular detail. Such knowledge is needed for the identification of the sensor that detects changes in ambient tonicity and signals to TonEBP.

Disputes over memory ownership: What memories are disputed?

The ownership of memories is sometimes disputed, particularly by twins. Examination of 77 disputed memories, 71 provided by twins, showed that most of the remembered events are negative and that the disputants appear to be self-serving. They claim for themselves memories for achievements and suffered misfortunes but are more likely to give away memories of personal wrongdoing. The research suggests that some of the memories in which we play a leading role might in fact have been the experiences of others.

Twins dispute memory ownership: a new false memory phenomenon.

In three experiments, we examined a new memory phenomenon: disputed memories, in which people dispute ownership of a memory. For example, in one disputed memory each of two twins recollected being sent home from school for wearing too short a skirt, although only one of them was actually sent home. In Experiment 1, 20 sets of same-sex adult twins were asked to produce a memory for each of 45 words, and most twins spontaneously produced at least one disputed memory. In Experiment 2,20 different sets of same-sex adult twins rated disputed memories as higher in recollective experience, imagery, and emotional reliving than nondisputed memories. In Experiment 3, siblings who were close in age as well as same-sex friends were also found to have disputed memories, but less often than twins.

A panel of monoclonal antibodies targeting the rabies virus phosphoprotein identifies a highly variable epitope of value for sensitive strain discrimination.

A recombinant rabies virus phosphoprotein fusion product (GST-P) was used to generate a series of monoclonal antibodies (MAbs) with anti-P reactivity. Competitive binding assays classified 27 of these MAbs into four groups (I to IV), and 24 of them were deemed to recognize linear epitopes, as judged by their reaction in immunoblots. The linear epitope recognized in each case was mapped by using two series of N- and C-terminally deleted recombinant phosphoproteins. Assessment of the reactivities of representative MAbs to a variety of lyssavirus isolates by an indirect fluorescent antibody test indicated that group I MAbs, which recognized a highly conserved N-terminal epitope, were broadly cross-reactive with all lyssaviruses assayed, while group III MAbs, which reacted with a site overlapping that of group I MAbs, exhibited variable reactivities and group IV MAbs reacted with most isolates of genotypes 1, 6, and 7 only. In contrast, group II MAbs, which recognized an epitope located within a highly divergent central portion of the protein, were exquisitely strain specific. These anti-P MAbs are potentially useful tools for lyssavirus identification and discrimination.

Predictive factors for the development of rubeosis following proton beam radiotherapy for uveal melanoma.

AIMS/BACKGROUND: Proton beam radiotherapy can effectively treat primary uveal melanomas of any size. Some patients, however, develop adverse late effects following treatment and the purpose of this study was to determine which factors give rise to a poor local outcome. METHODS: The hospital records from a first cohort of 127 patients treated by protons from 1989 to 1992 were reviewed retrospectively. The presence of rubeosis was selected as a measure of significant ocular damage. Split file analysis was performed with 73 cases forming a test group with the remaining 54 cases acting as a validation group. RESULTS: Large tumour size and the presence of retinal detachment were significant, independent risk factors for developing rubeosis for both the test and validation groups. These factors also predicted subsequent enucleation for uncontrolled ocular pain. Patients with tumours too large to plaque and with an associated retinal detachment had a 90% chance of developing rubeosis within 4 years of proton beam radiotherapy. CONCLUSIONS: Patients with a uveal melanoma too large for plaque therapy and an associated retinal detachment run a very high risk of developing rubeosis after proton beam radiotherapy and one third of individuals developing rubeosis required enucleation for pain even if local tumour control was satisfactory.

Arterial infusion chemotherapy in far advanced cancer.

From 1978 to 1994, more than 2000 advanced cancers were treated by arterial infusion chemotherapy in the Department of Surgery, Kaohsiung Medical College Hospital. During these 16 years there are a lot of improvements in arterial therapy. The catheter changed from external catheter to implantable port catheter system. The infusion pump changed from spring driven pump to more accurate battery operated electric pump. But the principle of the higher the regional tumor drug exposure, the better the treatment result is the same. There are 3 main factors affecting the successful treatment, proper placement of the catheter, suitable selection of the drugs and adequate regional tumor blood supply. The first two factors can be improved by learning and experience. However, we can do little about the third one. The blood supply of the tumor had decided most of the outcome of the treatment. Those tumors over locations with very rich blood supply such as cancers of head, breast, external genitals and hands, always respond better to chemotherapy no matter the drugs were given regionally or systemically. Of course if the anticancer drug was administered by arterial route, very high concentration of anticancer drug can be delivered to the tumor region to induced rapid shrinkage of the tumor within a relative short time.

The 62 MeV proton beam for the treatment of ocular melanoma at Clatterbridge.

A second treatment room and beam line has been constructed at the Cyclotron Unit at Clatterbridge for the purpose of using 62 MeV protons for the treatment of ocular melanoma. A uniform beam is produced by a double foil scattering system. The initial Bragg peak is spread across the target volume by the use of beam modulators. These are rotating four-vaned stepped absorbers made from Perspex. Two beam lines can be configured with different positions of modulators and range limiters. The first has a maximum penetration of 31.9 +/- 0.2 mm in water and the second a penetration of 31.2 +/- 0.2 mm. The second configuration has the advantage of less variation in beam penumbra, with a typical value of 1.7 +/- 0.1 mm for the 90% to 10% decrement lines. The patients are treated with individually shaped collimators. Beam output varies by less than 2% over the range of collimator areas used. The resulting whole-body dose equivalent to patient has also been assessed. In the first three years of operation over 250 patients have been treated.

Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma.

Independent and interactive effects related to the development of hepatocellular carcinoma were assessed using a community-based case-control study for hepatitis B virus, habitual alcohol drinking, cigarette smoking, peanut consumption and history of hepatocellular carcinoma among the immediate family. All 200 male newly diagnosed hepatocellular carcinoma patients were recruited consecutively through the period of study as the case group from two teaching medical centers in northern and southern Taiwan. Healthy community residents matched one-to-one with cases on age, sex, ethnic group and residential area were selected as the control group. The carrier status of HBsAg and HBeAg was determined by blind radioimmunoassays, and other risk factors were obtained through standardized interviews according to a structured questionnaire. Conditional logistic regression analysis showed a significant association between hepatocellular carcinoma and the carrier status of HBsAg and HBeAg with an odds ratio of 16.7 and 56.5, respectively, for carriers of HBsAg alone and for carriers of both HBsAg and HBeAg. There was a dose-response relationship between cigarette smoking and hepatocellular carcinoma with an odds ratio of 1.1, 1.5 and 2.6, respectively, for those who smoked 1 to 10, 11 to 20 and more than 20 cigarettes a day. A significant association with hepatocellular carcinoma was also observed for the habitual alcohol consumer with an odds ratio of 3.4. Those whose immediate family had a history of hepatocellular carcinoma were more likely to have the disease develop, with an odds ratio of 4.6. However, the frequency of peanut consumption was not significantly associated with hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Congenital longitudinal deficiency of the tibia.

Fifty-seven patients (seventy-one limbs) who had congenital longitudinal deficiency of the tibia (tibial hemimelia) were retrospectively categorized according to radiographic type (Types 1 through 4, as described by Jones et al.). At an average follow-up of nine years, fifty-six of fifty-seven patients walked independently. An ablative surgical procedure was performed on sixty-one of the seventy-one lower extremities. According to the classification of Jones et al., fifty-four limbs had a Type-1 (a or b) or Type-2 deficiency. In twenty-two of these extremities, disarticulation of the knee was performed; in twenty-five, a Syme amputation; and in one, a Chopart amputation. The ipsilateral foot was retained in six extremities that had a severe Type-1 or Type-2 deficiency. Medial transfer of the fibula (the Brown procedure) generally yielded less than satisfactory results; in ten of fourteen extremities, one or more additional operations were needed. Seventeen extremities were classified as having a Type-3 or Type-4 deficiency; Syme amputation was done in nine and Chopart amputation, in four. Despite satisfactory reconstruction of the ankle, a Syme amputation was necessary in most extremities that had a Type-4 deficiency because a major leg-length discrepancy was projected. In four limbs that had a Type-3 or Type-4 deficiency, the foot was retained.