A practical and ethical toolkit for last-minute refusal of anesthetic in children.

Children's fear of a procedure, including the anesthetic, is a common issue that operating theatre staff face. This fear is generally mitigated by preesthetic preparation and information sharing. Last-minute refusal of a procedure creates unique difficulties for the anesthetist and proceduralist. Refusal for a procedure raises issues of whether the dissent is binding, and if not, how best to get the child to theatre without creating moral injury. In this case review of a young adolescent who refuses to go to the operating theatre, we explore practical and ethical options to resolve the situation. We discuss respect for persons (including assent and consent), best interests, truth-telling, harm minimization, and restraint. The importance of a postevent debrief is discussed. We also assess the value of a clinical ethics service with team members embedded in clinical teams.

Experiences of Pain in Hospitalized Children During Hematopoietic Stem Cell Transplantation Therapy.

Children undergoing hematopoietic stem cell transplantation (HSCT) are vulnerable to pain due to the intensity and toxicity of this treatment. An instrumental case study design of two qualitative phases was conducted to examine the pain experiences of hospitalized children during HSCT therapy and how contextual factors related to the pediatric HSCT environment influenced their experience of pain. The Social Communication Model of Pain provided the conceptual framework for the study. In Phase 1, semi-structured interviews were conducted with parents of a child undergoing HSCT therapy at two time points. Phase 2 was conducted as a naturalistic observational study of the clinical care provided to children and semi-structured interviews with health-care providers. Children experienced complex and multifaceted pain with physical, psychological, and contextual contributors. Understanding the many factors contributing to the child's pain experience can inform strategies to improve the management of pain during HSCT therapy.

Cellular Mucins: Targets for Immunotherapy.

Mucins are attracting great interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucinl (MUC1) (e.g., breast, pancreas, ovary, and others) as there is (1) a 10-fold increase in the amount in adenocarcinomas; (2) an alteration in expression where they become ubiquitous, and (3) due to altered glycosylation, new epitopes appear on the cell surface that are absent in normal tissues. These new epitopes can be carbohydrate; others are peptide in nature. The cloning of the cDNAs from mucins, particularly MUC1, has led to rapid advances being made, and it is clear that a highly immunogenic peptide exists within the variable number of tandem repeats (VNTR) found in all mucins. This peptide is immunogenic in mice, giving rise to strong antibody production, and most monoclonal antibodies made to breast cancer, which react with the protein core, react with the peptide APDTR. It is now also clear that humans with breast cancer have, in their draining lymph nodes, precursors of cytotoxic T cells that can be stimulated in vitro to react against breast cancer and indeed against the APDTR or a closely related peptide - shown from antibody-blocking studies. These CTLs are unique in that they are non-MHC restricted. The identification of suitable targets, coupled with the known immunogenicity of both the peptide and neo-carbohydrate epitopes, has led to the development of several different programs to immunize humans against breast cancer using either synthetic carbohydrates or peptides conjugated with adjuvants, and clinical trials are now in progress to evaluate their immunogenicity and anti-cancer effects.

Pre-Existing Mature Oligodendrocytes Do Not Contribute to Remyelination following Toxin-Induced Spinal Cord Demyelination.

Remyelination is the regenerative response to demyelination. Although the oligodendrocyte progenitor is established as the major source of remyelinating cells, there is no conclusive evidence on whether mature, differentiated oligodendrocytes can also contribute to remyelination. Using two different inducible myelin-CreER mouse strains in which mature oligodendrocytes were prelabeled by the expression of membrane-bound Green fluorescent protein, we found that after focal spinal cord demyelination, the surrounding surviving labeled oligodendrocytes did not proliferate but remained at a consistent density. Furthermore, existing (prelabeled) oligodendrocytes showed no evidence of incorporation or migration into the lesioned area, or of process extension from the peripheral margins into the lesion. Thus, mature oligodendrocytes do not normally contribute to remyelination and are therefore not a promising target for regenerative therapy.

Pain assessment and management in paediatric oncology: a cross-sectional audit.

AIMS AND OBJECTIVES: To describe the pain assessment and management practices documented by health professionals within a tertiary-level Children's Cancer Centre and to evaluate how these practices were compared with international recommendations. BACKGROUND: Children with cancer are vulnerable to pain due to the intensity of antineoplastic therapy. Therefore, it is imperative to ensure that current pain management practices provided to paediatric oncology inpatients are of a high quality. DESIGN: A single-site cross-sectional audit. METHODS: A 24-hour period of documented pain-related care in randomly selected inpatients of an Australian tertiary-level Children's Cancer Centre was examined. The current pain management practices were audited over a two-month period resulting in 258 episodes of pain-related care being reviewed. RESULTS: Pain related to medical treatment for cancer was common (n = 146/258, 57%) and persistent. The presence of pain was not consistently recorded by health professionals (n = 75/146, 51%). Pain was mild (n = 26/75, 35%) and opioids were the mainstay of pain management interventions (n = 63/112, 56%). Adjuvants were an important component of pain management (n = 47/112, 42%), and nonpharmacological methods of managing pain were under-represented in this audit (n = 38/146, 26%). According to the Pain Management Index, pain was appropriately managed for the majority of children (n = 65/76, 87%). CONCLUSIONS: Pain management practices did not fully reflect the recommendations of contemporary paediatric pain management. Due to limitations in the documentation of children's pain, it was difficult to determine the effectiveness of pain management interventions. RELEVANCE TO CLINICAL PRACTICE: This study highlights the ongoing problem of pain for children receiving antineoplastic therapy. It is recommended that health professionals routinely screen for the presence of pain during hospitalisation and assess the efficacy of pain-related care.

Four-factor Prothrombin Complex Concentrate During Liver Transplantation: A Retrospective Cohort Study.

Background: Four-factor prothrombin complex concentrate (PCC) is a plasma product that contains factors II, VII, IX, X, protein C, and protein S. PCC can be used off-label to treat coagulopathy during orthotopic liver transplantation (OLT). However, its use comes with safety concerns regarding thrombosis. The purpose of our study is to determine the safety of PCC in OLT. Methods: We conducted a retrospective cohort study of patients who received 4-factor PCC during OLT at our institution from January 1, 2018, to May 1, 2022, with a 1:1 match of 83 patients who received PCC and 83 patients who did not. We evaluated 30-d mortality, 1-y mortality, prevalence of thrombotic complications (portal vein thrombosis, deep venous thrombosis, myocardial infarction, and pulmonary embolus), and postoperative intensive care (ICU) length of stay (LOS). Results: There was no significant difference in 30-d mortality (odds ratio [OR] 5; 95% confidence interval [CI], 0.58-42.8; P = 0.14), 1-y mortality (OR 3; 95% CI, 0.61-14.86; P = 0.18), or ICU LOS (OR -13.8; 95% CI, -39.2 to 11.6; P = 0.29). There was no increased incidence of thrombotic complications among patients receiving PCC 90 d after surgery, including portal vein thrombosis (OR 1.5; 95% CI, 0.42-5.32; P = 0.53), pulmonary embolus (OR 1; 95% CI, 0.14-7.1; P = 0.99), deep venous thrombosis (OR 0.67; 95% CI, 0.11-3.99; P = 0.66), and myocardial infarction (OR 1.67; 95% CI, 0.4-6.97; P = 0.48). Conclusions: Although there was a statistically insignificant increase in mortality after PCC administration during OLT, we did not see a significant increase in perioperative complications, including thrombotic events and increased ICU LOS.

Sensitivity of the Social Behavior Observer Checklist to Early Symptoms of Patients With Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes. METHODS: Asymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy. RESULTS: 1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p<0.001, -2.00, [-2.55, -1.45]) disease stages in behavioral variant frontotemporal dementia regardless of mutation status. Asymptomatic GRN pathogenic gene variant carriers showed more Reactive behaviors (preoccupation with time: p=0.001, 1.11, [1.06, 1.16]; self-consciousness: p=0.003, 1.77, [1.52, 2.01]) than asymptomatic non-carriers (1.01, [0.98, 1.03]; 1.31, [1.20, 1.41]). Insensitive score increased to a clinically abnormal level in advanced stages of behavioral variant frontotemporal dementia (p=0.003, -0.73, [-1.18, -0.29]). Higher scores on each subscale corresponded with higher caregiver burden (p<0.001). Greater change over time corresponded to greater fronto-subcortical atrophy in the semantic-appraisal and fronto-parietal intrinsically connected networks. DISCUSSION: The SBOCL is sensitive to early symptoms and reflects disease severity, with some evidence for progression across asymptomatic and symptomatic stages of FTLD syndromes; thus it may hold promise for early measurement and monitoring of behavioral symptoms in clinical practice and treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the Social Behavior Observer Checklist is sensitive to early behavioral changes in FTLD pathogenic variants and early symptomatic individuals in a highly educated patient cohort.

A dermal niche for multipotent adult skin-derived precursor cells.

A fundamental question in stem cell research is whether cultured multipotent adult stem cells represent endogenous multipotent precursor cells. Here we address this question, focusing on SKPs, a cultured adult stem cell from the dermis that generates both neural and mesodermal progeny. We show that SKPs derive from endogenous adult dermal precursors that exhibit properties similar to embryonic neural-crest stem cells. We demonstrate that these endogenous SKPs can first be isolated from skin during embryogenesis and that they persist into adulthood, with a niche in the papillae of hair and whisker follicles. Furthermore, lineage analysis indicates that both hair and whisker follicle dermal papillae contain neural-crest-derived cells, and that SKPs from the whisker pad are of neural-crest origin. We propose that SKPs represent an endogenous embryonic precursor cell that arises in peripheral tissues such as skin during development and maintains multipotency into adulthood.

Postoperative mortality in children after 101,885 anesthetics at a tertiary pediatric hospital.

BACKGROUND: Mortality is a basic measure for quality and safety in anesthesia. There are few anesthesia-related mortality data available for pediatric practice. Our objective for this study was to determine the incidence of 24-hour and 30-day mortality after anesthesia and to determine the incidence and nature of anesthesia-related mortality in pediatric practice at a large tertiary institution. METHODS: Children ≤ 18 years old who had an anesthetic between January 1, 2003, and August 30, 2008, at the Royal Children's Hospital, Melbourne, Australia, were included for this study. Data were analyzed by merging a database for every anesthetic performed with an accurate electronic record of mortality of children who had ever been a Royal Children's Hospital patient. Cases of children dying within 30 days and 24 hours of an anesthetic were identified and the patient history and anesthetic record examined. Anesthesia-related death was defined as those cases whereby a panel of 3 senior anesthesiologists all agreed that anesthesia or factors under the control of the anesthesiologist more likely than not influenced the timing of death. RESULTS: During this 68-month period, 101,885 anesthetics were administered to 56,263 children. The overall 24-hour mortality from any cause after anesthesia was 13.4 per 10,000 anesthetics delivered and 30-day mortality was 34.5 per 10,000 anesthetics delivered. The incidence of death was highest in children ≤ 30 days old. Patients undergoing cardiac surgery had a higher incidence of 24-hour and 30-day mortality than did those undergoing noncardiac surgery. From 101,885 anesthetics there were 10 anesthesia-related deaths. The incidence of anesthesia-related death was 1 in 10,188 or 0.98 cases per 10,000 anesthetics performed (95%confidence interval, 0.5 to 1.8). In all 10 cases, preexisting medical conditions were identified as being a significant factor in the patient's death. Five of these cases (50%) involved children with pulmonary hypertension. CONCLUSIONS: Anesthesia-related mortality is higher in children with heart disease and in particular those with pulmonary hypertension. The lack of anesthetic-related deaths in children who did not have major comorbidities reinforces the safety of pediatric anesthesia in healthy children.

Distress at induction: prevention and consequences.

PURPOSE OF REVIEW: Distress in children during hospitalization is increasingly seen as unacceptable and preventable. Surgery and anaesthesia are distressing events for children with maximum stress at induction of anaesthesia. This review aims to report the recent research relevant to reducing this distress in children with a focus on the preoperative period and the impact of this on behaviour at induction and long-term postoperatively. RECENT FINDINGS: The development of new measures of anxiety in children, which are specifically designed to measure anxiety in the perioperative period has allowed better assessment of the efficacy of interventions. Studies continue to demonstrate that a variety of nonpharmacological interventions have a modest effect in reducing anxiety and that sedative premedication is more effective. Clinical indications for preoperative sedative/anxiolytic medication across institutions are very variable. Clonidine and dexmedetomidine (α2-adrenergic agonists) produce satisfactory sedation in children but have long onset times. Recent focus on the importance of minimizing children's distress in clinical areas outside the operating suite is creating pressure on anaesthetists to reassess what is considered 'acceptable' in relation to distress at induction of anaesthesia. The ChildKind Initiative summarizes pain minimization strategies, which should be applied to children. It is logical to extend this concept to minimization of distress unrelated to pain. SUMMARY: New measures of anxiety will facilitate better evaluation of children clinically and better future research. The role of α2-adrenergic agonists in premedication remains unclear. There is still little research, which examines outcomes for techniques for minimizing distress, which are based on specific assessment of the child and family.

Study to assess the laryngeal and pharyngeal spread of topical local anesthetic administered orally during general anesthesia in children.

BACKGROUND: Topical local anesthesia of the airway of anaesthetized children has many potential benefits. In our institution, lignocaine is topically instilled blindly into the back of the mouth with the expectation that it will come into contact with the larynx. The volume and method of application varies between clinicians. There is no published evidence to support the plausibility of this technique. AIM: To determine whether this technique of instillation results in the local anesthetic coming into contact with key laryngeal structures and whether this is influenced by volume or additional physical maneuvers. METHODS/MATERIALS: Sixty-three healthy anaesthetized children between 6 months and 16 years old had lignocaine stained with methylene blue poured into the back of their mouths. The volume and subsequent physical maneuver were determined by randomization. A blinded observer assessed staining of the vocal cords, epiglottis, vallecula and piriform fossae by direct laryngoscopy. Airway complications were recorded. RESULTS: Fifty-three of the 63 children had complete staining of all four areas. Four children had one area unstained, and all others had at least partial staining of all four structures. Nine children coughed following induction of anesthesia. Coughing was more likely in children with incomplete staining (P = 0.03), low volume lignocaine (P = 0.003) and following a head lift (P = 0.02). CONCLUSION: Oral administration of lignocaine without use of a laryngoscope frequently results in widespread coverage of key laryngeal structures and may reduce the risk of coughing.

A custom, functional and lifelike passive prosthetic hand for infants and small toddlers: Clinical note.

BACKGROUND AND AIM: For infants and small toddlers with congenital upper limb deficiencies, terminal devices mainly provide either cosmesis or functionality. We report a clinical note about fitting a child with a low-cost passive hand targeting both functionality and cosmesis. TECHNIQUE: An elastomeric, alloy-wire-reinforced hand was fabricated using additive manufacturing to allow independent positioning of the digits. A clinical pilot in-home evaluation was conducted on a child with upper limb loss. DISCUSSION: The fabricated hand met the functional requirements but required a cover for cosmesis due to a poor surface finish associated with the fabrication technique. The participant child was comfortable using the prosthesis for various tasks. The parents were satisfied with the hand's function and cosmesis when covered with a cosmetic glove. This work demonstrated a new design and process that may in the future improve the utilization of prosthetic hands to promote early prosthesis use and a child's development. CLINICAL RELEVANCE: Early prosthesis use is important for infants and toddlers. Additive manufacturing may enable the fabrication of custom passive prosthetic hands that provide both cosmesis and functionality.

Identification of barriers and enablers to rapid diagnosis along the paediatric stroke chain of recovery using Value-Focused Process Engineering.

Coordinated systems of care are required to improve access to reperfusion therapies in paediatric stroke. A conceptual model was developed to map the process-of-care from symptom onset to confirmation of diagnosis. Value-Focused Process Engineering with event-driven process modelling was used to identify barriers and enablers to timely and accurate paediatric stroke diagnosis. Stakeholder interviews were conducted to inform model design, development, demonstration and validation. Barriers included: (i) ambulance dispatcher failure to allocate high-priority response, (ii) childrens' exclusion from paramedic clinical practice guidelines, (ii) non-allocation of high triage category on hospital arrival, (iii) absence of emergency department guidelines for focal neurological deficits, and (iv) computed tomography as the first imaging investigation. Enablers included: (i) public awareness programs, (ii) childrens' inclusion in prehospital emergency stroke algorithms, (iii) re-organisation of health services, with primary paediatric stroke centres, (iv) implementation of triage and neuroimaging decision support tools, and (iv) rapid stroke MRI imaging protocols.

Skin-derived precursors generate myelinating Schwann cells for the injured and dysmyelinated nervous system.

Although neural stem cells hold considerable promise for treatment of the injured or degenerating nervous system, their current human sources are embryonic stem cells and fetally derived neural tissue. Here, we asked whether rodent and human skin-derived precursors (SKPs), neural crest-related precursors found in neonatal dermis, represent a source of functional, myelinating Schwann cells. Specifically, cultured SKPs responded to neural crest cues such as neuregulins to generate Schwann cells, and these Schwann cells proliferated and induced myelin proteins when in contact with sensory neuron axons in culture. Similar results were obtained in vivo; 6 weeks after transplantation of naive SKPs or SKP-derived Schwann cells into the injured peripheral nerve of wild-type or shiverer mutant mice (which are genetically deficient in myelin basic protein), the majority of SKP-derived cells had associated with and myelinated axons. Naive rodent or human SKPs also generated Schwann cells that myelinated CNS axons when transplanted into the dysmyelinated brain of neonatal shiverer mice. Thus, neonatal SKPs generate functional neural progeny in response to appropriate neural crest cues and, in so doing, provide a highly accessible source of myelinating cells for treatment of nervous system injury, congenital leukodystrophies, and dysmyelinating disorders.

Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma.

PURPOSE: Tumor antigen-loaded dendritic cells show promise for cancer immunotherapy. This phase I study evaluated immunization with autologous dendritic cells pulsed with mannan-MUC1 fusion protein (MFP) to treat patients with advanced malignancy. EXPERIMENTAL DESIGN: Eligible patients had adenocarcinoma expressing MUC1, were of performance status 0 to 1, with no autoimmune disease. Patients underwent leukapheresis to generate dendritic cells by culture ex vivo with granulocyte macrophage colony-stimulating factor and interleukin 4 for 5 days. Dendritic cells were then pulsed overnight with MFP and harvested for reinjection. Patients underwent three cycles of leukapheresis and reinjection at monthly intervals. Patients with clinical benefit were able to continue with dendritic cell-MFP immunotherapy. RESULTS: Ten patients with a range of tumor types were enrolled, with median age of 60 years (range, 33-70 years); eight patients were of performance status 0 and two of performance status 1. Dendritic cell-MFP therapy led to strong T-cell IFNgamma Elispot responses to the vaccine and delayed-type hypersensitivity responses at injection sites in nine patients who completed treatments. Immune responses were sustained at 1 year in monitored patients. Antibody responses were seen in three patients only and were of low titer. Side effects were grade 1 only. Two patients with clearly progressive disease (ovarian and renal carcinoma) at entry were stable after initial therapy and went on to further leukapheresis and dendritic cell-MFP immunotherapy. These two patients have now each completed over 3 years of treatment. CONCLUSIONS: Immunization produced T-cell responses in all patients with evidence of tumor stabilization in 2 of the 10 advanced cancer patients treated. These data support further clinical evaluation of this dendritic cell-MFP immunotherapy.

Remarkable Stability of Myelinating Oligodendrocytes in Mice.

New myelin-forming oligodendrocytes (OLs) are generated in the mouse central nervous system during adulthood. These adult-born OLs might augment the existing population, contributing to neural plasticity, or else replace OLs that die in use (turnover). To distinguish between these alternatives, we induced genetic labeling of mature myelinating OLs in young adult mice and tracked their subsequent survival. OL survival rates were region dependent, being higher in corpus callosum (∼90% survival over 20 months) and motor cortex (∼70% survival) than in corticospinal tract or optic nerve (50%-60% survival). Survival rates over the first 8 months were 90%-100% in all regions except the optic nerve. In the corpus callosum, new OLs accumulate during young adulthood and are therefore likely to participate in adaptive myelination. We also found that the number of myelin internodes maintained by individual cortical OLs is stable for at least 8 months but declines ∼12% in the following year.

Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835].

INTRODUCTION: Mucin 1 (MUC1) is a high molecular weight glycoprotein overexpressed on adenocarcinoma cells and is a target for immunotherapy protocols. To date, clinical trials against MUC1 have included advanced cancer patients. Herein, we report a trial using early stage breast cancer patients and injection of oxidized mannan-MUC1. METHOD: In a randomized, double-blind study, 31 patients with stage II breast cancer and with no evidence of disease received subcutaneous injections of either placebo or oxidized mannan-MUC1, to immunize against MUC1 and prevent cancer reoccurrence/metastases. Twenty-eight patients received the full course of injections of either oxidized mannan-MUC1 or placebo. Survival and immunological assays were assessed. RESULTS: After more than 5.5 years had elapsed since the last patient began treatment (8.5 years from the start of treatment of the first patient), the recurrence rate in patients receiving the placebo was 27% (4/15; the expected rate of recurrence in stage II breast cancer); those receiving immunotherapy had no recurrences (0/16), and this finding was statistically significant (P = 0.0292). Of the patients receiving oxidized mannan-MUC1, nine out of 13 had measurable antibodies to MUC1 and four out of 10 had MUC1-specific T cell responses; none of the placebo-treated patients exhibited an immune response to MUC1. CONCLUSION: The results suggest that, in early breast cancer, MUC1 immunotherapy is beneficial, and that a larger phase III study should be undertaken.

Pim-1 kinase stability is regulated by heat shock proteins and the ubiquitin-proteasome pathway.

Elevated expression of the serine/threonine kinase Pim-1 increases the incidence of lymphomas in Pim-1 transgenic mice and has also been found to occur in some human cancers. Pim-1 acts as a cell survival factor and may prevent apoptosis in malignant cells. It was therefore of interest to understand to what extent maintenance and degradation of Pim-1 protein is affected by heat shock proteins (Hsp) and the ubiquitin-proteasome pathway in K562 and BV173 human leukemic cells. The half-life of Pim-1 protein in these cells was found to increase from 1.7 to 3.1 hours when induced by heat shock or by treating the cells with the proteasome inhibitor PS-341 (bortezomib). The Hsp90 inhibitor geldanamycin prevented the stabilization of Pim-1 by heat shock. Using immunoprecipitation, it was determined that Pim-1 is targeted for degradation by ubiquitin and that Hsp70 is associated with Pim-1 under these circumstances. Conversely, Hsp90 was found to protect Pim-1 from proteasomal degradation. A luminescence-based kinase assay showed that Pim-1 kinase bound to Hsp70 or Hsp90 remains active, emphasizing the importance of its overall cellular levels. This study shows how Pim-1 levels can be modulated in cells through degradation and stabilization.

Cripto: a novel target for antibody-based cancer immunotherapy.

Cripto, a member of the epidermal growth factor-Cripto-FRL-Criptic (EGF-CFC) family, has been described recently as a potential target for immunotherapy (Adkins et al., J Clin Invest 2003;112:575-87). We have produced rat monoclonal antibodies (mAbs) to a Cripto 17-mer peptide, corresponding to the "EGF-like" motif of Cripto. The mAbs react with most cancers of the breast, colon, lung, stomach, and pancreas but do not react or react weakly with normal tissues. The mAbs inhibit cancer cell growth in vitro, and this effect was greater with cytotoxic drugs such as 5-fluorouracil, epirubicin, and cisplatin. The anti-Cripto mAbs prevent tumor development in vivo and inhibit the growth of established tumors of LS174T colon xenografts in Scid mice. The growth inhibitory effects with these mAbs may be greater than those described elsewhere, possibly because of IgM giving more effective cross-linking or binding to a different epitope (EGF-like region versus CFC region). The mechanism of inhibitory effects of the Cripto mAbs includes both cancer cell apoptosis, activation of c-Jun-NH(2)-terminal kinase and p38 kinase signaling pathways and blocking of Akt phosphorylation. Thus, Cripto is a unique target, and mAbs to Cripto could be of therapeutic value for human cancers.