Increased Y Chromosome Microdeletions in Cord Blood of Male Newborns From Assisted Reproductive Technology Compared to Natural Conception.

OBJECTIVES: To investigate the incidence of Y chromosome microdeletions in male newborns conceived by intracytoplasmic sperm injection (ICSI), in vitro fertilization (IVF), and natural conception (NC). METHODS: A total of 186 male newborns were recruited, including 35 conceived by ICSI, 37 conceived by IVF, and 114 conceived naturally. DNA was extracted from umbilical cord blood after birth. The Yq genetic status of the newborns was determined according to 18 Y-specific sequence tagging sites (STS) markers covering 3 azoospermia factor (AZF) sub-regions and internal control sequences. RESULTS: Partial AZF microdeletions were identified in 8 of 35 (22.9%) ICSI newborns, 4 of 37 (10.8%) IVF newborns, and 1 of 114 (0.9%) NC newborns. There was a statistically significant difference in the proportion of newborns with partial Y chromosome microdeletions between the ICSI, IVF, and NC groups. When analyzed individually, only the SY114 and SY152 STS markers showed a statistically significant difference in incidence between the 3 cohorts. CONCLUSIONS: Our study indicates that the population of male children conceived through assisted reproductive technologies (ART), particularly ICSI, is at an increased risk of genetic defect in the form of partial Y chromosome microdeletions. The growing population of ART-conceived children emphasizes the importance of studying the genetic repercussions of these procedures regarding the future fertility of males conceived in vitro.

Usability assessment of an open-source simulated electronic medical record in pharmacy education.

BACKGROUND AND PURPOSE: The growth of electronic medical records (EMRs) has been a critical component of evolving pharmacy practice, catalyzed by foundational initiatives such as the HITECH Act in 2009. The objective of this study was to evaluate the usability and student perceptions of a novel, open-source, educational EMR (EdEMR) for integration in the PharmD program at the University of British Columbia (UBC). EDUCATIONAL ACTIVITY AND SETTING: Participants were PharmD students at UBC and had to complete a series of survey questions and EdEMR tasks including a Systems Usability Scale (SUS) evaluation. Task completion time, mouse clicks, SUS score, and 5-point Likert scale rankings of student opinions on the use of the EdEMR were collected. FINDINGS: Seven students successfully completed the study. Participants self-ranked themselves as novice EMR users who used EMRs a few times a week. The mean time to complete the tasks was 6 min, 42 seconds and was approximately double that of benchmark times (mean benchmark = 2 min, 20 seconds). The EdEMR scored within the upper quartile of SUS scores (mean = 83), indicating good usability. Participants identified that the EMR would most optimally be used for distance learning and case-based learning. SUMMARY: The EdEMR showed good usability as demonstrated by the successfully completed tasks and SUS score. Participants were receptive to the EdEMR's application as an online learning tool and for case-based learning. The EdEMR is an enticing, open-source tool currently available to all pharmacy programs and could further support online and remote teaching.

Can Topical Vancomycin Prevent Periprosthetic Joint Infection in Hip and Knee Arthroplasty? A Systematic Review.

BACKGROUND: Periprosthetic joint infection (PJI) after hip and knee arthroplasty is a leading cause of revision surgery, inferior function, complications, and death. The administration of topical, intrawound vancomycin (vancomycin powder) has appeared promising in some studies, but others have found it ineffective in reducing infection risk; for that reason, a high-quality systematic review of the best-available evidence is needed. QUESTIONS/PURPOSES: In this systematic review, we asked: (1) Does topical vancomycin (vancomycin powder) reduce PJI risk in hip and knee arthroplasty? (2) Does topical vancomycin lead to an increased risk of complications after hip and knee arthroplasty? METHODS: A search of Embase, MEDLINE, and PubMed databases as of June 2020 was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies comparing topical vancomycin in addition to standard infection prevention regimens (such as routine perioperative intravenous antibiotics) with standard regimens only in primary hip and knee arthroplasty were identified. Patients 18 years or older with a minimum follow-up of 3 months were included. No restrictions on maximal loss to follow-up or PJI definition were imposed. Studies were excluded if they included patients with a history of septic arthritis, used an antibiotic other than vancomycin or a different route of administration for the intervention, performed additional interventions that differed between groups, or omitted a control group. A total of 2408 studies were screened, resulting in nine eligible studies reviewing 3371 patients who received topical vancomycin (vancomycin powder) during a primary THA or TKA and 2884 patients who did not receive it. Groups were comparable with respect to duration of follow-up and loss to follow-up when reported. Study quality was assessed using the Newcastle-Ottawa scale, showing moderate-to-high quality for the included studies. The risks of PJI and overall complications in the topical vancomycin group were compared with those in the control group. RESULTS: One of nine studies found a lower risk of PJI after primary THA or TKA, while eight did not, with odds ratios that broadly bracketed the line of no difference (range of odds ratios across the nine studies 0.09 to 1.97). In the six studies where overall complications could be compared between topical vancomycin and control groups in primary THA or TKA, there was no difference in overall complication risks with vancomycin (range of ORs across the six studies 0.48 to 0.94); however, we caution that these studies were underpowered to detect differences in the types of uncommon complications associated with vancomycin use (such as allergy, ototoxicity, and nephrotoxicity). CONCLUSION: In the absence of clear evidence of efficacy, and without a sufficiently large evidence base reporting on safety-related endpoints, topical vancomycin (vancomycin powder) should not be used in routine primary THA and TKA. Adequately powered, multicenter, prospective trials demonstrating clear reductions in infection risk and large registry-driven audits of safety-related endpoints are required before the widespread use of topical vancomycin can be recommended. LEVEL OF EVIDENCE: Level III, therapeutic study.

The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages.

Sterile tissue injury is thought to locally activate innate immune responses via damage-associated molecular patterns (DAMPs). Whether innate immune pathways are remotely activated remains relatively unexplored. Here, by analyzing ~145,000 single-cell transcriptomes at steady state and after myocardial infarction (MI) in mice and humans, we show that the type I interferon (IFN) response, characterized by expression of IFN-stimulated genes (ISGs), begins far from the site of injury, in neutrophil and monocyte progenitors within the bone marrow. In the peripheral blood of patients, we observed defined subsets of ISG-expressing neutrophils and monocytes. In the bone marrow and blood of mice, ISG expression was detected in neutrophils and monocytes and their progenitors, intensified with maturation at steady-state and after MI, and was controlled by Tet2 and Irf3 transcriptional regulators. Within the infarcted heart, ISG-expressing cells were negatively regulated by Nrf2 activation in Ccr2- steady-state cardiac macrophages. Our results show that IFN signaling begins in the bone marrow, implicate multiple transcriptional regulators (Tet2, Irf3, and Nrf2) in governing ISG expression, and provide a clinical biomarker (ISG score) for studying IFN signaling in patients.

Provision of Virtual Outpatient Care during the COVID-19 Pandemic and Beyond: Enabling Factors and Experiences from the UBC Pharmacists Clinic.

The COVID-19 pandemic has generated an unprecedented level of interest in, and uptake of, technology-enabled virtual health care delivery as clinicians seek ways to safely care for patients with physical distancing. This paper describes the UBC Pharmacists Clinic's technical systems and lessons learned using enabling technology and the provision of virtual patient care by pharmacists. Of 2036 scheduled appointments at the clinic in 2019, only 1.5% of initial appointments were conducted virtually which increased to 64% for follow-up appointments. Survey respondents (n = 18) indicated an overall high satisfaction with the format, quality of care delivery, ease of use and benefits to their overall health. Other reports indicate that the majority of patients would like the option to book appointments electronically, email their healthcare provider, and have telehealth visits, although a small minority (8%) have access to virtual modes of care. The Clinic team is bridging the technology gap to better align virtual service provision with patient preferences. Practical advice and information gained through experience are shared here. As the general population and health care providers become increasingly comfortable with video conferencing as a result of COVID-19, it is anticipated that requests for video appointments will increase, technological barriers will decrease and conditions will enable providers to increase their virtual care capabilities. Lessons learned at the Clinic have application to pharmacists in both out-patient and in-patient care settings.

Periprosthetic atypical femoral fractures exist and are associated with duration of bisphosphonate therapy.

AIMS: Currently, periprosthetic fractures are excluded from the American Society for Bone and Mineral Research (ASBMR) definition of atypical femoral fracture (AFFs). This study aims to report on a series of periprosthetic femoral fractures (PFFs) that otherwise meet the criteria for AFFs. Secondary aims were to identify predictors of periprosthetic atypical femoral fractures (PAFFs) and quantify the complications of treatment. PATIENTS AND METHODS: This was a retrospective case control study of consecutive patients with periprosthetic femoral fractures between 2007 and 2017. Two observers identified 16 PAFF cases (mean age 73.9 years (44 to 88), 14 female patients) and 17 typical periprosthetic fractures in patients on bisphosphonate therapy as controls (mean age 80.7 years (60 to 86, 13 female patients). Univariate and multivariate analysis was performed to identify predictors of PAFF. Management and complications were recorded. RESULTS: Interobserver agreement for the PAFF classification was excellent (kappa = 0.944; p < 0.001). On univariate analysis compared with controls, patients with PAFFs had higher mean body mass indices (28.6 kg/m2 (sd 8.9) vs 21.5 kg/m2 (sd 3.3); p = 0.009), longer durations of bisphosphonate therapy (median 5.5 years (IQR 3.2 to 10.6) vs 2.4 years (IQR 1.0 to 6.4); p = 0.04), and were less likely to be on alendronate (50% vs 94%; p = 0.02) with an indication of secondary osteoporosis (19% vs 0%; p = 0.049). Duration of bisphosphonate therapy was an independent predictor of PAFF on multivariate analysis (R2 = 0.733; p = 0.05). Following primary fracture management, complication rates were higher in PAFFs (9/16, 56%) than controls (5/17, 29%; p = 0.178) with a relative risk of any complication following PAFF of 1.71 (95% confidence interval (CI) 0.77 to 3.8) and of reoperation 2.56 (95% CI 1.3 to 5.2). CONCLUSION: AFFs do occur in association with prostheses. Longer duration of bisphosphonate therapy is an independent predictor of PAFF. Complication rates are higher following PAFFs compared with typical PFFs, particularly of reoperation and infection. Cite this article: Bone Joint J 2019;101-B:1285-1291.

Unpacking the Literature on Stress and Resiliency: A Narrative Review Focused on Learners in the Operating Room.

PURPOSE: The operating room is a high pressure environment for surgical trainees as they attempt to reach a high level of performance in the midst of a multitude of stressors. The purpose of this work was to examine the relationships between stress, coping, and psychological resilience and their effects on performance and learning in surgical training. METHODS: A narrative review was carried out of the existing literature on stress, coping, and resilience in surgeons and surgical trainees. Multiple fields of study were examined including medical education, surgery, surgical safety, anesthesia, workplace ergonomics, and psychology. RESULTS: Sources of intraoperative stress include fatigue, disruptions, interpersonal conflicts, time pressure, a complex case or high risk patient, surgical errors, and surgeon temperament. These stressors can negatively impact the performance of surgeons and trainees and may inhibit learning. How a learner responds to stress in the operating room is highly variable and influenced by the context of the stress, the coping mechanisms available, and individual psychological resilience. Stress management techniques, such as mental rehearsal, are beneficial for reducing stress. Resilience is protective against stress and burnout, and resilience training is useful for reducing stress and improving mental health in physicians and medical students. CONCLUSIONS: Surgical trainees experience significant stress in the operating room and their experience of stress is modulated by cognitive and behavioral factors. Further research is required on the development of effective interventions to help trainees manage intraoperative stress, with the potential to improve surgical performance, learning, and patient safety.

Excellent 10-year patient-reported outcomes and survival in a single-radius, cruciate-retaining total knee arthroplasty.

PURPOSE: Over 2 million Triathlon single-radius total knee arthroplasties (TKAs) have been implanted worldwide. This study reports the 10-year survival and patient-reported outcome of the Triathlon TKA in a single independent centre. METHODS: From 2006 to 2007, 462 consecutive cruciate-retaining Triathlon TKAs were implanted in 426 patients (median age 69 (21-89), 289 (62.5%) female). Patellae were not routinely resurfaced. Patient-reported outcome measures (SF-12, Oxford Knee Scores (OKS), satisfaction) were assessed preoperatively and at 1, 5 and 10 years when radiographs were reviewed. Forgotten Joint Scores (FJS) were collected at 10 years. Kaplan-Meier survival analysis was performed. RESULTS: At 10-11.6 years, 123 patients (128 TKAs) had died and 8 TKAs were lost to follow-up. There were four aseptic failures (two cases of tibial loosening, two cases of instability) and four septic failures requiring revision. Symptomatic aseptic radiographic loosening was present in three further cases at 11 years. Four (1%) patellae were secondarily resurfaced. OKS score improved by 17.7 ± 9.7 points at 1 year (p < 0.001), and was maintained at 34.7 ± 9.6 at 10 years with FJS 48.5 ± 31.4. Patient satisfaction was 88% at each timepoint. Ten-year survival was 97.9% (95% confidence interval 96.5-99.3) for revision for any reason, 98.9% (97.7-100) for mechanical failure, and 98.6% (97.4-99.8) for aseptic loosening (symptomatic radiographic or revised). CONCLUSION: The Triathlon TKA continues to show excellent longer-term results with high implant survivorship, low rates of aseptic failure, consistently maintained PROMs and excellent patient satisfaction rates of 88% at 10 years. LEVEL OF EVIDENCE: II, Prospective cohort study.

Results of Octaplex for reversal of warfarin anticoagulation in patients with hip fracture.

BACKGROUND: Patients with hip fracture who present anticoagulated with warfarin often require reversal of anticoagulation for safe hip fracture surgery. Vitamin K is typically administered for this, but requires 24-48 hours for maximal effect. These patients have an increased delay to surgery and increased mortality. Octaplex is a prothrombin complex concentrate (PCC) that reverses warfarin anticoagulation in less than an hour. This study assesses the effectiveness and safety of Octaplex for reversal of warfarin anticoagulation for hip fracture surgery. METHODS: We reviewed the medical records of all patients with hip fracture in Calgary who received Octaplex between 2009 and 2015. Timing of admission, Octaplex administration and hip fracture surgery were recorded. Mortality and cardiac, thrombotic and orthopedic complications were assessed. RESULTS: Median time from Octaplex administration to an international normalized ratio of 1.4 or lower was 1.1 hours. The median time from admission to surgery was 22 hours. Thirty-day mortality was 15.2%, with 4 cases of cardiac arrest and 1 respiratory arrest. Patients who received both Octaplex and fresh frozen plasma (FFP) had a lower rate of 30-day survival than those who received only Octaplex (95.7% v. 60.0%, p = 0.002). CONCLUSION: There were significant rates of cardiac events and 30-day mortality among patients who received Octaplex, but this is unsurprising in this population with multiple medical comorbidities. We caution against administrering both FFP and a PCC in patients for warfarin reversal. Octaplex is effective for rapidly reversing warfarin anticoagulation and reducing delays to hip fracture surgery. Further study comparing Octaplex to reversal using only vitamin K is required.

CONTEXTE: Les patients avec fracture de la hanche qui sont sous anticoagulothérapie par warfarine au moment de consulter ont souvent besoin qu'on inverse leur anticoagulation pour être opérés sans danger. La vitamine K est généralement administrée à cette fin, mais il lui faut de 24 à 48 heures pour exercer son plein effet. Chez ces patients, le délai est plus long avant la chirurgie et la mortalité est plus élevée. Octaplex est un concentré de complexe prothrombique (CCP) qui inverse l'anticoagulation due à la warfarine en moins d'une heure. Cette étude évalue l'efficacité et l'innocuité d'Octaplex pour l'inversion de l'anticoagulation due à la warfarine lors d'une chirurgie pour fracture de la hanche. MÉTHODES: Nous avons passé en revue les dossiers médicaux de tous les patients avec fracture de la hanche à Calgary qui ont reçu Octaplex entre 2009 et 2015. Nous avons enregistré le moment de l'admission, de l'administration d'Octaplex et de la chirurgie pour fracture de la hanche. Nous avons évalué la mortalité et les complications cardiaques, thrombotiques et orthopédiques. RÉSULTATS: L'intervalle médian entre l'administration d'Octaplex et l'obtention d'un ratio international normalisé de 1,4 ou moins a été de 1,1 heure. L'intervalle médian entre l'admission et la chirurgie a été de 22 heures. La mortalité à 30 jours a été de 15,2 %, incluant 4 arrêts cardiaques et 1 arrêt respiratoire. Les patients qui ont reçu Octaplex et du plasma frais congelé (PFC) ont eu un taux de survie à 30 jours moins élevé que ceux qui ont reçu Octaplex seulement (95,7 % c. 60,0 %, p = 0,002). CONCLUSION: On a observé des taux significatifs d'événements cardiaques et de mortalité à 30 jours chez les patients traités par Octaplex, mais cela est peu surprenant dans cette population présentant plusieurs comorbidités médicales. Nous formulons une mise en garde contre l'utilisation de PFC et d'un CCP chez les patients soumis à une inversion de l'effet de la warfarine. Octaplex est efficace pour inverser rapidement l'anticoagulation due à la warfarine et accélérer l'accès à la chirurgie pour fracture de la hanche. Il faudra approfondir la recherche et comparer l'inversion par Octaplex plutôt que par la vitamine K seulement.

IRF3 and type I interferons fuel a fatal response to myocardial infarction.

Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.

The predictive value of early molecular response in chronic myeloid leukaemia patients treated with imatinib in a single real-world medical centre in a developing country.

INTRODUCTION: The prognosis of patients with chronic myeloid leukaemia (CML) has improved since the introduction of imatinib. However, patients who do not achieve complete cytogenetic response (CCyR) and major molecular response (MMR) have poorer prognosis. Recent clinical trials have demonstrated that early and deeper cytogenetic and molecular responses predict a better long-term outcome. This study aimed to analyse the relationship between early molecular response and clinical outcome in a real-life setting. METHODS: This retrospective study included all patients with CML, in chronic or accelerated phase, who were treated with imatinib at University of Malaya Medical Centre, Malaysia. RESULTS: A total of 70 patients were analysed. The median follow-up duration was 74 months, and the cumulative percentages of patients with CCyR and MMR were 80.0% and 65.7%, respectively. Overall survival (OS) and event-free survival (EFS) at ten years were 94.3% and 92.9%, respectively. Patients who achieved CCyR and MMR had significantly better OS and EFS than those who did not. At six months, patients who had a BCR-ABL level ≤ 10% had significantly better OS and EFS than those who had a BCR-ABL level > 10%. The target milestone of CCyR at 12 months and MMR at 18 months showed no survival advantage in our patients. CONCLUSION: Our data showed that imatinib is still useful as first-line therapy. However, vigilant monitoring of patients who have a BCR-ABL level > 10% at six months of treatment should be implemented so that prompt action can be taken to provide the best outcome for these patients.

Pilot Evaluation of the Informant AD8 as a Case-Finding Instrument for Cognitive Impairment in General Practitioner Clinics of Singapore: A Brief Report.

BACKGROUND: Case-finding services using a composite total risk score (TRS) and the informant AD8 have been previously recommended to detect cognitive impairment (CI) in government subsidized primary health care centers of Singapore (ie, polyclinics). OBJECTIVE: We compared the feasibility of implementing the services recommended for government-subsidized primary health care in private, primary health care service providers such as general practitioner (GP) clinics. METHOD: 123 patients ≥60 years of age were recruited from 2 GP clinics within Singapore. Trained research personnel administered the AD8 to informants. Patients of the present study were compared against a random sample of 123 patients selected from polyclinics. RESULTS: Significantly higher positive screening rates (AD8 ≥3) were found among patients in polyclinics than GP clinics (P < .001). Patients attending polyclinics reported more comorbid medical issues such as subjective cognitive complaint (P < .001) and heart disease (P < .001). The TRS of patients attending polyclinics was significantly higher than those attending GP clinics (P < .001), indicating a higher proportion of patients at risk of CI in polyclinics. Therefore, patients attending polyclinics were found to have higher AD8 scores compared with patients in GP clinics (P < .001). CONCLUSION: Compared with GP clinics, polyclinics may be more suited to provide case-finding services for the detection of CI in primary health care.

Components and developmental differences of executive functioning for school-aged children.

This study examined the developmental differences, components, and underlying factor structure of executive functioning (EF) in school-aged children by utilizing subtests from Test of Everyday Attention for Children and some additional EF tests. The developmental differences identified across age groups between 7 to 14 years for a sample of 185 children support a multistage interpretation of EF development. Structural equation modeling was used to test models with three first-order EF components which included shifting, working memory/updating, and inhibition. Results indicated that the first-order full, three-factor model was the best model among all the alternative first-order and second-order models.

The National Stem Cell Therapy Patient Registry of Malaysia--measuring clinical outcomes of stem cell therapy.

Very few registries worldwide focus on clinical outcomes of stem cell therapy (SCT) as the large number of applications and rapid development of the field complicates registry design considerably. The National Stem Cell Therapy Patient Registry of Malaysia aims to accommodate this by using a main protocol which covers the overall design and administration of the registry, and condition-specific sub-protocols which deal with outcome measures. The registry will start with a few sub-protocols covering existing modes of SCT in Malaysia, with new sub-protocols released periodically as the need arises.

A technique for controlled partial closure of a transjugular intrahepatic portosystemic shunt tract in a patient with hepatic encephalopathy.

A novel endovascular technique to reduce flow through a transjugular intrahepatic portosystemic shunt (TIPS) is described in a patient with severe hepatic encephalopathy. This technique allows controlled and potentially adjustable partial closure of the TIPS without thromboembolic risk. The patient experienced a dramatic clinical improvement after the procedure.

Methodologies for interventional myopia studies.

Myopia studies are notoriously difficult to carry out. Past studies on intervention in myopia progression have given conflicting results. Beside inaccurate and inadequate measurements, the most important cause for this is the very variable nature of myopia, which makes it difficult to achieve baseline comparability between the control and the study group. Although there were inclusion criteria in these studies, for age, sex, race, degree of myopia and stigmatism, the most important variate-- the rate of myopia progression-- was not included. Randomisation can achieve baseline comparability of the myopia progression rate, provided the sample sizes are large enough. Unfortunately, past studies have been limited to 100 to 200 children only. Studies on twins are more reliable than random groups because myopia progression rates are more likely to be the same in a pair of twins. Studies on the same subject, comparing the right eye and the left eye would be even better, but this method is practicable for some studies only (e.g., we cannot have a spectacle lens for one eye and a contact lens on the fellow eye). There is another method of doing an interventional study on myopia. Because myopia progression is linear in its early stage until the early teenage years, it is possible to observe what happens to the linear progression upon intervention. In this way, we avoid the problem of trying to compare "apples with apples" but use the "same apple" instead.

Accelerated growth of skin carcinoma following fludarabine therapy for chronic lymphocytic leukemia.

We present four patients with chronic lymphocytic leukemia treated with fludarabine, who developed aggressive skin cancer after years of quiescence, a short time after institution of treatment. Their leukemias responded well to therapy with fludarabine with initial treatment as well as relapse. Three patients had recurrence with basal cell carcinomas with multiple, rapidly growing tumors and one had recurrence of both basal and squamous cancers and eventually died of metastatic squamous cell carcinoma. Fludarabine induces prolonged period of lymphopenia, affecting especially the T cell population, which is crucial in the defense against skin cancers. There appears to be a direct association between fludarabine and the flare up of skin cancers in these patients, possibly analogous to the increased incidence of these malignancies in patients on chronic cyclosporine immunosuppression.