Mouse-INtraDuctal (MIND): an in vivo model for studying the underlying mechanisms of DCIS malignancy.

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Similar to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression, while 17 (46%) samples injected into 107 xenografts remained non-invasive. Among the 20 samples that showed invasive progression, nine samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained non-invasive. Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and the extent of in vivo growth in xenografts predicted an invasive outcome. The Tempus XT assay was used on 16 patient DCIS formalin-fixed, paraffin-embedded sections including eight DCISs that showed invasive progression, five DCISs that remained non-invasive, and three DCISs that showed a mixed pattern in the xenografts. Analysis of the frequency of cancer-related pathogenic mutations among the groups showed no significant differences (KW: p > 0.05). There were also no differences in the frequency of high, moderate, or low severity mutations (KW; p > 0.05). These results suggest that genetic changes in the DCIS are not the primary driver for the development of invasive disease. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Cryopreserved venous allograft is an acceptable conduit in patients with current or prior angioaccess graft infection.

OBJECTIVE: The durability of cryopreserved allograft has been previously demonstrated in the setting of infection. The objective of this study was to examine the safety, efficacy, patency, and cost per day of graft patency associated with using cryopreserved allograft (vein and artery) for hemodialysis access in patients with no autogenous tissue for native fistula creation and with arteriovenous graft infection or in patients at high risk for infection. METHODS: Patients implanted with cryopreserved allograft for hemodialysis access between January 2004 and January 2014 were reviewed using a standardized, multi-institutional database that evaluated demographic, comorbidity, procedural, and outcomes data. RESULTS: There were 457 patients who underwent placement of cryopreserved vein (femoral: n = 337, saphenous: n = 11) or artery (femoral: n = 109) for hemodialysis access at 20 hospitals. Primary indications for allograft use included high risk of infection in 191 patients (42%), history of infected prosthetic graft in 169 (37%), and current infection in 97 (21%). Grafts were placed more frequently in the arm (78%) than in the groin, with no difference in allograft conduit used. Mean time from placement to first hemodialysis use was 46 days (median, 34 days). Duration of functional graft use was 40 ± 7 months for cryopreserved vein and 21 ± 8 months for cryopreserved artery (P < .05), and mean number of procedures required to maintain patency at follow-up of 58 ± 21 months was 1.6 for artery and 0.9 for vein (P < .05). Local access complications occurred in 32% of patients and included late thrombosis (14%), graft stenosis (9%), late infection (9%), arteriovenous access malfunction (7%), early thrombosis (3%), and early infection (3%). Early and late infections both occurred more frequently in the groin (P = .030, P = .017, respectively), and late thrombosis occurred more frequently with cryopreserved artery (P < .001). Of the 82 patients (18%) in whom the cryopreserved allograft was placed in the same location as the excised infected prosthetic graft, 13 had infection of the allograft during the study period (early: n = 4; late: n = 9), with no significant difference in infection rate (P = .312) compared with the remainder of the study population. The 1-, 3-, and 5-year primary patency was 58%, 35%, and 17% for cryopreserved femoral vein and 49%, 17%, and 8% for artery, respectively (P < .001). Secondary patency at 1, 3, and 5 years was 90%, 78%, and 58% for cryopreserved femoral vein and 75%, 53%, and 42% for artery, respectively (P < .001). Mean allograft fee per day of graft patency was $4.78 for cryopreserved vein and $6.97 for artery (P < .05), excluding interventional costs to maintain patency. CONCLUSIONS: Cryopreserved allograft provides an excellent conduit for angioaccess when autogenous tissue is not available in patients with current or past conduit infection. Cryopreserved vein was associated with higher patency and a lower cost per day of graft patency. Cryopreserved allograft allows for immediate reconstruction through areas of infection, reduces the need for staged procedures, and allows early use for dialysis.

The relationship of CD34+ dosage and platelet recovery following high dose chemotherapy and autologous CD34+ reinfusion in multiple myeloma.

Autologous hematopoietic stem cell transplantation (ASCT) is an established treatment for multiple myeloma (MM), yet the impact of transplanted CD34+ cell dose remains unresolved, especially in patients over the age of 65 years. Data was collected from 207 consecutive ASCT patients to determine the relationship between CD34+ infusion count and short-term and long-term platelet recovery. For MM patients under the age of 65 years (n=155), CD34+ dosage correlates with time to platelet engraftment (p<0.001) and platelet count at 30 days (p=0.003), but not with long-term platelet counts at 180 or 360 days from the CD34+ reinfusion. For MM patients aged 65 years or older (n=46), CD34+ dosage did not correlate with time to platelet engraftment, but did correlate with both short-term and long-term platelet counts at 30 (p<0.001), 180 (p=0.021), and 360 days (p=0.005). Exploratory regression analysis was done to explore platelet stability following the current minimum CD34+ dosage reinfusion. For MM patients under the age of 65 years, the minimum standard CD34+ dosage of 2×106cells/kg was sufficient for a timing to platelet engraftment of <21 days and short-term platelets count ≥150×109/L at 30 days. Alternatively, for MM patients aged 65 years or older, the CD34+ dosage of 2×106cells/kg was insufficient for platelet counts ≥150×109/L at 30 and only marginally attainable at 360 days suggesting that in elderly MM patients a higher CD34+ dosage may be required for platelet recovery and possibly long-term platelet stability.

The influence of gender on functional outcomes of lower extremity bypass.

OBJECTIVE: Our aim was to evaluate the effect of gender on early and late procedural and functional outcomes of lower extremity bypass (LEB). METHODS: We reviewed the records of 2576 patients (828 women; 32%) who underwent LEB for claudication or critical limb ischemia (CLI) in the Vascular Study Group of New England from 2003 to 2010. Logistic regression and proportional hazards models were used to adjust for potential confounding differences between genders. Morbidity, mortality, graft patency, freedom from major amputation, ambulation, and living status were analyzed postoperatively and over 1 year. RESULTS: Women were older (70 vs 68 years; P < .001), had more hypertension (89% vs 85%; P = .006), less coronary artery disease (35% vs 39%; P = .03), smoking (73% vs 88%; P < .001), and preoperative statin use (60% vs 64%; P = .04). Women were more likely to have CLI (76% vs 71%; P = .003), and ambulate with assistance at presentation (19% vs 16%; P = .02). Morbidity was similar except women had higher rates of reoperation for thrombosis (4% vs 2%; P < .001) without differences in major amputation (2% vs 1%; P = .13) or in-hospital mortality (1.7% vs 1.7%; P = .96). Women and men with claudication had similar 1-year graft patency rates. Women with CLI had lower rates of primary (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.48; P = .02), assisted primary (HR, 1.42; 95% CI, 1.15-1.76; P = .001) and secondary patency (HR, 1.40; 95% CI, 1.10-1.77; P = .006) during the first year compared with men. Freedom from amputation was similar for men and women with CLI (HR, 1.17; 95% CI, 0.84-1.63; P = .36). There were no differences in late survival between women and men with claudication (HR, 0.89; 95% CI, 0.60-1.31; P = .36) or CLI (HR, 0.94; 95% CI, 0.81-1.09; P = .39). More female claudicants were not independently ambulatory at discharge (30% vs 19%; P = .002) and were discharged to a nursing home (15% vs 5%; P < .001) but these differences did not persist at 1 year. Women with CLI were more likely to be nonambulatory at discharge (13% vs 9%; P = .006) and at 1 year (13% vs 8%; P < .001). More women with CLI were discharged to a nursing home (44% vs 35%; P = .01) and resided there at 1 year (11% vs 7%; P = .02). CONCLUSIONS: Women have complication rates similar to men with inferior early and late functional outcomes after LEB. The reduced patency rates in women with CLI did not translate into differences in limb salvage. These findings might help define physician and patient expectations for women before revascularization.

Crew resource management: using aviation techniques to improve operating room safety.

INTRODUCTION: Since the publication of the Institute of Medicine report estimating nearly 100,000 deaths per year from medical errors, hospitals and physicians have a renewed focus upon error reduction. We implemented a surgical crew resource management (CRM) program for all operating room (OR) personnel. METHODS: In our academic medical center, 19,000 procedures per year are performed in 27 operating rooms. Mandatory CRM training was implemented for all peri-operative personnel. Aviation techniques introduced included a pre-operative checklist and brief, post-operative debrief, read and initial files, and various other aviation-based techniques. Compliance with conduct of the brief/debrief was monitored as well as wrong-site surgeries and retained foreign body events. The malpractice insurance database for claims was also queried for the period prior to and after training. RESULTS: Initial training was accomplished for 517 people, including all anesthesiologists, surgeons, nurses, technicians, and OR assistants. Pre-operative briefing increased from 6.7 to 99% within 4 mo. Wrong site surgeries and retained foreign bodies decreased from a high of seven in 2007 to none in 2008, but, after 14 mo without additional training, these rose to five in 2009. Malpractice expenses (payouts and legal fees) totaled $793,000 (2003-2007), but have been zero since 2008. DISCUSSION: CRM training and implementation had an impact on reducing the incidence of wrong site surgery and retained foreign bodies in our operating rooms. However, constant reinforcement and refresher training is necessary for sustained results. Though no one technique can prevent all errors, CRM can effect culture change, producing a safer environment.

Telemedicine to a moving ambulance improves outcome after trauma in simulated patients.

BACKGROUND: Rural trauma victims often require prolonged transport by s with limited scopes of practice. We evaluated the impact of telemedicine (TM) to a moving ambulance on outcomes in simulated trauma patients. METHODS: This is an institutional review board approved, prospective double-blind study. Three trauma scenarios (blunt torso trauma, epigastric stab wound, and closed head injury) were created for a human patient simulator. Intermediate emergency medical technicians (EMTs; n = 20) managed the human patient simulator, in a moving ambulance. In the TM group, physicians (n = 12) provided consultation. In the non-TM group, EMTs communicated with medical control by radio, as necessary. We tabulated the fraction of 13 key signs, 5 pathologic processes, and 12 key interventions that were performed. Vital signs and Sao2 (%) were recorded. Data were compared using the Wilcoxon rank-sum test. RESULTS: Lowest Sao2 (84 ± 0.7 vs. 78 ± 0), lowest systolic blood pressure (70 ± 1 vs. 53 ± 1), and highest heart rate (144 ± 0.9 vs. 159 ± 0.5) were significantly improved in the TM group (p < 0.001). Recognition rates for key signs (0.96 ± 0.01 vs. 0.79 ± 0.05), processes (0.98 ± 0.02 vs. 0.75 ± 0.05), and critical interventions (0.92 ± 0.02 vs. 0.49 ± 0.03) were higher in the TM group (p < 0.003). EMTs were successfully guided through needle decompression procedures in 22 of 24 cases (zero in the non-TM group). CONCLUSION: TM to a moving ambulance improved the care of simulated trauma patients. Furthermore, procedurally naïve EMTs were able to perform needle thoracostomy and pericardiocentesis with TM guidance.

Benefits of a telepsychiatry consultation service for rural nursing home residents.

Psychiatric care for nursing home residents is difficult to obtain, especially in rural areas, and this deficiency may lead to significant morbidity or death. Providing this service by videoconference may be a helpful, cost-effective, and acceptable alternative to face-to-face treatment. We analyzed data for 278 telepsychiatry encounters for 106 nursing home residents to estimate potential cost and time savings associated with this modality compared to in-person care. A total of 843.5 hours (105.4 8-hour work days) of travel time was saved compared to in-person consultation for each of the 278 encounters if they had occurred separately. If four resident visits were possible for each trip, the time saved would decrease to 26.4 workdays. Travel distance saved was 43,000 miles; 10,750 miles if four visits per trip occurred. More than $3,700 would be spent on gasoline for 278 separate encounters; decreased to $925 for four visits per roundtrip. Personnel cost savings estimates ranged from $33,739 to $67,477. Physician costs associated with additional travel time ranged from $84,347 to $253,040 for 278 encounters, or from $21,087 to $63,260 for four encounters per visit. The telepsychiatry approach was enthusiastically accepted by virtually all residents, family members, and nursing home personnel, and led to successful patient management. Providing psychiatric care to rural nursing home residents by videoconference is cost effective and appears to be a medically acceptable alternative to face-to-face care. In addition, this approach will allow many nursing homes to provide essential care that would not otherwise be available.

Use of the rectus abdominis muscle flap to fill a retroperitoneal defect following blast injury.

Wartime injuries from explosive devices have created the need for atypical responses to devastating and unusual injuries. We report a case of an explosive abdominal injury that produced a huge defect in the posterior abdominal wall which was ultimately repaired with a rectus abdominus flap, an usual use of this versatile muscle flap. The rectus abdominus muscle may be another tool available for the repair of wartime injuries.

Are Two-Part Intertrochanteric Femur Fractures Stable and Does Stability Depend on Fixation Method?

OBJECTIVES: To determine stability of 2-part intertrochanteric femur fractures and to determine whether secondary collapse is related to fixation method. DESIGN: A retrospective cohort series. SETTING: Single Level I Trauma Center. PATIENTS: One hundred fourteen patients (82 female) older than 50 years (average age 75 years, range 50-100 years) with an acute low-energy standard obliquity 2-part intertrochanteric femur fracture (OTA/AO 31A) identified from an orthopaedic trauma database were studied. INTERVENTION: Twenty-three patients were treated with a sliding hip screw (dynamic hip screw [DHS]), 53 with a dual screw trochanteric entry nail (INTERTAN), and 38 with a single-blade or screw trochanteric entry intramedullary nail (trochanteric fixation nail [TFN]) based on surgeon choice by 4 fellowship-trained orthopaedic trauma surgeons. MAIN OUTCOME MEASURES: Fracture collapse was measured by comparing immediate postoperative radiographs to those at final follow-up while controlling for magnification and rotation. RESULTS: Collapse averaged 6.8 mm in the DHS group, 3.7 mm in the INTERTAN group, and 7.3 mm in the TFN group. When comparing groups, there was significantly more collapse in the DHS group compared with the INTERTAN group (P = 0.021), and significantly more collapse in the TFN group compared with the INTERTAN group (P < 0.001). Six patients (26%) in the DHS group had >10-mm collapse including 4 (17%) with greater than 20-mm collapse (max = 34.2 mm). Four patients (8%) in the INTERTAN group had >10-mm collapse and none had greater than 12.9 mm. Ten patients (26%) in the TFN group had >10-mm collapse and 3 (5%) had greater than 20-mm collapse (max = 30.7 mm). CONCLUSION: Stability of 2-part intertrochanteric femur fractures is dependent on the fixation device. These fractures are not necessarily stable when treated with a sliding hip screw as 26% treated with this method collapsed greater than 10 mm and 17% more than 20 mm. Dual screw intramedullary nail fixation seems to be most effective to maintain stability for patients with this fracture pattern. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Two cases of brachial plexus compression secondary to displaced clavicle fractures.

Brachial plexus compression is a rare complication of displaced clavicle fractures, with few reports existing in the literature. Neurologic symptoms can present immediately after the injury or in a delayed fashion months later. Following polytrauma, two patients presented with displaced middle-third left clavicle fractures initially treated conservatively at other institutions. Both patients developed neurologic symptoms in the left upper extremity consistent with brachial plexus compression. Magnetic resonance imaging and electrodiagnostic testing were used to help confirm the diagnosis of thoracic outlet syndrome/brachial plexopathy, and both patients underwent open reduction internal fixation with dual plating, local bone grafting and brachial plexus decompression. Both patients experienced successful relief of neurologic symptoms postoperatively. The purpose of this case series is to report on a rare complication of delayed- and non-united clavicle fractures and describe successful treatment with a novel fracture fixation construct.

Magnetic design for the PediaFlow ventricular assist device.

This article describes a design process for a new pediatric ventricular assist device, the PediaFlow. The pump is embodied in a magnetically levitated turbodynamic design that was developed explicitly based on the requirements for chronic support of infants and small children. The procedure entailed the consideration of multiple pump topologies, from which an axial mixed-flow configuration was chosen for further development. The magnetic design includes permanent-magnet (PM) passive bearings for radial support of the rotor, an actively controlled thrust actuator for axial support, and a brushless direct current (DC) motor for rotation. These components are closely coupled both geometrically and magnetically, and were therefore optimized in parallel, using electromagnetic, rotordynamic models and fluid models, and in consideration of hydrodynamic requirements. Multiple design objectives were considered, including efficiency, size, and margin between critical speeds to operating speed. The former depends upon the radial and yaw stiffnesses of the PM bearings. Analytical expressions for the stiffnesses were derived and verified through finite element analysis (FEA). A toroidally wound motor was designed for high efficiency and minimal additional negative radial stiffness. The design process relies heavily on optimization at the component level and system level. The results of this preliminary design optimization yielded a pump design with an overall stability margin of 15%, based on a pressure rise of 100 mm Hg at 0.5 lpm running at 16,000 rpm.

The feasibility of using ultrasound and video laryngoscopy in a mobile telemedicine consult.

Emergency healthcare systems in rural communities often have limited access to experienced trauma and emergency physicians. Advanced telecommunication technologies may offer an opportunity to help meet this need. We evaluated healthcare providers' satisfaction with the audio and visual components of an existing telemedicine system, and asked them whether emergency medical services (EMS) personnel could be supported via telemedicine guidance, using video laryngoscopy and ultrasonography, during vulnerable transport periods. Physicians and technologists at a central workstation were linked to a telemedicine-equipped ambulance providing real-time audio and visual communications during patient transport. A scoring system was created for system evaluation using a scale of 1-9. Seven evaluators observed ultrasonography of the carotid vessels and abdominal aorta. Nine evaluators observed an intubation with video laryngoscopy. These observers rated the quality of the images transmitted from the ambulance. Evaluators were asked if this telemedicine system would be suitable for telementoring advanced technical procedures. Mean rating for technical satisfaction with ultrasound was 5.1, the majority of evaluators estimated that they could telementor an abdominal ultrasound examination. The mean rating for technical satisfaction with laryngoscopy was 7.2 with 100% of evaluators estimating they could use the system to telementor intubation. The rating for laryngoscopy was significantly higher than for ultrasound (p = 0.01). Results of this study suggest that telemedicine may provide an advanced support mechanism for rural EMS personnel and patients. Procedures for advanced airway management and ultrasound diagnosis may someday be managed using a remote telepresence.

Toward optimal recording of surgical complications: concurrent tracking compared to the discharge data set.

BACKGROUND: Information extracted from the hospital discharge data set is used increasingly for outcomes research and for benchmarking hospital and provider performance. The accuracy of these data in detecting vascular complications has never been validated. METHODS: We compared morbidity and mortality data derived from the hospital discharge data set to similar data recorded concurrently by our Surgical Activity Tracking System (SATS) for 1 year on the vascular surgery service. RESULTS: Of 798 total admissions, no complications were detected by either system in 598 admissions (75%). In 200 admissions (25%), there were 335 complications, including 24 deaths (3.0%), that occurred either in-hospital or within 30 days of the date of operation or the date of discharge for nonoperative admissions. Of the 335 complications, 180 (53.7%) were recorded by both systems; the SATS missed 59 complications recorded in the hospital discharge data set (17.6%), whereas the hospital discharge data set missed 96 complications recorded in the SATS (28.7%, P = .003). Of the 289 in-hospital complications, the SATS recorded 230 (79.5%), whereas the hospital discharge data set recorded 229 (79.2%). Of the 24 deaths, the hospital discharge data set missed 6 that occurred after discharge but within the 30-day reporting period CONCLUSIONS: Both systems are not completely accurate for tracking inpatient complications. The SATS was more representative than the hospital discharge data set in capturing 30-day morbidity and mortality. An amalgamation of the 2 systems would provide more optimal tracking of complications.

In vitro evaluation of multiobjective hemodynamic control of a heart-assist pump.

Ventricular assist devices now clinically used for treatment of end-stage heart failure require responsive and reliable hemodynamic control to accommodate the continually changing demands of the body. This is an essential ingredient to maintaining a high quality of life. To satisfy this need, a control algorithm involving a trade-off between optimal perfusion and avoidance of ventricular collapse has been developed. An optimal control strategy has been implemented in vitro that combines two competing indices: representing venous return and prevalence of suction. The former is derived from the first derivative of diastolic flow with speed, and the latter derived from the harmonic spectra of the flow signal. The responsiveness of the controller to change in preload and afterload were evaluated in a mock circulatory simulator using a HeartQuest centrifugal blood pump (CF4b, MedQuest Products, Salt Lake City, UT). To avoid the need for flow sensors, a state estimator was used, based on the back-EMF of the actuator. The multiobjective algorithm has demonstrated more robust performance as compared with controllers relying on individual indices.

Relation of augmented platelet reactivity to the magnitude of distribution of atherosclerosis.

The extent of luminal involvement of atherosclerotic vascular disease and platelet reactivity portend subsequent cardiovascular events. This study was designed to determine whether platelet reactivity correlates with the extent of the territorial distribution of vascular disease. Blood was obtained from 130 patients who had known atherosclerotic vascular disease categorized as being in > or =1 of the following territories: coronary artery disease (CAD; n = 89), cerebrovascular disease (n = 36), and peripheral arterial disease (n = 61). Platelet reactivity, i.e., the activation of platelets in response to a low concentration of adenosine diphosphate (0.2 micromol/L), was measured using flow cytometry. Patients with vascular disease in >1 territory compared with those with disease in only 1 territory had greater platelet reactivity with respect to P-selectin expression (p = 0.01). The percentages of platelets expressing P-selectin (mean +/- SD) were 6.4 +/- 4.2 in patients who had involvement of 1 territory (n = 88), 10.0 +/- 6.8 in those who had involvement of 2 territories (n = 28), and 10.1 +/- 9.9 in those who had involvement of 3 territories (n = 14). Patients who had CAD and diabetes mellitus had greater P-selectin expression than did those who had CAD without diabetes (p <0.02 for interaction). Thus, platelet reactivity is greater in patients who have more extensive territorial distribution of atherosclerotic vascular disease and in those who have CAD and diabetes mellitus. Accordingly, patients who have more widely distributed vascular disease are likely to derive particular benefit from antiplatelet regimens that suppress platelet function to a greater extent.

Documentation of competency: Maintaining an outcomes database.

Medical practice in the 21st century will include increased scrutiny of the competency of vascular surgeons measured in large part by treatment outcomes. At least part of the drive behind this is that the public demand for clinical competency of its doctors is greater than ever as the unassailable position of the "all-knowing physician" is (appropriately) vanishing. Two general types of variables need to be considered in the assessment of treatment outcomes: key outcome variables and key process variables. Key outcome variables are the critical results from a treatment plan, whereas key process variables affect these results. Ideal tracking methods do not exist in most hospital systems, and many variables are out of the control of the individual surgeon. Difficulties recording and reporting outcomes and determining competencies are numerous, but vascular surgeons must accept and overcome these difficulties. Standardized definitions for preoperative, surgical, and postoperative variables as well as treatment results must be decided before attempting to determine competency. Once the variables and definitions to define competency are determined, commercially available computer software can make the task of data recording and data output realistic. Eventually, systemwide "enterprise" solutions from computer companies will make this task even more uncomplicated.

Advances in haplo-identical stem cell transplantation in adults with high-risk hematological malignancies.

Allogeneic bone marrow transplant is a life-saving procedure for adults and children that have high-risk or relapsed hematological malignancies. Incremental advances in the procedure, as well as expanded sources of donor hematopoietic cell grafts have significantly improved overall rates of success. Yet, the outcomes for patients for whom suitable donors cannot be found remain a significant limitation. These patients may benefit from a hematopoietic cell transplant wherein a relative donor is fully haplotype mismatched. Previously this procedure was limited by graft rejection, lethal graft-versus-host disease, and increased treatment-related toxicity. Recent approaches in haplo-identical transplantation have demonstrated significantly improved outcomes. Based on years of incremental pre-clinical research into this unique form of bone marrow transplant, a range of approaches have now been studied in patients in relatively large phase II trials that will be summarized in this review.