Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Myasthenia and Basedow's hyperthyroidism

The authors report an exceptional case of myasthenia gravis associated with Graves' disease. Myasthenia gravis appeared at age 8 years. Hyperthyroidism was diagnosed at age 12 1/2 and quickly worsened, with signs of cardiothyrotoxicosis. In addition to the diagnostic difficulties, the immunologic origin seems to be implicated in these diseases. Thymectomy associated with subtotal thyroidectomy was performed, with good results during an 18 months follow-up.     

Anesthesia for pediatric renal transplantation with and without epidural analgesia--a review of 7 years experience

BACKGROUND: Few objective data exist describing current anesthesia practice for pediatric renal transplantation. We describe here, the experience from an Australian tertiary pediatric center that has continued an active pediatric renal transplantation program after relocation in 1995. Areas of interest include preoperative status, fluid management, hemodynamic stability, perioperative complications, and the use of epidural analgesia. In particular, the influence of perioperative epidural analgesia on hemodynamic stability is addressed. METHODS: A retrospective review of anesthesia records of all patients undergoing pediatric renal transplantation performed at the Children's Hospital at Westmead (CHW), from November 1995 to October 2002 was carried out. RESULTS: Fifty-three pediatric renal transplants were performed in 50 patients. Average age and weight were 10.2 years (range: 1-18 years) and 31.4 kg (range: 9-66 kg), respectively. A total of 14 recipients were less than or equal to 6 years of age. Twenty-four children were recipients of cadaveric transplants, 29 children received kidneys from living related donors. Few children presented with severe anemia (two patients) gross electrolyte abnormalities (three patients) or uncontrolled hypertension. Intraoperatively, all children had central venous pressure monitoring and only four had invasive arterial blood pressure monitoring. Average intraoperative fluid administration was 88 ml x kg(-1) (range: 30-190). Twenty-three children received blood transfusions intraoperatively. Postoperative analgesia was provided using an epidural infusion in 39 patients and an opioid infusion/patient controlled analgesia in the remainder. There was a tendency to greater hemodynamic stability in the group, which received intra-operative epidural analgesia. Half the patients who had epidural analgesia required parenteral opioid supplementation. Five patients had postoperative pulmonary edema. Minor postoperative adverse events included epidural associated motor block (three cases) and opioid related oversedation (one patient). No perioperative mortality or major morbidity was recorded. CONCLUSIONS: Anesthesia for renal transplantation in pediatric patients at CHW is safe and effective using a selected range of drugs and techniques. Pretransplant medical optimization, careful preoperative assessment, adequate monitoring and precise fluid management together with appropriate postoperative analgesia typify the perioperative care of CHW renal transplant recipients.     

Acetabular fractures revisited: part 2, a new CT-based classification

OBJECTIVE: The objective of this investigation was to provide a new CT-based classification of acetabular fractures. MATERIALS AND METHODS: The axial CT scans of 112 randomly selected acetabular fractures in patients admitted to a level 1 trauma center between January 1998 and December 2000 were analyzed by an experienced orthopedic trauma surgeon and two experienced emergency radiologists. When available, 3D reformatted images were analyzed as well. The fracture pattern for each acetabular fracture, with respect to column walls and extension beyond the acetabulum, when present, was recorded. Fracture comminution was not a defining characteristic. RESULTS: Analysis of the 112 acetabular fracture patterns showed that each fracture fell into one of four broad categories. Category 0 included wall fractures only. Category I included acetabular fractures limited to a single (anterior or posterior) column. Category II fractures included those involving both the anterior and posterior columns; category II fractures were further subdivided into those with no fracture extension beyond the acetabulum, those with superior or inferior extension, and those with both superior and inferior extensions beyond the acetabulum. Category III fractures included only the "floating" acetabulum, which is defined as an acetabular fracture in which the acetabulum is separated from the axial skeleton both anteriorly and posteriorly. CONCLUSION: The axial CT display of acetabular fracture patterns provides a basis for a classification of acetabular fractures that is simple, unambiguous, readily understood by both radiologists and orthopedic surgeons and provides clear direction for both diagnosis and surgical treatment planning. Category and subcategory fracture specificity creates a mechanism for intra- and interdepartmental postoperative assessment of any of the individual acetabular fracture types.     

Spatially and temporally restricted chemoattractive and chemorepulsive cues direct the formation of the nigro-striatal circuit

Identifying cellular and molecular mechanisms that direct the formation of circuits during development is thought to be the key to reconstructing circuitry lost in adulthood to neurodegenerative disorders or common traumatic injuries. Here we have tested whether brain regions situated in and around the developing nigro-striatal pathway have particular chemoattractive or chemorepulsive effects on mesencephalic dopamine axons, and whether these effects are temporally restricted. Mesencephalic explants from embryonic day (E)12 rats were either cultured alone or with coexplants from the embryonic, postnatal or adult medial forebrain bundle region (MFB), striatum, cortex, brain stem or thalamus. Statistical analysis of axon growth responses revealed a potent chemoattraction to the early embryonic MFB (i.e. E12-15) that diminished (temporally) in concert with the emergence of chemoattraction to the striatum in the late embryonic period (i.e. E19+). Repulsive responses by dopaminergic axons were obvious in cocultures with embryonic brain stem and cortex, however, there was no effect by the thalamus. Such results suggest that the nigro-striatal circuit is formed via spatially and temporally distributed chemoattractive and chemorepulsive elements that: (i) orientate the circuit in a rostral direction (via brain stem repulsion); (ii) initiate outgrowth (via MFB attraction); (iii) prevent growth beyond the target region (via cortical repulsion); and (iv) facilitate target innervation (via striatal chemoattraction). Subsequent studies will focus on identifying genes responsible for these events so that their products may be exploited to increase the integration of neuronal transplants to the mature brain, or provide a means to (re)establish the nigro-striatal circuit in vivo.     

Acute diquat poisoning with intracerebral bleeding

A case of severe diquat poisoning complicated by the development of aggressive behaviour, oliguric renal failure, and intracerebral bleeding is described. The patient was successfully managed and made a complete recovery. In this paper special attention has been given to the major clinical differences between diquat and paraquat intoxication.