Factors associated with mortality in patients with COVID-19 admitted to intensive care: a systematic review and meta-analysis.

Identification of high-risk patients admitted to intensive care with COVID-19 may inform management strategies. The objective of this meta-analysis was to determine factors associated with mortality among adults with COVID-19 admitted to intensive care by searching databases for studies published between 1 January 2020 and 6 December 2020. Observational studies of COVID-19 adults admitted to critical care were included. Studies of mixed cohorts and intensive care cohorts restricted to a specific patient sub-group were excluded. Dichotomous variables were reported with pooled OR and 95%CI, and continuous variables with pooled standardised mean difference (SMD) and 95%CI. Fifty-eight studies (44,305 patients) were included in the review. Increasing age (SMD 0.65, 95%CI 0.53-0.77); smoking (OR 1.40, 95%CI 1.03-1.90); hypertension (OR 1.54, 95%CI 1.29-1.85); diabetes (OR 1.41, 95%CI 1.22-1.63); cardiovascular disease (OR 1.91, 95%CI 1.52-2.38); respiratory disease (OR 1.75, 95%CI 1.33-2.31); renal disease (OR 2.39, 95%CI 1.68-3.40); and malignancy (OR 1.81, 95%CI 1.30-2.52) were associated with mortality. A higher sequential organ failure assessment score (SMD 0.86, 95%CI 0.63-1.10) and acute physiology and chronic health evaluation-2 score (SMD 0.89, 95%CI 0.65-1.13); a lower PaO2 :FI O2 (SMD -0.44, 95%CI -0.62 to -0.26) and the need for mechanical ventilation at admission (OR 2.53, 95%CI 1.90-3.37) were associated with mortality. Higher white cell counts (SMD 0.37, 95%CI 0.22-0.51); neutrophils (SMD 0.42, 95%CI 0.19-0.64); D-dimers (SMD 0.56, 95%CI 0.43-0.69); ferritin (SMD 0.32, 95%CI 0.19-0.45); lower platelet (SMD -0.22, 95%CI -0.35 to -0.10); and lymphocyte counts (SMD -0.37, 95%CI -0.54 to -0.19) were all associated with mortality. In conclusion, increasing age, pre-existing comorbidities, severity of illness based on validated scoring systems, and the host response to the disease were associated with mortality; while male sex and increasing BMI were not. These factors have prognostic relevance for patients admitted to intensive care with COVID-19.

Exposure to risperidone versus other antipsychotics and risk of osteoporosis-related fractures: a population-based study.

OBJECTIVE: Antipsychotics may increase serum prolactin, which has particularly been observed with risperidone. Further, hyperprolactinemia has been linked to osteoporosis-related fractures. Therefore, we investigated fracture risk in a nationwide cohort exposed to antipsychotics. METHODS: Swedish registers were used to identify adults with two consecutive dispensations of risperidone (n = 38 211), other atypical antipsychotics not including paliperidone (n = 60 691), or typical antipsychotics (n = 17 445) within three months between 2006 and 2013. An osteoporosis-related fracture was defined as a non-open hip/femur fracture in primary analyses. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Risperidone users were on average older (mean age of 68, 44, and 63 years for risperidone, other atypical antipsychotics, and typical antipsychotics respectively). Compared with other atypical antipsychotics, there was no association between risperidone and osteoporosis-related fractures in the overall (HR = 1.04, CI: 0.91-1.19) or age-stratified analyses. A significantly increased risk of typical antipsychotics (HR = 1.24, CI: 1.07-1.45) compared with other atypical antipsychotics remained for ages >45 years. CONCLUSION: Risperidone does not appear to be associated with an increased risk of osteoporosis-related fracture compared with other atypical antipsychotic agents as a group. For typical antipsychotics, a moderately elevated risk of hip fractures was noted compared with other atypical antipsychotics, possibly because of residual confounding.

Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study.

Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.

The minimum inhibitory concentration (MIC) assay with Escherichia coli: An early tier in the environmental hazard assessment of nanomaterials?

There are now over a thousand nano-containing products on the market and the antibacterial properties of some nanomaterials has created interest in their use as cleaning agents, biocides and disinfectants. Engineered nanomaterials (ENMs) are being released into the environment and this raises concerns about their effects on microbes in the receiving ecosystems. This study evaluated the bacterial toxicity of a wide range of nanomaterials with different surface coatings on Escherichia coli K-12 MG1655. The minimum inhibitory concentration (MIC) assay, which quantifies the threshold for growth inhibition in suspensions of bacteria, was used to rank the toxicity of silver (Ag), cupric oxide (CuO), cadmium telluride (CdTe) quantum dots, titanium dioxide (TiO2), nanodiamonds and multi-walled carbon nanotubes (MWCNTs). Bacteria were exposed for 12 h at 37 °C to a dilution series of the test suspensions in 96-well plates. The precision and accuracy of the method was good with coefficients of variation < 10%. In terms of the measured MIC values, the toxicity order of the ENMs was as follows: CdTe quantum dots ammonium-coated, 6 mg L-1 > Ag nanoparticles, 12 mg L-1 > CdTe quantum dots carboxylate-coated, 25 mg L-1 > CdTe quantum dots polyethylene glycol-coated, 100 mg L-1. The MIC values were above the highest test concentration used (100 mg L-1) for CuO, TiO2, nanodiamonds and MWCNTs, indicating low toxicity. The MIC assay can be a useful tool for the initial steps of ENMs hazard assessment.

Higher mortality after myocardial infarction in patients with severe mental illness: a nationwide cohort study.

OBJECTIVES: The aim of this study was to explore the impact of severe mental illness (SMI) on myocardial infarction survival and determine the influence of risk factor burden, myocardial infarction severity and different treatments. DESIGN, SETTING AND PARTICIPANTS: This population-based cohort study, conducted in Sweden during the period 1997-2010, included all patients with a first diagnosis of myocardial infarction in the Swedish nationwide myocardial infarction register SWEDEHEART (n = 209 592). Exposure was defined as a diagnosis of SMI (i.e. bipolar disorder or schizophrenia) in the national patient register prior to infarction. Bias-minimized logistic regression models were identified using directed acyclic graphs and included covariates age, gender, smoking, diabetes, previous cardiovascular disease, myocardial infarction characteristics and treatment. MAIN OUTCOME MEASURES: The outcomes were 30-day and 1-year mortality, obtained through linkage with national population registers. RESULTS: Patients with bipolar disorder (n = 442) and schizophrenia (n = 541) were younger (mean age 68 and 63 years, respectively) than those without SMI (n = 208 609; mean age 71 years). The overall 30-day and 1-year mortality rates were 10% and 18%, respectively. Compared with patients without SMI, patients with SMI had higher 30-day [odds ratio (OR) 1.99, 95% confidence interval (CI) 1.55-2.56] and 1-year mortality (OR 2.11, 95% CI 1.74-2.56) in the fully adjusted model. The highest mortality was observed amongst patients with schizophrenia (30-day mortality: OR 2.58, 95% CI 1.88-3.54; 1-year mortality: OR 2.55, 95% CI 1.98-3.29). CONCLUSION: SMI is associated with a markedly higher mortality after myocardial infarction, also after accounting for contributing factors. It is imperative to identify the reasons for this higher mortality.

Pregabalin is increasingly prescribed for neuropathic pain, generalised anxiety disorder and epilepsy but many patients discontinue treatment.

AIM: To assess prescribing patterns, sociodemographic characteristics and previous disease history in patients receiving pregabalin. METHODS: An observational study using register data on dispensed drugs and recorded diagnoses for all patients in Stockholm, Sweden, who filled at least one prescription of pregabalin between July 2005 and December 2009. Analyses focused on prevalence, incidence, diagnosis patterns, prior dispensing of other analgesics/psychotropics and persistence to treatment over time. RESULT: A total of 18,626 patients (mean age 55 years, 63% women) were initiated on treatment between July 2006 and December 2009. Approved indications were recorded in hospital and/or primary care within 1 year prior to the first dispensing for 40% of the patients (epilepsy 1.3%, neuropathic pain 35.5% and generalised anxiety disorder (GAD) 3.6%). Antidepressants were used by 55%, opioids by 49% and sedatives by 48% prior to initiation of pregabalin. One-third (34%) only purchased one prescription and the proportion purchasing pregabalin 1 year after initiation was 42.1% for epilepsy, 36.3% for GAD, 21.5% for neuropathic pain and 25.6% for those without any of the included diagnoses. CONCLUSION: Pregabalin was mainly used as a second-line drug for the treatment of GAD or neuropathic pain and to a lesser extent as add-on therapy in epilepsy. However, a large proportion of all patients only purchased one prescription and the persistence declined rapidly over time. The issue of potential off-label prescribing or poor registration of diagnoses should also be noted as a high proportion had been prescribed the drug without a record of any of the approved indications.

Loose body following cross-pin fixation for anterior cruciate ligament reconstruction.

We report a case of loosening of a bioabsorbable cross-pin fixation device for anterior cruciate ligament reconstruction. Forty-two months following a bone tendon bone reconstruction of the anterior cruciate ligament, the patient presented with a subcutaneous collection in the medial side of the knee. At subsequent surgery, a RIGIDFIX cross-pin fixator (Mitek, Westwood, MA, USA) was retrieved, intact, from the sterile fluctuant mass around the superomedial aspect of the knee. The graft was stable both radiologically and clinically, and the patient remains symptom free. This case raises concern about the use of this smooth cross-pin fixator and the consequences of backing out and the resultant intraarticular loose body. We suggest consideration of a loose body if the patient becomes symptomatic postoperatively, and early intervention to prevent chondral damage is recommended.

Surgical training and capacity development in the South African internship programme.

Medical practitioners in South Africa manage a quadruple burden of disease. Junior doctors, who contribute significantly to the health workforce, must complete 2 years of internship training and 1 year of community service work in state health facilities after graduation to register as an independent medical practitioner. The aim of this article is to give a critical appraisal of the current national internship programme and why it was implemented, and outline suggestions for future changes. There is a compelling need to train competent, confident doctors while ensuring that the requirements and demands of our health system remain a central concern.

Dorsomedial prefrontal theta burst stimulation to treat anhedonia, avolition, and blunted affect in schizophrenia or depression - a randomized controlled trial.

BACKGROUND: Intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (DMPFC) has shown promise in open-label trials of depression. METHODS: In this randomized, double-blind, sham controlled trial we evaluate iTBS over the DMPFC for anhedonia, avolition, and blunted affect in patients with schizophrenia or depression. Active iTBS was delivered over the DMPFC with 1200 pulses per session, twice daily over ten weekdays at target intensity with an angled figure-of eight coil. Sham condition comprised the magnetically shielded side of the coil and simultaneous transcutaneous electrical nerve stimulation. Primary outcome was change on the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: Twenty-eight patients were randomized to active iTBS and 28 to sham. Mean (standard deviation) change in CAINS score from baseline to the day after last treatment was -5.3 (8.1) in active iTBS and -2.1 (7.1) in sham. A linear model showed no significant effect of treatment, accounting for baseline scores p=.088. Sub analyses per diagnostic group showed a significant effect in patients with depression, p=.038, but not in the schizophrenia group, p=.850. However, overall depressive symptoms did not change significantly in patients with depression. There were three serious adverse events, all in the sham group. LIMITATIONS: Possibly too short treatment course and few patients with schizophrenia. CONCLUSION: In this first transdiagnostic randomized controlled trial of iTBS over DMPFC for anhedonia, avolition, and blunted affect it can be concluded that it was generally tolerable and safe but only more effective than sham in the subgroup of patients with depression.

Binding of C4b-binding protein to porin: a molecular mechanism of serum resistance of Neisseria gonorrhoeae.

We screened 29 strains of Neisseria gonorrhoeae and found 16/21 strains that resisted killing by normal human serum and 0/8 serum sensitive strains that bound the complement regulator, C4b-binding protein (C4bp). Microbial surface-bound C4bp demonstrated cofactor activity. We constructed gonococcal strains with hybrid porin (Por) molecules derived from each of the major serogroups (Por1A and Por1B) of N. gonorrhoeae, and showed that the loop 1 of Por1A is required for C4bp binding. Por1B loops 5 and 7 of serum-resistant gonococci together formed a negatively charged C4bp-binding domain. C4bp-Por1B interactions were ionic in nature (inhibited by high salt or by heparin), whereas the C4bp-Por1A bond was hydrophobic. Only recombinant C4bp mutant molecules containing the NH2-terminal alpha-chain short consensus repeat (SCR1) bound to both Por1A and Por1B gonococci, suggesting that SCR1 contained Por binding sites. C4bp alpha-chain monomers did not bind gonococci, indicating that the polymeric form of C4bp was required for binding. Using fAb fragments against C4bp SCR1, C4bp binding to Por1A and Por1B strains was inhibited in a complement-dependent serum bactericidal assay. This resulted in complete killing of these otherwise fully serum resistant strains in only 10% normal serum, underscoring the importance of C4bp in mediating gonococcal serum resistance.

Intermittent theta burst stimulation over the dorsomedial prefrontal cortex modulates resting-state connectivity in depressive patients: A sham-controlled study.

The mechanisms underlying repetitive transcranial magnetic stimulation (rTMS) treatment are largely unknown. Although there is a general lack of sham controlled studies, findings show altered functional connectivity to the stimulated region following treatment. When targeting the dorsolateral prefrontal cortex (dlPFC), connectivity with the subgenual anterior cingulate cortex (sgACC) is predictive of response, but less is known about the effects on functional connectivity of targeting the dorsomedial PFC (dmPFC). Here, 30 patients with an ongoing depressive episode were recruited and randomized to 20 sessions at target intensity of either active or sham intermittent theta burst stimulation (iTBS) over dmPFC. Those receiving sham were offered active treatment in a subsequent open phase. A seven minute resting-state scan and depressive symptom assessment was performed before and after treatment. After exclusions due to attrition and excessive head movements 23 patients remained for analysis. Seed-based resting-state connectivity was calculated using two seeds for the dmPFC target as well as the sgACC. A symptom related increase in dmPFC connectivity after active treatment, compared to sham treatment, was found. The effect was observed in a region overlapping the precuneus and the posterior cingulate cortex (PCC), suggesting an increase in the connectivity between the targeted salience network and the default mode network mediating improvement in depressive symptoms. Connectivity between the precuneus and both the sgACC and the treatment target was predictive of symptom improvement following active treatment. The findings have implications for understanding the mechanisms behind iTBS and may inform future efforts to individualize the treatment.

Autonomic modulation networks in schizophrenia: The relationship between heart rate variability and functional and structural connectivity in the brain.

Heart rate variability (HRV), a measurement of autonomic nervous system (ANS) activity, has been found reduced in schizophrenia. The anterior cingulate cortex (ACC), which is important in regulating the ANS, is structurally and functionally affected in schizophrenia. We investigate the relationship between HRV and functional and structural connectivity of the ACC in patients with schizophrenia and healthy controls. Ten patients with a diagnosis of schizophrenia and ten healthy controls were recruited. Heart rate was monitored in a naturalistic out-of-clinic setting. Magnetic resonance imaging (MRI) was performed, including resting-state functional MRI and diffusion tensor imaging. Patients with schizophrenia had significantly lower HRV compared to controls. A positive correlation between ACC connectivity with the bilateral cerebellum and HRV was found in the patients. HRV was also positively correlated with amplitude of low frequency fluctuations (ALFF) in the cerebellum, and with axial diffusivity in the middle cerebellar peduncle, in the patients. There was a significant negative relationship between antipsychotic medication dosage, HRV and all neuroimaging measures related to HRV. We conclude that ACC connectivity seems to be affected in schizophrenia, both structurally and functionally, and that the ACC-cerebellum connectivity, as well as cerebellar function, is associated with ANS regulation in patients with schizophrenia.

Rotational dislocation of the proximal interphalangeal joint of the finger.

We describe a case of rotational dislocation of the proximal interphalangeal joint of the ring finger. This injury was not initially appreciated and therefore closed reduction failed. The clinical findings included puckering of the skin on the dorsum of the joint and rotational incongruity on radiographs. At open reduction there was interposition of the lateral band. Identification of the pathology allows early successful treatment.

Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study.

The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [11C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [11C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [11C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [11C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

Surgical management of soft tissue sarcoma in patients over 80 years.

AIMS: To report outcome on patients over 80years of age with soft tissue sarcoma (STS), with respect to surgical treatment, co-morbidity, complications and survival. METHODS: From a prospective database of 3400 patients with STS presenting over a 13-year period, all patients over 80years of age were identified and reviewed, with respect to tumour characteristics morbidity, mortality and outcome. RESULTS: 128 patients over 80years were treated for STS with 63 referred for treatment of primary disease, of whom 50 underwent resectional surgery. The remaining 65 patients were treated for recurrent or incompletely excised disease. Of the 50 patients treated primarily with surgery, 56% of tumours where high grade and 56% were greater than 10cm in diameter. The overall complication rate was 34%, with a 30-day mortality of 4%. Two- and 5-year survival rates were 56% and 46%, with a local recurrence rate of 22% at a mean follow-up of 22months. CONCLUSION: This patient group presented with poor prognosis tumours that were associated with poor outcomes in the medium to long term. Age need not be considered a contra-indication to radical surgery with curative intent.

Ablation of colorectal xenografts with combined radioimmunotherapy and tumor blood flow-modifying agents.

Radioimmunotherapy (RIT) does not readily eradicate common solid tumors and therefore requires augmentation by complementary therapies that do not increase normal tissue damage. We have examined the efficacy of RIT combined with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a drug which induces immunomodulation and cytokine production and preferentially reduces tumor blood flow, using a colorectal xenograft model in nude mice. Although an optimal i.p. dose (27.5 mg/kg) of drug alone induced massive hemorrhagic necrosis of all but a thin peripheral rim of viable tumor cells, survival was unaffected. However, when combined with i.v. 18.5 MBq 131I-labeled anti-carcinoembryonic antigen IgG, DMXAA significantly potentiated the RIT without increased toxicity, with five of six mice showing complete cures. Scheduling was critical because the antibody must be allowed to reach maximum tumor accumulation before initiation of drug-induced blood flow inhibition. Subsequently, the antibody was retained preferentially in the tumor, reaching approximately twice control levels by 5 days after drug delivery. In combined studies, the drug had a narrow therapeutic window, 30 mg/kg being toxic to two of six mice, whereas 20 mg/kg were ineffective. However, the addition of a second vasoactive agent, serotonin, to RIT plus 20 mg/kg DMXAA enhanced therapy without increasing systemic toxicity. Tumor histology and phosphor image plate analysis reflected these results. When given without RIT, the two drugs combined, although not alone, also significantly inhibited tumor growth. Drug-induced tumor necrosis and tumor retention of radioantibody may both contribute to the enhanced RIT produced by this combined complementary therapy.

Enhancement of antibody-directed enzyme prodrug therapy in colorectal xenografts by an antivascular agent.

The irregular nature of solid tumor vasculature produces a heterogeneous distribution of antibody-targeted therapies within the tumor mass, which frequently results in reduced therapeutic efficacy. We have, therefore, combined two complementary therapies: Antibody-directed Enzyme Prodrug Therapy (ADEPT), which targets tumor cells, and an agent that selectively destroys tumor vasculature. A single i.p. dose (27.5 mg/kg) of the drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), given to nude mice bearing the LS174T colorectal xenograft, destroyed all but a peripheral rim of tumor cells, without enhancing survival. The ADEPT system, in which a pretargeted enzyme activates a prodrug, consisted of the F(ab')2 fragment of anti-carcinoembryonic antigen antibody A5B7 conjugated to the bacterial enzyme carboxypeptidase G2 and the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid, which was given i.p. in three doses of 500 mg/kg at 72, 84, and 96 h post-conjugate administration (25 units of carboxypeptidase G2). The antibody-enzyme conjugate could be selectively retained at approximately twice the control levels by administration of the antivascular agent at the time of optimal conjugate localization within the tumor (20 h post-conjugate administration), as demonstrated by gamma counting, phosphor plate image analysis, and active enzyme measurement. This resulted in significantly enhanced tumor growth inhibition in groups of six mice, compared to conventional ADEPT therapy, with no concomitant increase in systemic toxicity. In a separate experiment, aimed at trapping the prodrug within the tumor, a 16-fold increase over control values was produced (means, 44.8 versus 2.8 microg/g tumor) when DMXAA was given 4 h prior to 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid. The therapeutic window was small, with no significant enhancement of prodrug retention when DMXAA was given at either earlier or later time points. This correlated with the time of vascular shut-down induced by the antivascular agent. We are currently investigating whether it is more advantageous to trap increased levels of conjugate or prodrug within the tumor for maximal enhancement of conventional ADEPT. These studies demonstrate that combined use of antibody-directed and antivascular therapies can significantly benefit the therapeutic outcome of either strategy alone.

Eradication of colorectal xenografts by combined radioimmunotherapy and combretastatin a-4 3-O-phosphate.

Solid tumors have a heterogeneous pathophysiology, which has a major impact on therapy. Using SW1222 colorectal xenografts grown in nude mice, we have shown that antibody-targeted radioimmunotherapy (RIT) effectively treated the well-perfused tumor rim, producing regressions for approximately 35 days, but was less effective at the more hypoxic center. By 72 h after RIT, the number of apoptotic cells rose from an overall value of 1% in untreated tumors to 35% at the tumor periphery and 10% at the center. The antivascular agent disodium combretastatin A-4 3-O-phosphate (CA4-P) rapidly reduced tumor blood flow to 62% of control values by 1 h, 23% by 3 h, and between 32-36% from 6 to 24 h after administration. This created central hemorrhagic necrosis, but a peripheral rim of cells continued to grow, and survival was unaffected. Changes in the pattern of perfusion across the tumor over time were zonal. Untreated mice showed perfusion throughout the tumor, with greatest activity at the rim. There was an overall reduction at 1 h, and total cessation of central perfusion from 3 h onward. A narrow peripheral rim of perfusion was always present, which increased in intensity and extent between 6 and 24 h, either through reperfusion or new vessel growth. Combining these two complementary therapies (7.4 MBq (131)I-labeled anti-carcinoembryonic antigen IgG i.v. plus a single 200 mg/kg dose of CA4-P i.p.) produced complete cures in five of six mice for >9 months. Allowing maximal tumor localization of antibody (48 h) before blood flow inhibition by CA4-P increased tumor retention by two to three times control levels by 96 h without altering normal tissue levels, as confirmed by gamma counting and phosphor image analysis. The success of this combined, synergistic therapy was probably the result of several factors: (a) the killing of tumor cells in the outer, radiosensitive region by targeted radiotherapy; (b) enhancement of RIT by entrapment of additional radioantibody after combretastatin-induced vessel collapse; and (c) destruction of the central, more hypoxic and radioresistant region by CA4-P. This work demonstrates the need to consider cancer treatment in a biologically heterogeneous setting, if results are to be effectively translated to the clinic.