A mixed methods pilot and feasibility open trial of internet-delivered cognitive behaviour therapy (iCanADAPT Advanced) for people with advanced cancer with depression and/or anxiety.

PURPOSE: Evaluate the feasibility, acceptability and potential efficacy of a form of online therapy for clinical depression and/or anxiety in people living with advanced cancer. METHODS: A single-arm open trial of a six-lesson clinician-supervised, internet-delivered cognitive behavioural therapy (iCBT) transdiagnostic intervention (iCanADAPT Advanced) was undertaken. Qualitative (semi-structured telephone interview conducted at 3-months) and quantitative data (questionnaires collected at pre-, post-, and 3-month follow-up) were analysed. RESULTS: 27 participants partook (26 women, 56% breast cancer, mean age 56yo; average number of mental health diagnoses 1.8, with majority (81%) meeting criteria for generalised anxiety disorder). Feasibility - Unanticipated numbers (48%) of participants had physical health deterioration (cancer progression or death). iCBT had high adherence overall (completion rates: 37% did 6 lessons; 70% did 4 lessons) but adherence was higher for those whose cancer remained stable (completion rates: 43% did 6 lessons; 85% did 4 lessons). Acceptability - the intervention was acceptable to the majority of participants, with high treatment satisfaction. Advisory data was achieved regarding future versions. Potential efficacy - regardless of physical health status, participants who completed the iCBT showed a significant decrease over time in anxiety and depression symptoms. CONCLUSIONS: Online therapies may be useful in assisting those living with advanced cancer dealing with clinical depression and anxiety disorders. The specific modality of clinician supervised iCBT has significant potential to be a suitable modality of online therapy.

Randomised controlled trial of internet-delivered cognitive behaviour therapy for clinical depression and/or anxiety in cancer survivors (iCanADAPT Early).

PURPOSE: To evaluate internet-delivered cognitive behavioural therapy (iCBT) on clinical depression and/or anxiety, distress, fear of cancer recurrence, and quality of life in cancer survivors. METHODS: Random assignation of 114 participants to iCBT or treatment-as-usual (TAU). The clinician-supervised iCBT program (iCanADAPT Early) consisted of eight lessons over 16 weeks. Self-report questionnaires occurred at baseline, midpoint, and posttreatment for both groups with 3-month follow-up for iCBT participants. A mixed modelling approach to compare groups occurred. RESULTS: iCBT was superior to TAU on all outcome measures at posttreatment. Compared with TAU, the iCBT group showed a significant decrease over time in anxiety and depression symptoms (primary outcome, Hospital Anxiety and Depression Scale, Hedges g = 1.51). Additionally the iCBT group had significantly lower general distress (Kessler-10, g = 1.56), fear of cancer recurrence (Fear of Cancer Recurrence Inventory, g = 0.39), and significantly higher quality of life (Functional Assessment of Cancer Therapy-General, g = 0.74) at posttreatment compared with the TAU group. High adherence and satisfaction were found for iCBT with low clinician time. CONCLUSION: Clinician-supervised iCBT has significant benefits for cancer survivors with clinical depression and anxiety disorders.

Warty (follicular) dyskeratoma on the mons pubis.

Warty (follicular) dyskeratoma (WD) is a discrete nodular lesion that demonstrates the characteristic histopathologic findings of acantholysis and dyskeratosis. WDs most commonly occur on the head and neck of adults. We present a case of WD that occurred on the mons pubis of a 53-year-old woman. Only a few other cases of WDs occurring on the vulva have been reported. WD most likely represents a tumor of the follicular infundibulum. Despite its name, there is no evidence that WD is caused by a human papillomavirus (HPV) infection. Although occurrences on the vulva are rare, they must be distinguished from HPV-induced squamous tumors when found in this area.

iCanADAPT Early protocol: randomised controlled trial (RCT) of clinician supervised transdiagnostic internet-delivered cognitive behaviour therapy (iCBT) for depression and/or anxiety in early stage cancer survivors -vs- treatment as usual.

BACKGROUND: This RCT with two parallel arms will evaluate the efficacy of an internet-delivered transdiagnostic cognitive behavioural therapy (iCBT) intervention for the treatment of clinical depression and/or anxiety in early stage cancer survivors. METHODS/DESIGN: Early stage cancer survivors will be recruited via the research arm of a not-for-profit clinical research unit and randomised to an intervention (iCBT) group or a 'treatment as usual' (TAU) control group. The minimum sample size for each group is 45 people (assuming effect size > 0.6, power of 80%, and alpha at .05), but 10% more will be recruited to account for attrition. A solitary or cumulative diagnosis(es) of Major Depressive Episode (current), Generalised Anxiety Disorder, Illness Anxiety Disorder, Panic Disorder, Agoraphobia, and/or Adjustment disorder will be determined using modules from the Anxiety Disorders Interview Schedule for DSM-5. Depression and anxiety levels with be measured via the total score of the Hospital Anxiety and Depression scale (HADS-T), the primary outcome measure. Secondary measures will include the Kessler 10 to measure general distress, the Fear of Cancer Recurrence Inventory (FCRI) to measure the specific fear of cancer recurrence and the Functional Assessment of Cancer Therapy, General Version 4 (FACT-G) for self-report of physical, social, emotional and functional well-being. iCBT participants will complete the measures before lessons 1 and 5, at post-treatment and at 3-month follow-up. The TAU group will complete similar measures at weeks 1, 8 and 16 of the waiting period. Program efficacy will be determined using intent-to-treat mixed models. Maintenance of gains will be assessed at 3-month follow-up. Mediation analyses using PROCESS will be used to examine the association between change in depressive and anxious symptoms over time and changes in FCRI and FACT-G QOL in separate analysis. DISCUSSION: This is the first RCT looking at iCBT specifically for clinical depression and/or anxiety in a cancer population. Findings will help to direct the role of iCBT in streamlined psycho-social care pathways. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12616000231448, registered 19th February 2016 ( www.anzctr.org.au ). This trial protocol is in compliance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.

Acceptability of an internet cognitive behavioural therapy program for people with early-stage cancer and cancer survivors with depression and/or anxiety: thematic findings from focus groups.

PURPOSE: We developed an eight-lesson internet-delivered CBT (iCBT) program targeting anxiety and depression in early-stage cancer and cancer survivors. To explore the acceptability of the program, we showed volunteers the first two lessons and asked for their views. METHODS: Focus groups (n = 3) and individual interviews (n = 5) were undertaken with 15 participants (11 survivors) with mainly breast (11 of the 15) cancer, who had reviewed intervention materials. Participants were asked to consider the acceptability of the iCBT program content and implementation design (timing, duration). Semi-structured questions guided discussion. Thematic analysis was conducted of participant reactions to the acceptability and/or suitability of materials created for use in a psychological intervention. We took a data-driven (inductive) approach to semantic theme development across the data set. RESULTS: Participants reported high acceptability of the internet delivery format, good engagement and user-friendly material. Participants were broadly supportive of combining depression and anxiety iCBT resources for early-stage cancer patients and survivors. Participants further indicated that a separate course would be needed to address the needs of patients with advanced stage disease. CONCLUSIONS: Participants welcomed the general development of an internet-delivered CBT intervention program to treat patients with clinical depression and/or anxiety. Furthermore, the sessions reviewed were highly acceptable to all participants. Study findings informed researchers on the development of iCBT resources for the cancer community.

Nodular localized primary cutaneous amyloidosis: a bullous variant.

Primary cutaneous amyloidosis describes a group of disorders in which amyloid is deposited in the skin without evidence of systemic involvement. Nodular localized primary cutaneous amyloidosis (NLPCA) is a rare form of these skin-restricted amyloidoses. We present an unusual case of NLPCA in a 51-year-old man, who had clinical and histopathological evidence of subepidermal bullous formation, a unique feature in NLPCA. The possible pathogenesis of this change is discussed.

The effect of temperature elevation on cryopreserved mesenchymal stem cells.

BACKGROUND: Cryopreservation is of particular importance in stem cell research and regenerative medicine as it permits long term stabilisation of biological cells. Cells retain their regenerative capacity after years of storage at cryogenic temperatures. However, elevation of temperature may occur due to variety of reasons, for example in the event of equipment malfunction or during delays in transportation. To date, a limited amount research has been carried out to examine the effects of temperature elevation on stem cell survival during cryopreservation. METHODS: Mesenchymal Stem Cells (MSCs) obtained from 8-12 week Sprague Dawley male rats were cryopreserved according to the standard procedures. Under experimental conditions, cryopreserved specimens were exposed to elevated temperatures ranging from -20 C to 37 C and cellular membrane integrity assessed via trypan-blue exclusion at various time points. RESULTS: An approximating model of multiple regression was fitted to the experimental data and optimisation of model parameters was carried out. This model provides an approximation of cell viability in response to elevated temperature conditions. DISCUSSION: The results demonstrate that elevation of temperature has a dramatic effect, even over short periods of time, on the viability of cryopreserved specimens. The model presented here could be used to predict the damage suffered by a specimen due to exposure to elevated temperature over a defined period of time.

WE-E-213CD-05: A Non-Rigid Image Registration Algorithm That Accommodates Organ Segmentation Error.

PURPOSE: To introduce a new deformable image registration algorithm based on surface matching that accommodates organ delineation error in daily Cone-beam CT images based on a priori knowledge of inter-observer segmentation uncertainty. METHODS: The dataset includes four prostate cancer patients who underwent primary external beam radiotherapy and had tumors that were confined to the prostate. All imaging was performed without intravenous contrast. Organ surface segmentation errors in a multiple observer-contouring study on the pelvic organs in Fan-beam CT (FBCT) and Cone-beam CT (CBCT) were estimated from the training dataset. A novel deformable image registration algorithm is presented where the organ surface matching is penalized by this error. Portions of the organ surface that are delineated reliably are used to guide the registration whereas the portions that are highly uncertain are ignored. This approach reduces the impact of delineation errors in CBCT. An evaluation experiment compares three algorithms, namely intensity-only registration (INT), equally-weighted surface and image registration (EWSIR) and the proposed uncertainty- weighted surface and image registration. RESULTS: The surface dissimilarity was reduced from 0.172 to 0.134, 0.043 and 0.044 respectively after registration. The Jacobian of the transformation found by the proposed method was closer to one than that of EWSIR in the prostate. CONCLUSIONS: In prostate external-beam radiotherapy, slice-by-slice 2D manual contouring has variable spatial accuracy. For deformable image registration methods that match segmented surfaces, regions of high inaccuracy can misguide the registration. In contrast to the image registration methods where the FBCT and CBCT surfaces (or other features) are assumed to be exact, our method takes this uncertainty into account. Preliminary results show an improved registration performance suggesting a potential use in IGRT. This work was supported by National Cancer Institute Grant No. P01 CA 116602.

Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells.

Adult human mesenchymal stromal or stem cells (MSC) can differentiate into a variety of cell types and are candidate cellular therapeutics in regenerative medicine. Surprisingly, these cells also display multiple potent immunomodulatory capabilities, including allosuppression, making allogeneic cell therapy a possibility. The exact mechanisms involved in regulatory T cell induction by allogeneic human MSC was examined, using purified CD4+ populations and well-characterized bone marrow-derived adult human MSC. Allogeneic MSC were shown to induce forkhead box P3 (FoxP3)+ and CD25+ mRNA and protein expression in CD4+ T cells. This phenomenon required direct contact between MSC and purified T cells, although cell contact was not required for MSC induction of FoxP3 expression in an unseparated mononuclear cell population. In addition, through use of antagonists and neutralizing antibodies, MSC-derived prostaglandins and transforming growth factor (TGF)-beta1 were shown to have a non-redundant role in the induction of CD4+CD25+FoxP3+ T cells. Purified CD4+CD25+ T cells induced by MSC co-culture expressed TGF-beta1 and were able to suppress alloantigen-driven proliferative responses in mixed lymphocyte reaction. These data clarify the mechanisms of human MSC-mediated allosuppression, supporting a sequential process of regulatory T cell induction involving direct MSC contact with CD4+ cells followed by both prostaglandin E(2) and TGF-beta1 expression. Overall, this study provides a rational basis for ongoing clinical studies involving allogeneic MSC.

Increased urinary dopamine excretion in association with bilateral carotid body tumours-- clinical, biochemical and genetic findings.

This report describes a rare case of a patient with increased urinary dopamine excretion in association with bilateral carotid body tumours. Excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and 4-hydroxy-3-methoxymandelic acid (HMMA) were within the reference ranges, and an (123)I-meta-iodobenzylguanidine (MIBG) scan showed uptake in the neck masses, with no other abnormal uptake anywhere else in the body. The patient is being managed conservatively as the tumours are not amenable to resection on account of their size and vascularity. There are only four previous case reports of dopamine-secreting tumours of the carotid body described in the literature, all of whom were women. The tumours were unilateral in three cases and bilateral in the fourth case. Familial cases of carotid body tumours have a higher prevalence of bilateral tumours than non-familial cases. Recent reports in the literature have suggested that a significant number of patients with extra-adrenal catecholamine-secreting paragangliomas have a genetic mutation in one of the identified susceptibility genes for catecholamine-secreting tumours, despite having no other affected family members, and a mutation has been found in the succinate dehydrogenase gene for this patient.

Image-guided hypo-fractionated stereotactic radiosurgery to spinal lesions.

OBJECTIVE: This article demonstrates the technical feasibility of noninvasive treatment of unresectable spinal vascular malformations and primary and metastatic spinal tumors by use of image-guided frameless stereotactic radiosurgery. METHODS: Stereotactic radiosurgery delivers a high dose of radiation to a tumor volume or vascular malformation in a limited number of fractions and minimizes the dose to adjacent normal structures. Frameless image-guided radiosurgery was developed by coupling an orthogonal pair of x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the therapy beam to treatment sites within the spine or spinal cord, in an outpatient setting, and without the use of frame-based fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Sixteen patients with spinal lesions (hemangioblastomas, vascular malformations, metastatic carcinomas, schwannomas, a meningioma, and a chordoma) were treated with total treatment doses of 1100 to 2500 cGy in one to five fractions by use of image-guided frameless radiosurgery with the CyberKnife system (Accuray, Inc., Sunnyvale, CA). Thirteen radiosurgery plans were analyzed for compliance with conventional radiation therapy. RESULTS: Tests demonstrated alignment of the treatment dose with the target volume within +/-1 mm by use of spine fiducials and the CyberKnife treatment planning system. Tumor patients with at least 6 months of follow-up have demonstrated no progression of disease. Radiographic follow-up is pending for the remaining patients. To date, no patients have experienced complications as a result of the procedure. CONCLUSION: This experience demonstrates the feasibility of image-guided robotic radiosurgery for previously untreatable spinal lesions.

Granulomatous lymphangitis of the scrotum and penis. Report of a case and review of the literature of genital swelling with sarcoidal granulomatous inflammation.

BACKGROUND: Acquired lymphedema of the genitalia is a rare childhood presentation and is more common in elderly individuals secondary to pelvic/abdomenal malignancy or its therapy or worldwide due to filariasis. OBJECTIVE: Herein, we report a case of a healthy 11-year-old boy who presented with a 1-year history of chronic, asymptomatic scrotal and penile swelling. Biopsy revealed edema, lymphangiectases and peri- and intralymphatic sarcoidal type granulomas. This histologic pattern of granulomatous lymphangitis is most commonly associated with orofacial granulomatosis (granulomatous cheilitis and Melkersson-Rosenthal syndrome) and Crohn's disease. Treatment with topical steroids and physical support has resulted in marked improvement. No systemic disease (Crohn's disease) is evident 1 year later. Literature review revealed 44 cases of genital lymphedema with non-infectious granulomas. The majority of these young patients had Crohn's disease, frequently with anal involvement and a minority, both with and without Crohn's disease, had orofacial granulomatosis. CONCLUSIONS: Granulomatous lymphangitis should be considered in the differential diagnosis of chronic idiopathic swelling of the genitalia, particularly in younger individuals. Further clinical examination, additional laboratory studies and close follow-up for co-existing or subsequent development of Crohn's disease should be performed. The overlap between granulomatous lymphangitis of the genitalia, Crohn's disease and orofacial granulomatosis suggest that granulomatous lymphangitis of the genitalia may represent a forme fruste of Crohn's disease.

Ascitic fluid analysis: the role of biochemistry and haematology.

In specific settings, biochemical and haematological analysis of ascitic fluid may provide answers to important clinical questions. This review seeks to outline the value and limitations of ascitic fluid analysis and the main clinical scenarios in which it may be useful.

Image-guided radiosurgery in the treatment of spinal metastases.

OBJECT: The authors describe a new method for treating metastatic spinal tumors in which noninvasive, image-guided, frameless stereotactic radiosurgery is performed. Stereotactic radiosurgery delivers a high dose of radiation in a single or limited number of fractions to a lesion while maintaining delivery of a low dose to adjacent normal structures. METHODS: Image-guided radiosurgery was developed by coupling an orthogonal pair of real-time x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the radiation beam to treatment sites associated with radiographic landmarks. This procedure can be conducted in an outpatient setting without the use of framebased skeletal fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Four patients with spinal metastases underwent radiosurgery with total prescription doses of 1000 to 1600 cGy in one or two fractions. Alignment of the treatment dose with the target volume was accurate to within 1.5 mm. During the course of each treatment fraction, patient movement was less than 0.5 mm on average. Dosimetry was highly conformal, with a demonstrated ability to deliver 1600 cGy to the perimeter of an irregular target volume while keeping exposure to the cord itself below 800 cGy. CONCLUSIONS: These experiences indicate that frameless radiosurgery is a viable therapeutic option for metastatic spine disease.

Robotic motion compensation for respiratory movement during radiosurgery.

Tumors in the chest and abdomen move during respiration. The ability of conventional radiation therapy systems to compensate for respiratory motion by moving the radiation source is inherently limited. Since safety margins currently used in radiation therapy increase the radiation dose by a very large amount, an accurate tracking method for following the motion of the tumor is of the utmost clinical relevance. We investigate methods to compensate for respiratory motion using robotic radiosurgery. Thus, the therapeutic beam is moved by a robotic arm, and follows the moving target tumor. To determine the precise position of the moving target, we combine infrared tracking with synchronized X-ray imaging. Infrared emitters are used to record the motion of the patient's skin surface. A stereo X-ray imaging system provides information about the location of internal markers. During an initialization phase (prior to treatment), the correlation between the motions observed by the two sensors (X-ray imaging and infrared tracking) is computed. This model is also continuously updated during treatment to compensate for other, non-respiratory motion. Experiments and clinical trials suggest that robot-based methods can substantially reduce the safety margins currently needed in radiation therapy.

Image-guided radiosurgery for the spine and pancreas.

A robotic image-guided radiosurgical system has been modified to treat extra-cranial sites using implanted fiducials and skeletal landmarks to locate the treatment targets. The system has been used to treat an artero-venous malformation in the cervical spine, a recurrent schwannoma of the thoracic spine, a metastatic adenocarcinoma of the lumbar spine, and three pancreatic cancers. During each treatment, the image guidance system monitored the position of the target site and relayed the target coordinates to the beam-pointing system at discrete intervals. The pointing system then dynamically aligned the therapy beam with the lesion, automatically compensating for shifts in target position. Breathing-related motion of the pancreas lesions was managed by coordinating beam gating with breath-holding by the patient. The system maintained alignment with the spine lesions to within +/- 0.2 mm on average, and to within +/- 1 mm for the pancreatic tumors. This experience has demonstrated the feasibility of using image-guided robotic radiosurgery outside the cranium.

Midfacial tumours: a review of 72 cases.

We review 72 midfacial tumours managed during the 10-year period between 1985 and 1995. We describe presenting features, sites of lesions and histology, treatment regimens and outcomes, as well as the various surgical approaches for the resection of midfacial tumours, and their indications and contraindications. The choice of approach should be based on type of tumour, its site, and extent.