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Friday, June 8, 2018

Upfront MRI Could Rule Out Prostate Cancer in Most, Reduce Biopsy Need


Upfront use of biparametric magnetic resonance imaging (bpMRI), a more rapid and lower-cost version of multiparametric MRI, rules out almost all significant disease in men with suspected prostate cancer and thus would spare many from invasive biopsy, a new study indicated.
Among 1,020 men who underwent both bpMRI and standardized transrectal (TRUS) biopsy, low-suspicion bpMRI had a negative predictive value of 97% in ruling out significant prostate cancer (95% CI 95%-99%), reported Lars Boesen, MD, PhD, of Herlev Gentofte University Hospital in Denmark, and colleagues.
“The results suggest that bpMRI may be used as a triage test to exclude the presence of aggressive disease and avoid unnecessary biopsies with its inherent complications,” the investigators explained in JAMA Network Open.
Boesen’s group also found that restricting combined biopsies just to those with suspicious bpMRI findings meant 30% of men could avoid a TRUS biopsy. “Most of these men had low-risk disease qualifying for surveillance,” the authors noted.
Use of bpMRI also improved diagnoses of significant prostate cancer by 11% while insignificant prostate cancer diagnoses were reduced by 40% (P<0.001 for both endpoints). And this was done using fewer biopsy cores compared with standard TRUS biopsy alone. “If combined biopsies were restricted solely to patients with suspicious bpMRIs, only 8 men with significant prostate cancer would have been missed and significantly fewer men … with insignificant prostate cancer would have been diagnosed,” the authors observed.
The 715 men with suspicious bpMRI lesions underwent a targeted biopsy, and prostate cancer was detected in 67%, with clinically significant cancer found in 47% of the biopsied group. Standard TRUS biopsy detected prostate cancer in 63% of the men, and in 34% of them the cancer was significant.
Commenting on the study, Timothy Wilt, MD, MPH, and Philipp Dahm, MD, both of the University of Minnesota School of Medicine in Minneapolis, said that while the authors emphasized the sensitivity (98%) and negative predictive value (97%) of bpMRI, specificity (48%) and positive predictive values (56%) were less impressive.
They also point out that the rate of prostate cancer in the study seemed to be “extraordinarily high,” with a 40% rate of clinically significant disease. A more typical scenario in a standard U.S. practice would likely peg that risk at roughly 9% based on a standardized risk calculator, they said.
“For MRI-based triaging strategies to be cost-effective, patients and physicians must be willing to change management based on MRI findings,” Wilt and Dahm wrote. “The use of MRI will result in low-value rather than high-value care if patients with negative MRI findings … still undergo a biopsy or active surveillance imaging and if all men with MRI-defined clinically significant disease undergo radical interventions.”
The BIDOC (Biparametric MRI for Detection of Prostate Cancer) study required a clinical suspicion of prostate cancer in all participants as evidenced by either a prostatic-specific antigen (PSA) of 4.0 ng/mL or greater or an abnormal digital rectal exam that necessitated a diagnostic prostate biopsy. The median PSA level of the cohort was 8.0 ng/mL.
Clinically significant prostate cancer was defined as any high-grade prostate cancer (Gleason score 4+3 or maximum cancerous core length greater than 50% for Gleason 3+4). Prior to undergoing standard TRUS biopsy, men underwent bpMRI using a 3-T MRI magnet with a pelvic-phase-array coil positioned over the pelvis. All bpMRI images were reviewed by the same experienced radiologist, who was blinded to the clinical findings.
Patients also underwent standard 10-core extended sextant biopsies, and then any suspicious lesion detected by TRUS was sampled by a standard biopsy scheme. This was followed by targeted biopsies of any bpMRI suspicious lesions. Overall, 64% of the men had prostate cancer and 40% of them had significant prostate cancer.
Limitations of the study include the fact that it was carried out at a single center with a single dedicated radiologist reading the bpMRIs and two TRUS operators performing the biopsies.
The study was funded by the Beckett Foundation.
Boesen has received grants from the Beckett Foundation and fees from Sanofi-Aventis. Co-authors also reported relationships with industry.
Wilt and Dahm had no financial disclosures to make.
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CDC: 25% Rise in U.S. Suicides During 1999-2016


Rates of suicide rose by about 25% in the U.S. from 1999 to 2016, according to a new report from the CDC.
Additionally, over half of states saw an increase of over 30% over the past two decades — accounting for around 45,000 deaths in 2016 alone — according to a “Vital Signs” report.
The extent of this increase varied from state to state, with suicide rates rising across the country in all states except Nevada. North Dakota and and Vermont saw increases approaching or topping 50%. Not counting Nevada, Delaware saw the smallest increase at 5.9%.
“We don’t know for sure why the rates of suicide are increasing essentially across the board — across virtually all states and for both females and males,” Nadine Kaslow, PhD, of Emory University School of Medicine in Atlanta, explained to MedPage Today.
“Some reasons that people have concerned include the lack of adequate and accessible mental health services for everyone who is experiencing mental health problems and the limited social services for people with financial and employment challenges,” said Kaslow, who was not involved with the study.
“The CDC correctly points out that the suicide is multifactorial in its cause,” commented John Walkup, MD, of Ann and Robert H. Lurie Children’s Hospital of Chicago.
Although a public health approach to solving this is warranted, he explained to MedPage Today how tackling this issue is particularly difficult.
“Do you target suicide specifically or target the larger issues that contribute to suicide risk,” he questioned, suggesting how the greatest benefit will probably be seen by targeting those with risk factors for suicide in order to reduce suicide risk and morbidity on a larger scale due to reduction in risk factors. “For example, educating the public and screening teens for depression and engaging them in treatment will lower suicide risk and may be more universally beneficial than only referring for treatment those with positive suicide screens.”
CDC’s Findings
In their analysis, led by Deborah M. Stone, ScD, of the Division of Violence Prevention at the National Center for Injury Prevention and Control, and colleagues assessed suicide trends in all 50 states and Washington, D.C., from 1999 to 2016 among individuals 10 years and older.
Firearms were used in about half of suicides, making it by far the most common method. But increases were seen across all methods.
Notably, the report also found that 54% of people who died from suicide had no known mental condition, making it even more important for people to recognize the warning signs.
“What was striking to me as an anxiety disorder expert is the very low rate of reported anxiety disorders in the population of the deceased,” commented Walkup.
“This is especially important as untreated anxiety disorders are associated with suicidal behavior, poor educational outcome and problems transitioning to adulthood and substance use disorders. I think we are just beginning to understand the pathway from anxiety to suicide and much can be done to raise awareness that anxiety and depression contribute to suicide risk.”
Circumstances surrounding suicides were generally common among decedents with and without mental health conditions, the researchers found. The most common contributing factor being relationship problems, followed by life stressors, recent or impending crises, physical health problems, and substance abuse.
“While the CDC is correct to focus on known triggering events for a specific suicide it is important to note that those triggering events are ubiquitous in the US and not everyone who experiences economic duress, or relationship problems etc. is at risk for suicide,” Walkup warned. “Addressing those factors is important as it is directly relevant to the person in distress and the right thing to do.”
He continued, adding: “The flip side is the observation that is common in the suicide prevention literature. When common everyday events are linked to suicide in a causative way there are individuals who perceive such a link as “support or permission” for them to consider suicide. One of the problems with media portrayals of suicide is that it can support a person’s belief that suicide is logical outcome of economic distress or relationship problems. It is the reason people are concerned about media portrayals of suicide.”
Although methods of suicide were also generally similar between those with and without mental health conditions, those without any known mental health conditions were slightly more likely to die by a firearm (55% versus 41%). Among both groups, suffocation was the second most likely cause of death, followed by poisoning.
What Healthcare Providers Can Do
From a healthcare providers perspective, Daniel Dickstein, MD, of Bradley Hospital in Rhode Island, told MedPage Today it’s key that providers not be afraid to ask patients about suicide.
“It is really important for healthcare workers to try to encourage families to consider being part of a research study — because just as with cancer — such partnerships are the only way that the future will be brighter,” he encouraged. Dickstein also added when dealing with pediatric patients, it’s important to include parents in on the conversation, highlighting how suicide is the second leading killer of kids starting at age 10, all the way through young adulthood.
Men in particular may fall under the radar, warned Eric Caine, MD, of the University of Rochester Medical Center in New York, who said it’s men who typically don’t seek help, are less likely to share thoughts and feelings with others, and are also less prone to visits healthcare providers routinely.
“There is a substantial amount of work within healthcare systems, but it is most important to remember that most suicides occur in communities and most deaths happen with the first attempt,” he told MedPage Today.
Kaslow also suggested several steps to clinicians should bear in mind when talking with patients.
“First and foremost, [providers] should routinely ask people if they are feeling depressed, anxious, and or like hurting themselves. They also need to ask about substance use,” she explained. If patients respond affirmatively, providers should dive deeper and connect the patient with appropriate services.
She also recommended more integrated primary and specialty care, achieved by integrating behavioral health professions into various medical services. Providers should also readily have resources available for their patients who report mental health problem, such as crisis hotlines, mental health facilities and providers, apps and websites.
Dickstein agreed with this point, expressing that “more than ever, our healthcare system is fragmented,” adding that we all must work to improve access to mental healthcare, including tackling barriers such as lack of providers and lack of insurance coverage.
“All health professionals need to be trained in suicide assessment and prevention. This will enable them to be more comfortable talking to their patients about suicide and related topics,” Kaslow recommended.
None of the authors reported any conflicts of interest.
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Advaxis cuts staff as it seeks partner for troubled cancer vaccine


Just six weeks after taking the helm of biotech Advaxis, CEO Ken Berlin has launched a search for a partner for its stalled lead axalimogene filolisbac (AXAL) and will scale back trials of the immunotherapy in order to bring earlier stage programs forward. It will also eliminate almost a quarter of its workforce.
Berlin joined the company from Rosetta Genomics in April shortly after the FDA placed a clinical hold on a phase 1/2 study of AXAL in human papillomavirus-associated cancers—in combination with AstraZeneca’s PD-L1 inhibitor Imfinzi (durvalumab)—after a patient fatality. The trial was enrolling patients with both cervical and head-and-neck cancers, and the death was in a cervical cancer patient.
Advaxis says it will spend “a limited period of time” looking for a U.S. or European partner but, if it can’t find one, it will wind down an ongoing study in high-risk, locally advanced cervical cancer patients as well as a second planned trial in metastatic cervical cancer.

It will press ahead with head-and-neck cancer studies if it can find a cost-effective way to do so, but the net effect will be “a significant reduction in our spend on the HPV program,” according to Berlin. Advaxis will respond to the FDA’s concerns about the HPV trial shortly, he added.
That reduction means the company can accelerate plans to start clinical testing for two earlier-stage immunotherapies—ADXS-HOT and Amgen-partnered ADXS-NEO—which both target cancer neoantigens and are designed to stimulate T cells to attack tumor cells. Advaxis reckons they have potential applications across multiple tumor types, but the first ADXS-HOT candidate will be tested in non-small cell lung cancer. Trials of both will get underway this year and will generate data beginning in 2019.
“It is important that we allocate capital to invest in these programs in order to realize their potential, but this also requires us to reduce investments in other programs,” said Berlin on a conference call. “The HPV program is important to us, but we must be realistic about what we can and cannot develop on our own.”
Advaxis reported data from another immunotherapy candidate, ADXS-PSA, in prostate cancer at ASCO this year and says that the combination with Merck & Co’s PD-1 inhibitor Keytruda (pembrolizumab) is worthy of “further evaluation.” It will follow patients for another six to nine months before deciding on a path forward.
The ASCO trial showed evidence of “an early clinical signal in extending survival among patients,” according to Advaxis new chief medical officer Andres Gutierrez, M.D., Ph.D., who joined the firm at the same time as Berlin.
Shares in the company rose 11% in the wake of the announcement, which coincided with Advaxis’ second-quarter results statement, suggesting investors were happy with Berlin’s decisions. The company posted a net loss of just over $13 million in the three-month period, ending it with cash reserves of around $59 million.
The headcount reduction and rejigged R&D portfolio means that Advaxis has operating funds for at least one year, according to the company.
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Autolus, Magenta, MeiraGTx make 3 more biotech IPOs


Three clinical-stage biotechnology companies announced initial public offerings (IPOs) today. Here’s a summary.
Autolus Therapeutics Limited
The clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies says it has begun the roadshow for its initial public offering in the United States of up to 7,812,500 American Depositary Shares (“ADSs”) representing 7,812,500 ordinary shares. The initial public offering price is currently expected to be between $15.00 and $17.00 per ADS, before underwriting discounts and commissions, which would result in an approximate total offering size of between $117.2 million and $132.8 million. The company, which will soon be reorganized as Autolus Therapeutics plc, also expects to grant the underwriters a 30-day option to purchase up to an additional 1,171,875 ADSs at the initial public offering price after underwriting discounts and commissions. Using a broad suite of proprietary and modular T cell programming technologies, the company engineers precisely targeted, controlled and highly active T cell therapies designed to better recognize cancer cells, break down their defense mechanisms and eliminate these cells. Autolus has a pipeline of product candidates in development for the treatment of hematological malignancies and solid tumors. All ADSs to be sold in the proposed offering will be sold by Autolus, which has applied to list its ADSs on the Nasdaq Global Market under the ticker symbol “AUTL.”
Book running managers: Goldman Sachs & Co. LLC and Jefferies LLC.
Lead managers: Wells Fargo Securities, LLC and William Blair & Company, LLC.
Based in Cambridge, MA, Magenta is offering 6,666,667 shares of its common stock, subject to market and other conditions, and intends to grant the underwriters a 30-day option to purchase up to an additional 1,000,000 shares of common stock. The company develops therapeutics focused on critical areas of unmet need in the field of bone marrow transplant for patients with autoimmune diseases, blood cancers and genetic diseases. All shares to be sold in the proposed offering will be offered by Magenta. The initial public offering price is currently expected to be between $14.00 and $16.00 per share. Magenta has applied to list the shares on the NASDAQ Global Market under the symbol “MGTA.”
Book running managers: J.P. Morgan, Goldman Sachs & Co. LLC and Cowen.
Lead manager: Wedbush PacGrow.
MeiraGTx Holdings plc
The clinical stage gene therapy company is offering an IPO of 5,000,000 ordinary shares at a public offering price of $15.00 per share, for total gross proceeds of approximately $75.0 million. In addition, the company has granted the underwriters a 30-day option to purchase up to 750,000 additional ordinary shares from the company at the initial public offering price, minus the underwriting discounts and commissions. Headquartered in New York and London, MeiraGTx is a clinical-stage gene therapy company focused on developing potentially curative treatments for patients living with serious diseases. They currently have four ongoing clinical programs, including three ocular indications and a salivary gland condition. Trading is expected to begin today on the Nasdaq Global Select Market under the ticker symbol “MGTX.” The offering is expected to close on June 12, 2018, subject to customary closing conditions.
Book running managers: BofA Merrill Lynch, Barclays and Evercore ISI.
Lead manager: Chardan.
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LeMaitre started at buy by Roth


LeMaitre resumed with a Buy at Roth Capital. Roth Capital analyst Scott Henry resumed coverage of LeMaitre Vascular with a Buy rating and $38 price target, as he expects resumed sales-force expansion to drive organic growth in the near-term and thinks the company’s Reddick divestiture could help fund an acquisition, which could be a catalyst.
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AxoGen rivals ‘not a real threat’: Jefferies


AxoGen competition just noise, not a real threat, says Jefferies. After hosting management at his firm’s conference, Jefferies analyst Raj Denhoy says “all seems to be going the right direction” for AxoGen (AXGN). Not only is surgeon acceptance of the company’s nerve repair products growing but there is more product being used per procedure, Denhoy tells investors in a research note. Further, he believes questions on competition are just noise and not a real threat. The analyst remains skeptical that Integra LifeSciences (IART) “can do much to slow” AxoGen’s momentum. Denhoy keeps a Buy rating on AxoGen with a $45 price target.
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TapImmune raises $70M in a private placement


The private placement will be led by New Enterprise Associates (NEA) with participation from Aisling Capital and Perceptive Advisors, among other new and existing investors. TapImmune will issue 17,500,000 shares of its common stock at a price of $4.00 per share. The aggregate offering size, before deducting the placement agent fees and other offering expenses, is expected to be $70 million. Additionally, TapImmune will issue warrants to purchase 13,125,000 shares of TapImmune common stock at an exercise price of $5.00 per share that will be exercisable for a period of five years from the date of issuance.
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