OVPSYCH2: A randomized controlled trial of psychological support versus standard of care following chemotherapy for ovarian cancer.

BACKGROUND: Fear of disease progression (FOP) is a rational concern for women with Ovarian Cancer (OC) and depression is also common. To date there have been no randomized trials assessing the impact of psychological intervention on depression and FOP in this patient group. PATIENTS AND METHODS: Patients with primary or recurrent OC who had recently completed chemotherapy were eligible if they scored between 5 and 19 on the PHQ-9 depression and were randomized 1:1 to Intervention (3 standardized CBT-based sessions in the 6-12 weeks post-chemotherapy) or Control (standard of care). PHQ-9, FOP-Q-SF, EORTC QLQ C30 and OV28 questionnaires were then completed every 3 months for up to 2 years. The primary endpoint was change in PHQ-9 at 3 months. Secondary endpoints were change in other scores at 3 months and all scores at later timepoints. RESULTS: 182 patients registered; 107 were randomized; 54 to Intervention and 53 to Control; mean age 59 years; 75 (70%) had completed chemotherapy for primary and 32 (30%) for relapsed OC and 67 patients completed both baseline and 3-month questionnaires. Improvement in PHQ-9 was observed for patients in both study arms at three months compared to baseline but there was no significant difference in change between Intervention and Control. A significant improvement on FOP-Q-SF scores was seen in the Intervention arm, whereas for those in the Control arm FOP-Q-SF scores deteriorated at 3 months (intervention effect = -4.4 (-7.57, -1.22), p-value = 0.008). CONCLUSIONS: CBT-based psychological support provided after chemotherapy did not significantly alter the spontaneously improving trajectory of depression scores at three months but caused a significant improvement in FOP. Our findings call for the routine implementation of FOP support for ovarian cancer patients.

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm.

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFRC329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2V617F-positive clone in this PV patient harbors EGFRC329R, thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN samples, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2V617F disease clone in MPN.

Cardiac resynchronization therapy update: evolving indications, expanding benefit?

Cardiac resynchronisation therapy (CRT) is an effective intervention for appropriately selected patients with heart failure, but exactly how it works is uncertain. Recent data suggest that much, or perhaps most, of the benefits of CRT are not delivered by re-coordinating left ventricular dyssynchrony. Atrio-ventricular resynchronization, reduction in mitral regurgitation and prevention of bradycardia are other potential mechanisms of benefit that will vary from one patient to the next and over time. Because there is no single therapeutic target, it is unlikely that any single measure will accurately predict benefit. The only clinical characteristic that appears to be a useful predictor of the benefits of CRT is a QRS duration of >140 ms. Many new approaches are being developed to try to improve the effectiveness of and extend the indications for CRT. These include smart pacing algorithms, better pacing-site targeting, new sensors, multipoint pacing, remote device monitoring and leadless endocardial pacing. Whether CRT is effective in patients with atrial fibrillation or whether adding a defibrillator function to CRT improves prognosis awaits further evidence.

The effect of strict infection control policies on the rate of infection after elective foot and ankle surgery: a review of 1737 cases.

The rate of surgical site infection after elective foot and ankle surgery is higher than that after other elective orthopaedic procedures. Since December 2005, we have prospectively collected data on the rate of post-operative infection for 1737 patients who have undergone elective foot and ankle surgery. In March 2008, additional infection control policies, focused on surgical and environmental risk factors, were introduced in our department. We saw a 50% reduction in the rate of surgical site infection after the introduction of these measures. We are, however, aware that the observed decrease may not be entirely attributable to these measures alone given the number of factors that predispose to post-operative wound infection.

Growth factor plus preemptive ('just-in-time') plerixafor successfully mobilizes hematopoietic stem cells in multiple myeloma patients despite prior lenalidomide exposure.

Lenalidomide is associated with suboptimal autologous hematopoietic stem cell (AHSC) mobilization. We hypothesized that growth factor plus preemptive plerixafor is an effective strategy for AHSC mobilization in multiple myeloma (MM) despite prior exposure to lenalidomide. We retrospectively reviewed patient characteristics and mobilization outcomes of 89 consecutive MM patients undergoing first mobilization with filgrastim or pegfilgrastim +/- preemptive plerixafor using a previously validated algorithm based on day 4 peripheral blood CD34+ cell count (PB-CD34+) and mobilization target. Outcomes were analyzed according to the extent of prior exposure to lenalidomide: no prior exposure (group A, n=40), 1- 4 cycles (group B, n=30) and >4 cycles (group C, n=19). Multivariate analysis yielded only age and number of cycles of lenalidomide as negatively associated, and mobilization with pegfilgrastim as positively associated with higher PB-CD34+. Only 45% of patients in group A required plerixafor vs 63% in groups B and 84% in C, P=0.01. A higher proportion of patients in group A (100%) met the mobilization target than in groups B (90%) or C (79%), P=0.008. All patients yielded at least 2 × 10(6) CD34+/kg. Growth factor mobilization with preemptive plerixafor is an adequate upfront mobilization strategy for MM patients regardless of prior exposure to lenalidomide.

The prevalence of cognitive dysfunction after conventional and computer-assisted total knee replacement.

Post operative cognitive dysfunction (POCD) is common following lower limb arthroplasty. The prevalence varies from 41-75% at 7 days to 18-45% at 3 months post operatively. The wide range of prevalence is due to inconsistencies in defining and quantifying POCD. The aim of this study is to ascertain an accurate prevalence of POCD in patients who had either conventional TKR (n=31) or computer-assisted TKR (n=30). Cognition was assessed pre-operatively, 6 days and at 6 months post-operatively by a battery of 11 validated neuropsychological tests. We found the mean prevalence of POCD to be 72% at 6 days and 30% at 6 months post-operatively. When comparing the prevalence of POCD between the two groups, we found no statistically significant difference at 6 days or at 6 months post-operatively. The only statistically significant factor between the two groups was the mean procedure time which was longer in the computer-assisted TKR group (p=< 0.001). We found a correlation between procedure time and the prevalence of POCD at 6 days (p=0.02) but not 6 months (p=0.26). POCD occurs in approximately one-third of TKR patients at 6 months post-operatively. The cause is undoubtedly multi-factorial; however we have demonstrated that procedure time may be a contributing factor. Our results suggest that using an intra-medullary femoral jig has no effect on POCD. Further research into the cognitive effects following TKR with and without a tourniquet would be of benefit.

Psoas abscess: diagnosis and treatment.

Psoas abscess is an uncommon presentation on the acute medical take. However recognition and appropriate treatment is essential. This review is designed to highlight the clinical features, microbiology, diagnostic tests and treatment for this condition. In order to illustrate some of the pitfalls and complexities in the management of psoas abscess we have included a case history of a patient who was recently treated in our department.

Changes in arthroscopic findings in the anterior cruciate ligament deficient knee prior to reconstructive surgery.

We retrospectively compared the arthroscopic findings of 75 patients at the time of diagnosis of ACL rupture and the findings at the time of ACL reconstruction. We found that in the ACL deficient knee the deterioration in meniscal tears and osteochondral lesions was statistically greater with increased interval between diagnosis of ACL rupture and reconstruction. This study implies that in those patients where ACL reconstruction is indicated, a delay in reconstructive surgery can have a deleterious effect on the articular surface of the knee.

The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes.

There is increasing evidence that non-steroidal anti-inflammatory drugs (NSAIDs) can adversely affect bone repair. We have, therefore, studied the in vitro effects of NSAIDs, which differentially inhibit cyclooxygenases (COX), the prostaglandin/thromboxane synthesising enzymes, on human osteoblasts. Indomethacin and the new nitric oxide (NO)-donating NSAIDs block the activity of both COX-1 and COX-2. Indomethacin and 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulphonal) phenyl-2 (5H)-furanone (DFU) reduced osteoblast numbers in a dose-dependant manner and increased collagen synthesis and alkaline phosphatase activity. The reduction in osteoblast numbers was not caused by loss of adhesion and was reversible. Neither NSAID influenced DNA synthesis. There was no difference between the effects of indomethacin and DFU. NO-NSAIDs did not affect cell numbers. These results suggest that care should be taken when administering NSAIDs to patients with existing skeletal problems and that NO-NSAIDs may be safer.

Peptide insertions in domain 4 of hbeta(c), the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation.

A mutant form of the common beta-subunit of the GM-CSF, interleukin-3 (IL3) and IL5 receptors is activated by a 37 residue duplicated segment which includes the WSXWS motif and an adjacent, highly conserved, aliphatic/basic element. Haemopoietic expression of this mutant, hbeta(c)FIDelta, in mice leads to myeloproliferative disease. To examine the mechanism of activation of this mutant we targetted the two conserved motifs in each repeat for mutagenesis. Here we show that this mutant exhibits constitutive activity in BaF-B03 cells in the presence of mouse or human GM-CSF receptor alpha-subunit (GMRalpha) and this activity is disrupted by mutations of the conserved motifs in the first repeat. In the presence of these mutations the receptor reverts to an alternative conformation which retains responsiveness to human IL3 in a CTLL cell line co-expressing the human IL3 receptor alpha-subunit (hIL3Ralpha). Remarkably, the activated conformation is maintained in the presence of substitutions, deletions or replacement of the second repeat. This suggests that activation occurs due to insertion of extra sequence after the WSXWS motif and is not dependent on the length or specific sequence of the insertion. Thus hbeta(c) displays an ability to fold into functional receptor conformations given insertion of up to 37 residues in the membrane-proximal region. Constitutive activation most likely results from a specific conformational change which alters a dormant, inactive receptor complex, permitting functional association with GMRalpha and ligand-independent mitogenic signalling.

Mechanical partial small bowel obstruction in a patient with Fitz-Hugh-Curtis syndrome.

Perihepatitis or Fitz-Hugh-Curtis syndrome is a complication of pelvic inflammatory disease that usually leaves characteristic violin string adhesions on the anterior liver surface. These adhesions are common incidental findings on subsequent laparoscopy or laparotomy and are considered benign. We present a case of partial mechanical small bowel obstruction as a sequel of this syndrome that was diagnosed and treated laparoscopically.

Effects of benzoyl peroxide on lipogenesis in sebaceous glands using an animal model.

BACKGROUND: Benzoyl peroxide is the most widely used topical agent for acne since the 1960s. Concomitant treatment of benzoyl peroxide with oral, or topical antibiotics diminishes the multiplication of antibiotic-resistant strains of Propionibacteria acnes. Besides being antibacterial, the chemical also functions as a peeling agent, has comedolytic activity, reduces free fatty acid levels, and is touted to be sebosuppressive. OBJECTIVE: The purpose was to determine the ability of topically applied benzoyl peroxide to suppress lipogenesis of the sebaceous glands. METHODS: The data were obtained employing an animal model for human sebaceous glands, namely, the flank organs of female golden Syrian hamsters. RESULTS: Our results reveal no inhibition of lipogenesis in sebaceous glands by topical application of benzoyl peroxide. CONCLUSION: Despite many functions beneficial in acne therapy, benzoyl peroxide does not possess sebosuppressive capabilities. With the advent of water-soluble organic peroxides revealing similar antimicrobial activity to benzoyl peroxide, all therapeutic parameters (save for sebosuppression) will need to be assessed to weigh the benefits of these second-generation acne-fighting peroxides.

Molecular aspects of polycythemia vera (review).

Polycythemia vera (PV) is a rare, progressive myeloproliferative disorder thought to originate from the clonal expansion of a multipotent haemopoietic stem cell. This disease is characterised by hyperproliferation of the erythroid, myeloid and megakaryocyte lineages in the early phase, anaemia and fibrosis in the spent phase, and with a significant number of patients developing acute myeloid leukaemia (AML) in the final phase. Studies investigating the growth factor requirements of committed progenitors have shown hypersensitivity to a number of haemopoietic growth factors (HGF) in vitro and several HGF receptor and signalling molecule alterations have been reported. The findings to date, however, are unable to account for the transformation of a primitive stem cell and the many alterations to growth factor responses seen in PV progenitors. Identification of the primary lesion that leads to the pathogenesis of PV is of major importance given the profound effects on regulation of the haemopoietic stem cell compartment. In this article we focus on characteristics of the disease, research findings to date and possible mechanisms to explain altered growth factor responses, receptor alterations and signalling abnormalities in PV.

Propionibacterium acnes: interaction with complement and development of an enzyme-linked immunoassay for the detection of antibody.

OBJECTIVE: To characterize the immune response to Propionibacterium acnes in acne patients. DESIGN: Comparison of serologic responses in acne and normal patients using counterimmunoelectrophoresis for antibody and an enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin G (IgG) antibody. SETTING: The serum of acne and nonacne patients from the Dermatology Clinic at the Medical College of Ohio was utilized for analysis. RESULTS: Using counterimmunoelectrophoresis, antibody was detected in 13 of 20 acne patients. The antigen was detectable as an anion in the barbital buffer at pH 8.2, strongly suggesting a carbohydrate component. By ELISA, the antibody proved to be IgG, and the bacteria and its water-soluble fractions were capable of fixing complement. CONCLUSIONS: The primary instigator of inflammation in acne vulgaris is an immunologic reaction to extracellular products of P. acnes. The immunologic response involves both humoral and cell-mediated pathways. The antibodies to P. acnes have not been characterized fully, although they are largely of the IgG class. We have further characterized the dominant antigen to have a carbohydrate component.

Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice.

Previously we described activating mutations of hbetac, the common signaling subunit of the receptors for the hematopoietic and inflammatory cytokines, GM-CSF, IL-3, and IL-5. The activated mutant, hbetacFIDelta, is able to confer growth factor-independent proliferation on the murine myeloid cell line FDC-P1, and on primary committed myeloid progenitors. We have used this activating mutation to study the effects of chronic cytokine receptor stimulation. Transgenic mice were produced carrying the hbetacFIDelta cDNA linked to the constitutive promoter derived from the phosphoglycerate kinase gene, PGK-1. Transgene expression was demonstrated in several tissues and functional activity of the mutant receptor was confirmed in hematopoietic tissues by the presence of granulocyte macrophage and macrophage colony-forming cells (CFU-GM and CFU-M) in the absence of added cytokines. All transgenic mice display a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembles the human disease polycythemia vera, suggesting that activating mutations in hbetac may play a role in the pathogenesis of this myeloproliferative disorder. In addition, these transgenic mice develop a sporadic, progressive neurological disease and display bilateral, symmetrical foci of necrosis in the white matter of brain stem associated with an accumulation of macrophages. Thus, chronic hbetac activation has the potential to contribute to pathological events in the central nervous system.