Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype.

OBJECTIVE: Mitochondrial complex-I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. METHODS: This was a multicenter retrospective case series including five fetuses from three non-related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non-immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. RESULTS: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. CONCLUSIONS: Mitochondrial complex-I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex-I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non-immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Making meaning of cancer: A qualitative analysis of oral-digestive cancer survivors' reflections.

This qualitative study aimed to confirm and extend research on meaning making after cancer. In all, 119 adults aged 41 to 88 years (M = 65.50 years and standard deviation = 9.16 years) were interviewed 12 months after diagnosis of oral-digestive cancers. About half tried to understand why they got cancer (43%) and said that cancer changed their view of life (53%). Most (75%) reported that previous life experiences helped them cope with cancer. Cancer survivors made meanings in the areas of existential, social, and personal domains with both positive and negative content. Practitioners may wish to examine meaning making in these areas for those in distress after cancer.

Global connectivity of the fronto-parietal cognitive control network is related to depression symptoms in the general population.

We all vary in our mental health, even among people not meeting diagnostic criteria for mental illness. Understanding this individual variability may reveal factors driving the risk for mental illness, as well as factors driving subclinical problems that still adversely affect quality of life. To better understand the large-scale brain network mechanisms underlying this variability, we examined the relationship between mental health symptoms and resting-state functional connectivity patterns in cognitive control systems. One such system is the fronto-parietal cognitive control network (FPN). Changes in FPN connectivity may impact mental health by disrupting the ability to regulate symptoms in a goal-directed manner. Here we test the hypothesis that FPN dysconnectivity relates to mental health symptoms even among individuals who do not meet formal diagnostic criteria but may exhibit meaningful symptom variation. We found that depression symptoms severity negatively correlated with between-network global connectivity (BGC) of the FPN. This suggests that decreased connectivity between the FPN and the rest of the brain is related to increased depression symptoms in the general population. These findings complement previous clinical studies to support the hypothesis that global FPN connectivity contributes to the regulation of mental health symptoms across both health and disease.

Cognitive task information is transferred between brain regions via resting-state network topology.

Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive computations underlying these abilities. We developed a new approach-information transfer mapping-to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here, we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.

User-centered design of discharge warnings tool for colorectal surgery patients.

OBJECTIVES: Readmission following colorectal surgery, typically due to surgery-related complications, is common. Patient-centered discharge warnings may guide recognition of early complication signs after colorectal surgery. MATERIALS AND METHODS: User-centered design of a discharge warnings tool consisted of iterative health literacy review and a heuristic evaluation with human factors and clinical experts as well as patient end users to establish content validity and usability. RESULTS: Literacy evaluation of the prototype suggested >12th-grade reading level. Subsequent revisions reduced reading level to 8th grade or below. Contents were formatted during heuristic evaluation into 3 action-oriented zones (green, yellow, and red) with relevant warning lexicons. Usability testing demonstrated comprehension of this 3-level lexicon and recognition of appropriate patient actions to take for each level. DISCUSSION: We developed a discharge warnings tool for colorectal surgery using staged user-centered design. The lexicon of surgical discharge warnings could structure communication among patients, caregivers, and clinicians to improve post-discharge care.

Patient experience with discharge instructions in postdischarge recovery: a qualitative study.

OBJECTIVES: We examined the role of discharge instructions in postoperative recovery for patients undergoing colorectal surgery and report themes related to patient perceptions of discharge instructions and postdischarge experience. DESIGN: Semistructured interviews were conducted as part of a formative evaluation of a Project Re-Engineered Discharge intervention adapted for surgical patients. SETTING: Michael E. DeBakey VA Medical Center, a tertiary referral centre in Houston, Texas. PARTICIPANTS: Twelve patients undergoing elective colorectal surgery. Interviews were conducted at the two-week postoperative appointment. RESULTS: Participants demonstrated understanding of the content in the discharge instructions. During the interviews, participants reported several positive roles for discharge instructions in their postdischarge care: a sense of security, a reminder of inhospital education, a living document and a source of empowerment. Despite these positive associations, participants reported that the instructions provided insufficient information to promote access to care that effectively addressed acute issues following discharge. Participants noted difficulty reaching providers after discharge, which resulted in the adoption of workarounds to overcome system barriers. CONCLUSIONS: Despite concerted efforts to provide patient-centred instructions, the discharge instructions did not provide enough context to effectively guide postdischarge interactions with the healthcare system. Insufficient information on how to access and communicate with the most appropriate personnel in the healthcare system is an important barrier to patients receiving high-quality postdischarge care. Tools and strategies from team training programmes, such as team strategies and tools to enhance performance and patient safety, could be adapted to include patients and provide them with structured methods for communicating with healthcare providers post discharge.

Adaptive response to hypoxia and remote ischaemia pre-conditioning: a new hypoxia-inducible factors era in clinical medicine.

Transient ischaemia leads to tolerance to subsequent protracted ischaemia. This 'ischaemia pre-conditioning' results from the induction of numerous protective genes, involved in cell metabolism, proliferation and survival, in antioxidant capacity, angiogenesis, vascular tone and erythropoiesis. Hypoxia-inducible factors (HIF) play a pivotal role in this transcriptional adaptive response. HIF prolyl hydroxylases (PHDs), serving as oxygen sensors, control HIFα degradation. HIF-mediated ischaemic pre-conditioning can be achieved with the administration of PHD inhibitors, with the attenuation of organ injury under various hypoxic and toxic insults. Clinical trials are currently under way, evaluating PHD inhibitors as inducers of erythropoietin. Once their safety is established, their potential use might be further tested in clinical trials in various forms of acute ischaemic and toxic organ damage. Repeated transient limb ischaemia was also found to attenuate ischaemic injury in remote organs. This 'remote ischaemic pre-conditioning' phenomenon (RIP) has been extensively studied recently in small clinical trials, preceding, or in parallel with an abrupt insult, such as myocardial infarction, cardiac surgery or radiocontrast administration. Initial results are promising, suggesting organ protection. Large-scale multi-centre studies are currently under way, evaluating the protective potential of RIP in cardiac surgery, in the management of myocardial infarction and in organ transplantation. The mechanisms of organ protection provided by RIP are poorly understood, but HIF seemingly play a role as well. Thus, Inhibition of HIF degradation with PHD inhibitors, as well as RIP (in part through HIF), might develop into novel clinical interventions in organ protection in the near future.

Testosterone treatment and MMPI-2 improvement in transgender men: a prospective controlled study.

OBJECTIVE: Most transgender men desire to receive testosterone treatment in order to masculinize their bodies. In this study, we aimed to investigate the short-term effects of testosterone treatment on psychological functioning in transgender men. This is the 1st controlled prospective follow-up study to examine such effects. METHOD: We examined a sample of transgender men (n = 48) and nontransgender male (n = 53) and female (n = 62) matched controls (mean age = 26.6 years; 74% White). We asked participants to complete the Minnesota Multiphasic Personality Inventory (2nd ed., or MMPI-2; Butcher, Graham, Tellegen, Dahlstrom, & Kaemmer, 2001) to assess psychological functioning at baseline and at the acute posttreatment follow-up (3 months after testosterone initiation). Regression models tested (a) Gender × Time interaction effects comparing divergent mean response profiles across measurements by gender identity; (b) changes in psychological functioning scores for acute postintervention measurements, adjusting for baseline measures, comparing transgender men with their matched nontransgender male and female controls and adjusting for baseline scores; and (c) changes in meeting clinical psychopathological thresholds. RESULTS: Statistically significant changes in MMPI-2 scale scores were found at 3-month follow-up after initiating testosterone treatment relative to baseline for transgender men compared with female controls (female template): reductions in Hypochondria (p < .05), Depression (p < .05), Hysteria (p < .05), and Paranoia (p < .01); and increases in Masculinity-Femininity scores (p < .01). Gender × Time interaction effects were found for Hysteria (p < .05) and Paranoia (p < .01) relative to female controls (female template) and for Hypochondria (p < .05), Depression (p < .01), Hysteria (p < .01), Psychopathic Deviate (p < .05), Paranoia (p < .01), Psychasthenia (p < .01), and Schizophrenia (p < .01) compared with male controls (male template). In addition, the proportion of transgender men presenting with co-occurring psychopathology significantly decreased from baseline compared with 3-month follow-up relative to controls (p < .05). CONCLUSIONS: Findings suggest that testosterone treatment resulted in increased levels of psychological functioning on multiple domains in transgender men relative to nontransgender controls. These findings differed in comparisons of transgender men with female controls using the female template and with male controls using the male template. No iatrogenic effects of testosterone were found. These findings suggest a direct positive effect of 3 months of testosterone treatment on psychological functioning in transgender men.

Pain is prevalent and persisting in cancer survivors: differential factors across age groups.

OBJECTIVE: The Institute of Medicine documents a significant gap in care for long term side effects of cancer treatment, including pain. This paper characterizes age differences in the prevalence and predictive characteristics of pain to guide clinicians in identification and treatment. MATERIALS AND METHODS: A sample of 170 adults with head and neck, esophageal, gastric, or colorectal cancers were recruited from two regional Veterans Administration Medical Centers. Face to face interviews were conducted 6, 12, and 18 months after diagnosis with the PROMIS scale to assess pain and PHQ-9 scale to assess depression. Descriptive statistics characterized incidence and prevalence of pain impact and intensity ratings. Multivariate linear hierarchical regression identified clinical characteristics associated with pain in older versus younger age groups. RESULTS: Clinically significant pain was endorsed in one third (32%) of the sample, with younger adults reporting higher levels of the impact of pain on daily activities and work, and also higher pain intensity ratings than older adults. In younger adults, pain ratings were most associated with lower social support and higher depression, as well as advanced cancer stage. In older adults, pain was multifactorial, associated with baseline comorbidities, adjuvant treatment, and both combat post-traumatic stress disorder (PTSD) and depression. CONCLUSIONS: Pain is a significant persisting problem for one in three cancer survivors, requiring ongoing assessment, even months later. Important differences in pain's determinants and impact are present by age group. Identification and treatment of pain, as well as associated conditions such as depression, may improve the quality of life in cancer survivors.

VB-201, an oxidized phospholipid small molecule, inhibits CD14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis.

Atherosclerosis is an inflammatory disease of the vascular wall. Activated monocytes and dendritic cells (DC) in the intima layer of the vasculature promote atherogenesis. Toll-like receptor (TLR)-2 and TLR-4, which are predominantly expressed on these cells and mediate their activation, are essential for atherosclerosis development. In this study we demonstrate that VB-201, an oxidized phospholipid (Ox-PL) small molecule, inhibits TLR signalling restricted to TLR-2 and TLR-4 in human and mouse monocytes and DC. Mechanistically, we show that VB-201 binds directly to TLR-2 and CD14, the TLR-4 co-receptor, to impair downstream cues and cytokine production. In a rabbit model, oral administration of VB-201 constrained atherosclerosis progression. This effect was not due to reduced cholesterol abundance, as hyperlipidaemia was sustained. We suggest that VB-201 may counter inflammation where TLR-2 and/or CD14 complicity is essential, and is therefore beneficial for the treatment of atherosclerosis.

Comparative Hepatoprotective Activity of Ethanolic Extracts of Cuscuta australis against Acetaminophen Intoxication in Wistar Rats.

This study investigates the comparative hepatoprotective activity of crude ethanol extracts of Cuscuta australis against acetaminophen (APAP) intoxication. Thirty-six rats were randomly divided into six groups of 6 replicates: Group 1 which served as control received water. Group 2 was orally administered 835 mg/kg body wt. of paracetamol on day 8. Groups 3 and 4 were orally administered ethanolic extracts of the seed of Cuscuta australis in doses of 125 mg/kg and 250 mg/kg, respectively, for 7 days and then intoxicated as in Group 2 on the 8th day. Groups 5 and 6 received similar oral doses of Cuscuta australis stem extracts for 7 days and then intoxicated as in Groups 3 and 4. Group 2 rats showed severe periportal hepatic necrosis, significantly elevated serum hepatic injury markers, markedly increased lipid peroxidation, and decreased hepatic antioxidant enzymes activities. Remarkably, Cuscuta australis (seed and stem) extract pretreatments in Groups 3, 4, 5, and 6, most especially, the stem extract pretreatment in Groups 5 and 6, improved better the hepatic histoarchitecture, the hepatocellular, and the oxidative stress injury markers in a dose-dependent manner. Conclusively, ethanol extractions of Cuscuta australis stem appear to protect the liver from acetaminophen intoxication better than the seed counterpart.

VDAC1-based peptides: novel pro-apoptotic agents and potential therapeutics for B-cell chronic lymphocytic leukemia.

The voltage-dependent anion channel 1 (VDAC1), localized in the outer mitochondrial membrane, mediates metabolic cross-talk between the mitochondrion and the cytoplasm and thus serves a fundamental role in cell energy metabolism. VDAC1 also plays a key role in mitochondria-mediated apoptosis, interacting with anti-apoptotic proteins. Resistance of cancer cells to apoptosis involves quenching the mitochondrial apoptotic pathway by over-expression of anti-apoptotic/pro-survival hexokinase (HK) and Bcl-2 family proteins, proteins that mediate their anti-apoptotic activities via interaction with VDAC1. Using specifically designed VDAC1-based cell-penetrating peptides, we targeted these anti-apoptotic proteins to prevent their pro-survival/anti-apoptotic activities. Anti-apoptotic proteins are expressed at high levels in B-cell chronic lymphocytic leukemia (CLL), an incurable disease requiring innovative new approaches to improve therapeutic outcome. CLL is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Specifically, we demonstrate that the VDAC1-based peptides (Antp-LP4 and N-Terminal-Antp) selectively kill peripheral blood mononuclear cells (PBMCs) obtained from CLL patients, yet spare those obtained from healthy donors. The cell death induction competence of the peptides was well correlated with the amount of double positive CD19/CD5 cancerous CLL PBMCs, further illustrating their selectivity toward cancer cells. Moreover, these VDAC1-based peptides induced apoptosis by activating the mitochondria-mediated pathway, reflected in membrane blebbing, condensation of nuclei, DNA fragmentation, release of mitochondrial cytochrome c, loss of mitochondrial membrane potential, decreased cellular ATP levels and detachment of HK, all leading to apoptotic cell death. Thus, the mode of action of the peptides involves decreasing energy production and inducing apoptosis. Over 27 versions of cell-penetrating VDAC1-based peptides were designed and screened to identify the most stable, short and apoptosis-inducing peptides toward CLL-derived lymphocytes. In this manner, three optimized peptides suitable for in vivo studies were identified. This study thus reveals the potential of VDAC1-based peptides as an innovative and effective anti-CLL therapy.

Erythrocyte swelling and membrane hole formation in hypotonic media as studied by conductometry.

Hypoosmotic swelling of erythrocytes and the formation of membrane holes were studied by measuring the dc conductance (G). In accordance with the theoretical predictions, these processes are manifested by a decrease in G followed by its increase. Thus, unlike the conventional osmotic fragility test, the proposed methodological approach allows investigations of both the kinetics of swelling and the erythrocyte fragility. It is shown that the initial rate of swelling and the equilibrium size of the cells are affected by the tonicity of a hypotonic solution and the membrane rheological properties. Because the rupture of biological membranes is a stochastic process, a time-dependent increase in the conductance follows an integral distribution function of the membrane lifetime. The main conclusion which stems from reported results is that information about rheological properties of red blood cell (RBC) membranes and the resistivity of RBCs to a certain osmotic shock may be extracted from conductance signals.

A patient-centered early warning system to prevent readmission after colorectal surgery: a national consensus using the Delphi method.

BACKGROUND: Warnings of deteriorating condition provided to patients at hospital discharge are highly subjective, based on conventional wisdom, and lack systematic implementation. We conducted a standardized Delphi process to achieve national consensus on warning indicators and recommended action plans for patients after colorectal surgery. STUDY DESIGN: Expert panel eligibility was determined by pre-established criteria. A preliminary meeting was held at a national surgical conference followed by 5 rounds of email questionnaires and 1 teleconference using the Delphi method. Consensus was defined when at least 70% of the experts rated a symptom as 4 or more on a 5-point Likert scale (agree or strongly agree). RESULTS: Eleven experts were recruited to participate in the national consensus panel. A consensus was reached at Round 5. Experts identified 10 symptoms that indicate patients should notify their physician: "wound drainage," "wound opening," "wound redness or changes in the skin around the wound," "no bowel movement or lack of gas/stool from an ostomy for more than 24 hours," "increasing abdominal pain," "vomiting," "abdominal swelling," "high ostomy output and/or dark urine or no urine," "fever greater than 101.5°F," and "not being able to take anything by mouth for more than 24 hours." Two additional symptoms should alert the patient to seek emergency care: "shortness of breath or inability to breathe" and "chest pain." CONCLUSIONS: Expert consensus on discharge warning signs and appropriate action plans are identified for patients after colorectal surgery. The result of this study will help develop a more sophisticated patient-centered discharge tool for surgical patients.

Mucormycosis in a liver allograft: salvage re-transplantation and targeted immunosuppressive management.

Zygomycetes infection is associated with a high mortality in transplant populations. We describe a child with liver allograft Rhizopus oryzae infection who was salvaged by liver re-transplantation. A 10-year-old child presented with anastomotic bile leak that was repaired. A combined antibiotics and voriconazole regimen was introduced for Escherichia coli and Candida krusei growth in the peritoneal fluid. Despite broad antibiotic and antifungal coverage, the patient continued to have an ongoing infection. A follow-up computed tomography scan 8 weeks later showed 2 liver abscesses infiltrating the stomach and the diaphragm, with splenic infarcts and pericardial effusion. Aspirated samples from the liver abscess and the pericardial fluid revealed R. oryzae. Immunosuppression was discontinued and an antifungal regimen combining amphotericin B, posaconazole, and caspofungin was introduced. After 3 weeks of treatment with control of the systemic signs of infection, a positron emission tomography showed the fluorescence stain limited to the liver. With infection confined to the liver, the child underwent liver re-transplantation, splenectomy, and partial gastrectomy. Immunosuppression was reintroduced with recovery of the immune response observed by the CD4 cells adenosine triphophate release (Cylex(™) ImmuKnow(®) assay) and posaconazole was continued for another year. At 3-year follow-up, the child maintained normal graft function. We conclude that discontinuation of immunosuppression combined with a modern antifungal regimen may allow salvage re-transplantation in patients with liver mucormycosis.

Clomiphene as a novel modality for the treatment of acute myeloid leukemia: A pilot phase II study.

Clomiphene, an antiestrogen clinically used for ovulation induction, kills leukemic cells ex vivo via apoptosis. This study was designed to evaluate the antileukemic effect of clomiphene in patients with AML. Eleven patients with recurrent or chemoresistant AML aged 54-79 years received oral clomiphene (25-50mg per day), for seven consecutive days per cycle, up to three cycles while concurrent non intravenous chemotherapy was continued. Ten patients showed a partial response or remained stable during therapy; 7 had a rapid increase in disease parameters shortly after cessation of therapy while four patients survived 6-18 months. We believe that clomiphene contributes to stabilizing disease during therapy and appears to prolong survival in a subset of relapsed or refractory patients and may perhaps be considered as a new therapeutic option.

Patterns of social-experience-related c-fos and Arc expression in the frontal cortices of rats exposed to saccharin or moderate levels of ethanol during prenatal brain development.

Recent findings from our laboratory indicate that alterations in frontal cortex function, structural plasticity, and related social behaviors are persistent consequences of exposure to moderate levels of ethanol during prenatal brain development [24]. Fetal-ethanol-related reductions in the expression of the immediate early genes (IEGs) c-fos and Arc and alterations in dendritic spine density in ventrolateral and medial aspects of frontal cortex suggest a dissociation reminiscent of that described by Kolb et al. [38] in which these aspects of frontal cortex undergo reciprocal experience-dependent changes. In addition to providing a brief review of the available data on social behavior and frontal cortex function in fetal-ethanol-exposed rats, the present paper presents novel data on social-experience-related IEG expression in four regions of frontal cortex (Zilles LO, VLO, Fr1, Fr2) that are evaluated alongside our prior data from AID and Cg3. Social experience in normal rats was related to a distinct pattern of IEG expression in ventrolateral and medial aspects of frontal cortex, with generally greater expression observed in ventrolateral frontal cortex. In contrast, weaker expression was observed in all aspects of frontal cortex in ethanol-exposed rats, with the exception of an experience-related increase in the medial agranular cortex. Behaviors related to social investigation and wrestling/boxing were differentially correlated with patterns of activity-related IEG expression in the regions under investigation for saccharin- and ethanol-exposed rats. These observations suggest that recruitment and expression of IEGs in frontal cortex following social experience are potentially important for understanding the long-term consequences of moderate prenatal ethanol exposure on frontal cortex function, synaptic plasticity, and related behaviors.

Prenatal exposure to moderate levels of ethanol alters social behavior in adult rats: relationship to structural plasticity and immediate early gene expression in frontal cortex.

The goals of the present study were to characterize the effects of prenatal exposure to moderate levels of ethanol on adult social behavior, and to evaluate fetal-ethanol-related effects on dendritic morphology, structural plasticity and activity-related immediate early gene (IEG) expression in the agranular insular (AID) and prelimbic (Cg3) regions of frontal cortex. Baseline fetal-ethanol-related alterations in social behavior were limited to reductions in social investigation in males. Repeated experience with novel cage-mates resulted in comparable increases in wrestling and social investigation among saccharin- and ethanol-exposed females, whereas social behavioral effects among males were more evident in ethanol-exposed animals. Male ethanol-exposed rats also displayed profound increases in wrestling when social interaction was motivated by 24h of isolation. Baseline decreases in dendritic length and spine density in AID were observed in ethanol-exposed rats that were always housed with the same cage-mate. Modest experience-related decreases in dendritic length and spine density in AID were observed in saccharin-exposed rats housed with various cage-mates. In contrast, fetal-ethanol-exposed rats displayed experience-related increases in dendritic length in AID, and no experience-related changes in spine density. The only effect observed in Cg3 was a baseline increase in basilar dendritic length among male ethanol-exposed rats. Robust increases in activity-related IEG expression in AID (c-fos and Arc) and Cg3 (c-fos) were observed following social interaction in saccharin-exposed rats, however, activity-related increases in IEG expression were not observed in fetal-ethanol-exposed rats in either region. The results indicate that deficits in social behavior are among the long-lasting behavioral consequences of moderate ethanol exposure during brain development, and implicate AID, and to a lesser degree Cg3, in fetal-ethanol-related social behavior abnormalities.

Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma.

BACKGROUND: Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. PATIENTS AND METHODS: Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. RESULTS: Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01). CONCLUSIONS: These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.