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A 66-year-old woman gave a 6-year history of progressive weakness. Her initial symptoms were aching hips, shoulder pain and difficulty getting out of a chair. A rheumatologist diagnosed polymyalgia rheumatica—despite significant weakness—and gave prednisolone for several months. Despite initial improvement, her weakness slowly progressed until she could not climb stairs or walk a reasonable distance. At the time of presentation, she reported anorexia with 4 kg weight loss over 6 months and recent suprapubic swelling. She had difficulty raising her arms above her head, and problems with chewing and swallowing. There were no sensory symptoms, diplopia or difficulty breathing, and no change in cognition or behaviour. She had been diagnosed with breast cancer around the same time as polymyalgia rheumatica, and had undergone lumpectomy, radiotherapy and hormone therapy with curative intent. Two years before her current presentation, she developed a subacute bowel obstruction requiring colonoscopy; the surgical specimen showed bowel/sigmoid amyloid. Repeat colonoscopy a year later was normal. She also had a melanoma resected 10 years before. There was a family history of early onset dementia with prominent behavioural abnormalities in her sister, mother, maternal siblings and maternal grandmother. Her own two daughters were well. On examination, her blood pressure was 110/80 mm Hg lying and 90/70 mm Hg standing; other vital signs were normal. She had a protuberant abdomen with divarication of the rectus muscles and significant suprapubic pitting oedema. Her tongue was large. There was shoulder girdle wasting, with occasional fasciculations in the deltoid, trapezius, biceps and triceps muscles, and mild weakness of shoulder abduction, neck flexion and left wrist flexion. Her reflexes were all brisk. There was quadriceps wasting with occasional fasciculations and mild proximal hip flexor weakness. Her reflexes were brisk with one beat of clonus and her plantar responses were downgoing. ### Question 1 What are the differential diagnoses and how should she …

Individuation is the expression of the collective by a unique Individual. “The aim of individuation is nothing less than to divest the self of the false wrappings of the persona on the one hand and of the suggestive power of primordial Images on the other”. C. G. Jung described marriage as an emotional “container”. This containment can be thought of in three ways: the marriage itself is a container, one partner can contain the other partner and one partner can be contained by the other. Some marriages are apparently based on one partner seeking containment, the other wishing and being able to provide this containment. In using Jung’s definition of marriage as the container, the marriage can be used as a vehicle for maturation and for becoming a more complete person. The containment of marriage allows for some regression, and, if worst fears are not realized, there is the chance to go forward again.

The development of targeted next-generation sequencing (NGS) applications now promises to be a clinically viable option for the diagnosis of rare disorders. This approach is proving to have significant utility where standardized testing has failed to identify the underlying molecular basis of disease. We have developed a unique targeted NGS panel for the systematic sequence-based analysis of atypical iron disorders. We report the analysis of 39 genes associated with iron regulation in eight cases of atypical iron dysregulation, in which five cases we identified the definitive causative mutation, and a possible causative mutation in a sixth. We further provide a molecular and cellular characterization study of one of these mutations (TFR2, p.I529N) in a familial case as proof of principle. Cellular analysis of the mutant protein indicates that this amino acid substitution affects the localization of the protein, which results in its retention in the endoplasmic reticulum and thus failure to function at the cell surface. Our unique NGS panel presents a rapid and cost-efficient approach to identify the underlying genetic cause in cases of atypical iron homeostasis disorders.

Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.