Global Forum of Cancer Surgeons: Cancer Surgery During the COVID-19 Pandemic: Impact and Lessons Learned.

BACKGROUND: The purpose of this article is to summarize the opinions of the surgical oncology leaders from the Global Forum of Cancer Surgeons (GFCS) about the global impact of COVID-19 pandemic on cancer surgery. METHODS: A panel session (virtual) was held at the annual Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care to address the impact of COVID-19 on cancer surgery globally. Following the virtual meeting, a questionnaire was sent to all the leaders to gather additional opinions. The input obtained from all the leaders was collated and analyzed to understand how cancer surgeons from across the world adapted in real-time to the impact of COVID-19 pandemic. RESULTS: The surgical oncology leaders noted that the COVID-19 pandemic led to severe disruptions in surgical cancer care across all domains of clinical care, education, and research. Several new changes/protocols associated with increased costs were implemented to deliver safe care. Leaders also noted that preexisting disparities in care were exacerbated, and the pandemic had a detrimental effect on well-being and financial status. CONCLUSIONS: The COVID-19 pandemic has led to severe disruptions in surgical cancer care globally. Leaders of the GFCS opined that new strategies need to be implemented to prepare for any future catastrophic events based on the lessons learned from the current events. The GFCS will embark on developing such a roadmap to ensure that surgical cancer care is preserved in the future regardless of any catastrophic global events.

Fracture risk in people with developmental disabilities: results of a large claims data analysis.

Age- and sex-specific fracture rates of 18,000 people with developmental disabilities aged 0-69 years were compared to the general population. Age-standardized incidence of femoral fracture was 4.8- and 7.1-fold higher in women and men, respectively. Comparable fracture risks to the general population occurred 10-15 years earlier in females and 20-40 years earlier in males. INTRODUCTION: Previous studies suggested that fracture risks in people with developmental disabilities (DD) may be higher than in people in the general population. However, there are no current sufficiently large studies to compare age- and sex-specific fracture rates of single fracture types. METHODS: People with DD and incident fractures were identified by routine data of a health insurance company. Fractures in the general population were derived from the official fracture statistics. Age-specific and age-standardized fracture incidences were analyzed. To compare fracture risks in people with DD with that of the general population incidence ratios were calculated. RESULTS: Between 2008 and 2010, 148 femoral fractures and 469 other fractures were observed in nearly 18,000 people with DD aged 0-69 years. The three most frequent fracture types leading to hospital admission were fractures of the femur, lower leg/ankle, and shoulder/arm. For femoral fractures, a particularly high risk was observed in children and adolescents with DD. In adults with DD, the risk of femoral fractures increased with increasing age. Even if the youngest age category was not considered, the age-standardized incidence was 4.8- and 7.1-fold higher in women and men, respectively. For all other fracture types, except fractures of forearm/hand and of pelvis, people with DD had also higher fracture incidences than the general population. CONCLUSIONS: People with DD have a high fracture burden. Comparable risks of femoral fracture, for example, occurred about 10-15 years earlier in females and even 20-40 years earlier in males with DD than in the general population.

Tissue Factor Pathway Inhibitor Gene Polymorphism -33T → C Predicts Improved Disease-Free Survival in Colorectal Cancer.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is an anticoagulant with antimetastatic properties. The homozygous CC polymorphism of TFPI (-33T â†’ C) is associated with higher TFPI levels and lower venous thromboembolism risk. This study was the first to evaluate the impact of this polymorphism on disease-free survival (DFS) in cancer patients after curative resection. METHODS: A prospectively maintained tumor bank with clinical data was used to identify patients who underwent curative surgery for colorectal cancer between 1994 and 2006. Germline DNA was extracted from formalin-fixed, paraffin-embedded normal colonic mucosa. Single nucleotide polymorphisms for TFPI (-33T â†’ C), factor V Leiden (G1691A), and prothrombin (G20210A) were determined by polymerase chain reaction. Survival analysis was described using the Kaplan-Meier method. Multivariable regression analysis was performed using the Cox proportional hazard model. RESULTS: Of the 127 patients identified, the CC genotype was found in 11 %. Venous thromboembolism incidence was 18 % in the TT/TC (wild type/heterozygous) genotypes and 7 % in the CC genotype (p = 0.46). The CC genotype was associated with superior DFS (hazard ratio 0.34, 95 % confidence interval 0.14-0.84; p = 0.02) with 5-year DFS of 63 vs. 24 % for CC vs. TT/TC, respectively. In multivariate analysis, CC polymorphism (hazard ratio 0.28, p = 0.008) was independently associated with improved DFS. The prevalence of factor V Leiden (0.8 %) and prothrombin (1.6 %) polymorphisms was too low to detect interaction with TFPI polymorphism or DFS. CONCLUSIONS: These findings indicate that the inherited anticoagulant homozygous -33T â†’ C TFPI polymorphism may protect against colon cancer recurrence and suggests a mediating role for the coagulation system in cancer outcomes.

[Risk communication in travel medicine]. / Communication du risque en médecine des voyages.

Recommendations for malaria prevention for travelers planning a trip in medium to low risk countries differ between countries, despite the fact that people are exposed to the same risk in the travelled country. Decision aids have been developed and tested in a population of travelers planning a trip in such countries n order to present travelers the various prevention options and involve them in the decision. The use of the decision aid showed that he majority of people choose not to take chemoprophylaxis and that they could motivate their choice with valid reasons. The development of decision aids based on recognized quality criteria is foreseen; these will allow to improving the relevance of the recommendations and enable travelers to choose a prevention option that will be the closest to their values and preferences while following to the principles of medical ethics.

[Should we perform a screening ECG among asymptomatic adults?]. / Faut-il faire des ECG de dépistage chez les adultes asymptomatiques?

The resting ECG is a safe, low cost and widely available in the clinical investigation of several cardiac symptoms. However, there is controversy regarding the use as a screening tool or routine cardiovascular (CV) risk assessment test among healthy asymptomatic adults. Two recent studies reported that ECG adds supplemental information in the estimation of coronary artery disease (CAD) risk in asymptomatic patients, especially in those with intermediate risk. However, we currently need more data on the impact of ECG on the prevention of clinical CV outcomes, especially in a randomized clinical trial, and on additional costs of testing and treatment. For the time being, routine ECG testing is not recommended for the prevention of CV events among healthy asymptomatic adults.

Extended-duration thromboprophylaxis following major abdominopelvic surgery - For everyone or selected cases only?

Major abdominopelvic surgery is an important risk factor for postoperative venous thromboembolism (VTE). VTE is the leading cause of 30-day postoperative mortality in patients with cancer undergoing major abdominopelvic surgery. Randomized controlled trials have shown that extended duration thromboprophylaxis using a low molecular weight heparin or a direct oral anticoagulant significantly decreases the risk of overall VTE (symptomatic events and asymptomatic deep vein thrombosis). Hence, several clinical practice guidelines suggest the use of extended duration thromboprophylaxis for all high-risk patients undergoing major abdominopelvic surgery. Despite these recommendations by clinical practice guidelines, adoption of extended duration thromboprophylaxis in clinical practice remains low and clinical equipoise seems to persist. In this narrative review, we aim is to highlight and summarize the reasons that may explain discrepancy between clinical guideline recommendations and current practice regarding extended duration thromboprophylaxis in this patient population. We also aim to review different personalized approaches based on patients' individualized risk of VTE that may foster shared decision making and improve patient outcomes by reducing decisional conflict, increasing patient knowledge, and increasing risk perception accuracy.

Central nervous system involvement in mantle cell lymphoma: clinical features, prognostic factors and outcomes from the European Mantle Cell Lymphoma Network.

BACKGROUND: Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described. PATIENTS AND METHODS: We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions. RESULTS: The crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status ≥2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of ≥1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 × 109/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival. CONCLUSIONS: In MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

Trends in colon cancer surgery in Ontario: 2002-2009.

AIM: The safety and efficacy of laparoscopic surgery for colon cancer is well established but its uptake in the province has not been previously explored. We report an investigation of the trends of open and laparoscopic surgery for colon cancer in Ontario, Canada. METHOD: A retrospective cross-sectional time-series analysis examining population-based rates of elective surgery for colon cancer among 10.5 million adults in Ontario was conducted from 1 April 2002 to 31 March 2009. Databases were linked to assess quarterly elective procedure rates over time. RESULTS: During the study period, 3950 laparoscopic and 13 048 open elective colon cancer operations were performed in Ontario. The overall quarterly rate of colon cancer surgery remained stable at an average of 5.8 per 100000 population (P=0.10). From the first and last quarter, the rate of laparoscopic operations increased nearly threefold from 0.8 to 2.2 per 100000 population with a notable increase after 2005 (P<0.01). In contrast, open surgery decreased by more than 30% from 5.3 to 3.5 per 100 000 population (P<0.01). If current trends continue, the projected proportion of laparoscopic colon operations is estimated to reach 41% by 2015. Patients receiving open surgery had a significantly higher preoperative comorbidity (Charlson comorbidity score≥3) than those having laparoscopy (47.8%vs 39.1%, standardized difference 0.26). CONCLUSION: Trends in Ontario of laparoscopic colon cancer surgery show an increase between 2002 and 2009, but the incidence remains lower than for open surgery.

Changing trends in rectal cancer surgery in Ontario: 2002-2009.

AIM: The safety and efficacy of laparoscopic surgery for colon cancer have been demonstrated in large, multicentre clinical trials. The study aimed to determine the use of laparoscopic surgery for rectal cancer in Ontario over a 7-year period. METHOD: We conducted a retrospective study examining rates of elective rectal cancer surgery among 10.5 million adults in Ontario, Canada, from 1 April 2002 to 31 March 2009. We linked the Canadian Institute for Health Information Discharge Abstract Database, the Registered Persons Database and the database of the Ontario Cancer Registry to assess procedures used over the period. Data on demographics were collected. Trends were assessed using time series analysis. RESULTS: Over the 7-year period, 8189 open and 1079 laparoscopic elective operations for rectal cancer were identified. The annual rate of laparoscopic rectal cancer procedures increased from 0.60 per 100,000 population in 2003 to 2.24 per 100,000 population in 2008 (P < 0.01). Laparoscopic patients were similar to open with respect to age (66.5 ± 11.8 vs 66.2 ± 12.1 years; standardized difference 0.02), gender (63.2%vs 59.4%; standardized difference 0.08), Charlson Comorbidity Index score (standardized difference < 0.1) and socioeconomic status (standardized difference < 0.1). CONCLUSION: Laparoscopic rectal cancer surgery rates are increasing in Ontario. Ongoing research regarding the long-term safety and effectiveness of the laparoscopic approach for rectal cancer surgeries may lead to greater increases in its utilization.

Is Mini Beam Ready for Human Trials? Results of Randomized Study of Treating De-Novo Brain Tumors in Canines Using Linear Accelerator Generated Mini Beams.

The main challenge in treating malignant brain neoplasms lies in eradicating the tumor while minimizing treatment-related damage. Conventional radiation treatments are associated with considerable side effects. Synchrotron generated micro-beam radiation (SMBRT) has shown to preserve brain architecture while killing tumor cells, however physical characteristics and limited facility access restrict its use. We have created a new clinical device which produces mini beams on a linear accelerator, to provide a new type of treatment called mini-beam radiation therapy (MBRT). The objective of this study is to compare the treatment outcomes of linear accelerator based MBRT versus standard radiation treatment (SRT), to evaluate the tumor response and the treatment-related changes in the normal brain with respect to each treatment type. Pet dogs with de-novo brain tumors were accrued for treatment. Dogs were randomized between standard fractionated stereotactic (9 Gy in 3 fractions) radiation treatment vs. a single fraction of MBRT (26 Gy mean dose). Dogs were monitored after treatment for clinical assessment and imaging. When the dogs were euthanized, a veterinary pathologist assessed the radiation changes and tumor response. We accrued 16 dogs, 8 dogs in each treatment arm. In the MBRT arm, 71% dogs achieved complete pathological remission. The radiation-related changes were all confined to the target region. Structural damage was not observed in the beam path outside of the target region. In contrast, none of the dogs in control group achieved remission and the treatment related damage was more extensive. Therapeutic superiority was observed with MBRT, including both tumor control and the normal structural preservation. The MBRT findings are suggestive of an immune related mechanism which is absent in standard treatment. These findings together with the widespread availability of clinical linear accelerators make MBRT a promising research topic to explore further treatment and clinical trial opportunities.

Adjuvant oncolytic virotherapy for personalized anti-cancer vaccination.

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.

Computer-aided classification of colorectal polyps based on vascular patterns: a pilot study.

BACKGROUND AND STUDY AIMS: Recent studies have shown that narrow-band imaging (NBI) is a powerful diagnostic tool for differentiating between neoplastic and nonneoplastic colorectal polyps. The aim of the present study was to develop and evaluate a computer-based method for automated classification of colorectal polyps on the basis of vascularization features. PATIENTS AND METHODS: In a prospective pilot study with 128 patients who were undergoing zoom NBI colonoscopy, 209 detected polyps were visualized and subsequently removed for histological analysis. The proposed computer-based method consists of image preprocessing, vessel segmentation, feature extraction, and classification. The results of the automated classification were compared to those of human observers blinded to the histological gold standard. RESULTS: Consensus decision between the human observers resulted in a sensitivity of 93.8 % and a specificity of 85.7 %. A "safe" decision, i. e., classifying polyps as neoplastic in cases when there was interobserver discrepancy, yielded a sensitivity of 96.9 % and a specificity of 71.4 %. The overall correct classification rates were 91.9 % for the consensus decision and 90.9 % for the safe decision. With ideal settings the computer-based approach achieved a sensitivity of approximately 90 % and a specificity of approximately 70 %, while the overall correct classification rate was 85.3 %. The computer-based classification showed a specificity of 61.2 % when a sensitivity of 93.8 % was selected, and a 53.1 % specificity with a sensitivity of 96.9 %. CONCLUSIONS: Automated classification of colonic polyps on the basis of NBI vascularization features is feasible, but classification by observers is still superior. Further research is needed to clarify whether the performance of the automated classification system can be improved.

Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a clinical practice guideline.

Objective: The purpose of the present review was to provide evidence-based guidance about the provision of cytoreductive surgery (crs) with hyperthermic intraperitoneal chemotherapy (hipec) in the treatment of peritoneal cancers. Methods: The guideline was developed by the Program in Evidence-Based Care together with the Surgical Oncology Program at Ontario Health (Cancer Care Ontario) through a systematic review of relevant literature, patient- and caregiver-specific consultation, and internal and external reviews. Results: Recommendation 1a: For patients with newly diagnosed stage iii primary epithelial ovarian or fallopian tube carcinoma, or primary peritoneal carcinoma, hipec should be considered for those with at least stable disease after neoadjuvant chemotherapy at the time that interval crs (if complete) or optimal cytoreduction is achieved. Recommendation 1b: There is insufficient evidence to recommend the addition of hipec when primary crs is performed for patients with newly diagnosed advanced primary epithelial ovarian or fallopian tube carcinoma, or primary peritoneal carcinoma, outside of a clinical trial. Recommendation 2: There is insufficient evidence to recommend hipec with crs in patients with recurrent ovarian cancer outside the context of a clinical trial. Recommendation 3: There is insufficient evidence to recommend hipec with crs in patients with peritoneal colorectal carcinomatosis outside the context of a clinical trial. Recommendation 4: There is insufficient evidence to recommend hipec with crs for the prevention of peritoneal carcinomatosis in colorectal cancer outside the context of a clinical trial; however, hipec using oxaliplatin is not recommended. Recommendation 5: There is insufficient evidence to recommend hipec with crs for the treatment of gastric peritoneal carcinomatosis outside the context of a clinical trial. Recommendation 6: There is insufficient evidence to recommend hipec with crs for the prevention of gastric peritoneal carcinomatosis outside the context of a clinical trial. Recommendation 7: There is insufficient evidence to recommend hipec with crs as a standard of care in patients with malignant peritoneal mesothelioma; however, patients should be referred to hipec specialty centres for assessment for treatment as part of an ongoing research protocol. Recommendation 8: There is insufficient evidence to recommend hipec with crs as a standard of care in patients with disseminated mucinous neoplasm in the appendix; however, patients should be referred to hipec specialty centres for assessment for treatment as part of an ongoing research protocol.

Sedative and cardiopulmonary effects of acepromazine, midazolam, butorphanol, acepromazine-butorphanol and midazolam-butorphanol on propofol anaesthesia in goats.

UNLABELLED: The sedative, propofol-sparing and cardiopulmonary effects of acepromazine, midazolam, butorphanol and combinations of butorphanol with acepromazine or midazolam in goats were evaluated. Six healthy Boer - Indigenous African crossbreed goats were by randomised cross-over designated to 6 groups: Group SAL that received saline, Group ACE that received acepromazine, Group MID that received midazolam, Group BUT that received butorphanol, Group ACEBUT that received acepromazine and butorphanol and Group MIDBUT that received midazolam and butorphanol as premedication agents intramuscularly on different occasions at least 3 weeks apart. The degree of sedation was assessed 20 minutes after administration of the premedication agents. Thirty minutes after premedication, the dose of propofol required for induction of anaesthesia adequate to allow placement of an endotracheal tube was determined. Cardiovascular, respiratory and arterial blood-gas parameters were assessed up to 30 minutes after induction of general anaesthesia. Acepromazine and midazolam produced significant sedation when administered alone, but premedication regimens incorporating butorphanol produced inconsistent results. The dose of propofol required for induction of anaesthesia was significantly reduced in goats that received midazolam alone, or midazolam combined with either acepromazine or butorphanol. The quality of induction of anaesthesia was good in all groups, including the control group. Cardiovascular, respiratory and blood-gas parameters were within normal limits in all groups and not significantly different between or within all groups. IN CONCLUSION: sedation with midazolam alone, or midazolam combined with either acepromazine or butorphanol significantly reduces the induction dose of propofol with minimal cardiopulmonary effects in goats.

Genetic alteration associated with chronic lymphocytic leukemia.

The genetics of B-cell chronic lymphocytic leukemia (B-CLL) differ considerably from most other forms of hematologic malignancy which are usually characterized by chromosome translocations. B-CLL typically contains chromosomal deletions and chromosomes 13q14 and 11q22-->q23 are the most common. These two regions appear to share a common ancestral origin (Auer et al., 2007b). Overall, chromosomal abnormalities can be found in the majority of patients with B-CLL when using sensitive techniques (Dohneret al., 2000) and possibly reflects an underlying predisposition, with a small but significant number of familial cases. Although single and consistent abnormalities are most common, multiple rearrangements can occur, often with disease progression (Feganetal., 1995; Dohner et al., 2000). Regions of recurrent deletion suggest the presence of tumor suppressor genes if following Knudson's theoretical 2-hit model. However, despite extensive sequencing analysis over the last decade and lack of pathogenic mutations identified, there has been a move away from this suggested hypothesis and alternative mechanisms of gene inactivation involving epigenetic silencing or haploinsufficiency may be considered as more likely in this disease. This review focuses on the common genetic abnormalities in B-CLL and relates them to some of the more recent hypotheses on inactivation of genes within these regions of deletion.

Subcortical middle cerebral artery ischemia abolishes the digit flexion and closing used for grasping in rat skilled reaching.

That rats reach for and grasp a food item using a single paw has prompted their use in neurobiological studies of skilled movements and modeling neural injury including middle cerebral artery stroke. Although motor system lesions have been shown to disrupt various qualitative aspects of the transport of a limb to a food target and withdrawal of the limb with the food, no lesion has been found to abolish digit flexion for grasping. Here, rats received unilateral transient middle cerebral artery ischemia that was restricted mainly to subcortical tissue of the forebrain (caudate-putamen, globus pallidus, and associated fibers) or a sham operation. Both paws were later trained and evaluated on skilled reaching using a rating scale for digit use. Middle cerebral artery rats did not flex and close their digits to grasp food when using their contralateral-to-lesion limb. The grasp impairment was not due to a failure to learn the task as middle cerebral artery rats used the ipsilateral limb as successfully as control rats and they were reinforced for reaching by raking food into the reaching box using an open paw. The impairment was also not due to an inability to move the digits, as they were flexed and closed in other phases of the reach. The paradigm should prove useful for further studies of rehabilitation in relation to the idea that digit closure may be controlled by the joint action of a number of neural systems that converge in the basal ganglia.

Telemedicine in veterinary practice.

Veterinary surgeons have a long tradition of consulting one another about problem cases and many have unwittingly practised telemedicine when discussing cases by telephone or by sending laboratory reports by telefax. Specific veterinary telemedicine applications have been in use since the early 1980s, but little research has been undertaken in this field. The Pubmed and CAB International databases were searched for the following Boolean logic-linked keywords; veterinary and telemedicine, veterinary and telecare, animal and telemedicine, animal and telecare and veterinary and e-mail and an additional search was made of the worldwide web, using Google Scholar. This returned 25 papers which were reviewed. Of these only 2 report research. Sixteen papers had no references and 1 author was associated with 13 papers. Several themes emerge in the papers reviewed. These include remarks about the use of telemedicine, the benefits that can and are derived from the use of telemedicine, areas of practice in which telemedicine is being used, ethical and legal issues around the practice of telemedicine, image standards required for telemedicine, the equipment that is required for the practice of telemedicine, advice on ways in which digital images can be obtained and educational aspects of telemedicine. These are discussed. Veterinary practice has lagged behind its human counterpart in producing research on the validity and efficacy of telemedicine. This is an important field which requires further research.

Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia.

It has been repeatedly claimed that neuronal death in the hippocampal CA1 sector after untreated global ischemia occurs via apoptosis. This is based largely on DNA laddering, nick end labeling, and light microscopy. Delineation of apoptosis requires fine structural examination to detect morphological events of cell death. We studied the light and ultrastructural characteristics of CA1 injury after 5 min of untreated global ischemia in gerbils. To increase the likelihood of apoptosis, some ischemic gerbils were subjected to delayed postischemic hypothermia, a treatment that mitigates injury and delays the death of some neurons. In these gerbils, 2 d of mild hypothermia was initiated 1, 6, or 12 hr after ischemia, and gerbils were killed 4, 14, or 60 d later. Ischemia without subsequent cooling killed 96% of CA1 neurons by day 4, whereas all hypothermia-treated groups had significantly reduced injury at all survival times (2-67% loss). Electron microscopy of ischemic neurons with or without postischemic hypothermia revealed features of necrotic, not apoptotic, neuronal death even in cells that died 2 months after ischemia. Dilated organelles and intranuclear vacuoles preceded necrosis. Unique to the hypothermia-treated ischemic groups, some salvaged neurons were persistently abnormal and showed accumulation of unusual, morphologically complex secondary lysosomes. These indicate selective mitochondrial injury, because they were closely associated with normal and degenerate mitochondria, and transitional forms between mitochondria and lysosomes occurred. The results show that untreated global ischemic injury has necrotic, not apoptotic, morphology but do not rule out programmed biochemical events of the apoptotic pathway occurring before neuronal necrosis.