abstract
JAMA:Curing cancer has been a long-standing goal. What advances in the last 20 years and tools available today make it more feasible now to accomplish this goal?
Thursday, September 08, 2016
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population
abstract
Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.
Wednesday, September 07, 2016
open access: full text - Global trends and predictions in ovarian cancer mortality
Blogger's Note: previously posted as abstract
Global trends and predictions in ovarian cancer mortality
This Article
-
Ann Oncol (2016) doi: 10.1093/annonc/mdw306
- » AbstractFree
- Full Text (HTML)Free
- Full Text (PDF)Free
- Supplementary Data
Interview: (Dr Soon-Shiong) Surgeon, Scientist, and Entrepreneur: One Man’s Fight Against Cancer
JAMA interview/open access (Moonshot)
Dr Soon-Shiong:There are two issues. The first question is why haven't we cured cancer. I think the reason we haven't is because we were treating cancer based on wrong assumptions...
Cancer ‘moonshot’ panel names top 10 ways to speed progress against the disease +youtube
The Washington Post
The 10 ideas, which were developed by a blue-ribbon panel, dealt with an array of topics, including research, clinical trials, data mining, prevention and patient engagement.Youtube video (4 min)
Public Reporting of Hospital-Level Cancer Surgical Volumes in California (ovarian cancer not included in study)
abstract:
Public Reporting of Hospital-Level Cancer Surgical Volumes in California: An Opportunity to Inform Decision Making and Improve Quality
Methods: Hospital cancer surgery volumes for all California hospitals were calculated using ICD-9 coded hospital discharge summary data. Cancer surgeries included (bladder, brain, breast, colon, esophagus, liver, lung, pancreas, prostate, rectum, and stomach) were selected on the basis of a rigorous literature review to confirm sufficient evidence of a positive association between volume and mortality......
Results: In California in 2014, about 60% of surgeries were performed at top-quintile–volume hospitals, but the per-hospital median numbers of surgeries for esophageal, pancreatic, stomach, liver, or bladder cancer surgeries were four or fewer. At least 670 patients received cancer surgery at hospitals that performed only one or two surgeries for a particular cancer type; 72% of those patients lived within 50 miles of a top-quintile–volume hospital.
(NY) “Little Big Things”: A Qualitative Study of Ovarian Cancer Survivors and Their Experiences With the Health Care System
abstract:
“Little Big Things”: A Qualitative Study of Ovarian Cancer Survivors and Their Experiences With the Health Care System
Purpose: Navigation of
a complex and ever-changing health care system can be stressful and
detrimental to psychosocial well-being
for patients with serious illness. This study
explored women’s experiences with navigating the health care system
during treatment
for ovarian cancer.
Methods: Focus groups
moderated by trained investigators were conducted with ovarian cancer
survivors at an academic cancer center.
Personal experiences with cancer treatment,
provider relationships, barriers to care, and the health care system
were explored.
Sessions were audiotaped, transcribed, and coded
by using grounded theory. Subsequently, one-on-one interviews were
conducted
to further evaluate common themes.
Results: Sixteen
ovarian cancer survivors with a median age of 59 years participated in
the focus group study. Provider consistency,
personal touch, and patient advocacy positively
affected the care experience. Treatment with a known provider who was
well
acquainted with the individual’s medical history
was deemed an invaluable aspect of care. Negative experiences that
burdened
patients, referred to as the “little big
things,” included systems-based challenges, which were scheduling, wait
times, pharmacy,
transportation, parking, financial, insurance,
and discharge. Consistency, a care team approach, effective
communication,
and efficient connection to resources were
suggested as ways to improve patients’ experiences.
Conclusion:
Systems-based challenges were perceived as burdens to ovarian cancer
survivors at our institution. The role of a consistent,
accessible care team and efficient delivery of
resources in the care of women with ovarian cancer should be explored
further.
Two novel sequence variants in MSH2 gene in a patient who underwent cancer genetic counseling for a very early-onset epithelial ovarian cancer
abstract:
Two novel sequence variants in MSH2 gene in a patient who underwent cancer genetic counseling for a very early-onset epithelial ovarian cancer
- Article
- Abstract
- Background
- Methods
- Case presentation
- Discussion
- Conclusions
- Abbreviations
- Acknowledgements
- References
Discussion
Cancer
genetic counseling should be always offered during the work-up of young
patients with epithelial ovarian cancer, in order to screen the
presence of a hereditary syndrome and to improve the oncological
follow-up including intensified surveillance. Clinicians should be
particularly careful to the evaluation of a positive family history of
cancer, being ovarian cancer involved in three different syndromes, such
as site-specific, HBOC and Lynch Syndrome....
Conclusions
The present report finds out two unpublished sequence alterations in exon 11 of the MSH2
gene, one on which can be considered causative of Lynch phenotype.
Moreover, it stresses the importance of the multidisciplinary
onco-genetic counselling in order to correctly frame the hereditary
syndrome, suggest the right genetic test, and offer the most appropriate
management of the cancer risk for the patients and her family members.
Patient Focused Pathology Reports (patients as stakeholders = 0)
Blogger's Note: while this was part of a bladder cancer forum, the findings would apply to all cancers (patients/families)
Urology news
Dr. Mossonen gave a very interesting discussion regarding the interpretability of the pathology report to the true owner of the report… the patient. His research focuses around presenting information to the patient in a method in which the patient will understand, and be able to retain.
He presents his pilot study with Patient Centered care with regards to pathology reports with Bladder Cancer. Interestingly, his review of the literature in 5 most common cancers in men and women found that no literature identified the patient as a stakeholder of the pathology report.....
Editorial: Measuring the quality of cancer care in UK hospitals
The Lancet Oncology
...It is easy to call for greater transparency in the reporting of the quality of care, as politicians have done, and it is indeed laudable and necessary to do so. However, it is equally necessary to acknowledge the complexities and to avoid using single, misleading, metrics simply because they are available.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Linked Articles
Tuesday, September 06, 2016
sign the petition: Save Canada's public health care system! - SumOfUs
petition
Public health care is under attack. SumOfUs members have come forward in a HUGE way to raise thousands of dollars to defend it in the courts -- and we need your help again now to stand up for people over profits and save it.
This campaign couldn't be more personal. My mother is a breast cancer survivor. She received some of the best treatment and attention in the world under Canada’s health care system -- and never had to spend a dime to get it. And this legal challenge could put that all in jeopardy.
Dr. Brian Day, better known as “Dr. Profit,” has launched a reckless challenge to the B.C. Supreme Court aimed at allowing for-profit, U.S-style delivery of medically necessary services.
Thanks to the incredible support of SumOfUs members, we’re getting ready to hold a major press conference at the courthouse next week -- and we need your help to deliver a stack of petitions fatter than Dr. Day's profits.
Stand up for our health care system. Tell Dr. Brian Day to drop his dangerous and spurious lawsuit.
We know there’s room for improvement in our public health care system. But privatization is not the answer. Moving towards for-profit health care has been proven to increase costs, reduce safety, lengthen wait times and destabilize the public system.
Yet Dr. Day has been fighting to dismantle the Canadian public health care system for years. He barely lost the election to head the Doctors of BC two years in a row. His plan was to turn the organization into a vehicle for private health care lobbying. And he’s never been closer to privatizing our medical system than this moment.
If Dr. Day wins, all doctors will be able to charge unlimited amounts for publicly available services and big American insurance companies will be able to weasel their way into Canada. You better believe they’re licking their chops on the sidelines watching to see how this court case plays out.
Keep Canada’s public health care system public. Demand Cambie Surgeries drop the case.
At SumOfUs, we know how to protect public health care. Britain's public health care system has been under repeated assault from its right-wing government -- and 400,000 SumOfUs members have come together time and time again to defend it. Right here in Canada, we've demanded an end to for-profit blood plasma clinics. And we need to take action again to make sure we keep our health care system public and out of the grasp of people like Dr. Profit.
Add your voice now to protect public health care.
This Campaign was started by Emma Pullman -- Lead Digital Strategist at SumOfUs
More information
Federal government seeks intervenor status in B.C. health-care court case
Globe and Mail. 13 April 2016.
Globe and Mail. 13 April 2016.
The Legal Attack on Public Health Care
BC Health Coalition.
BC Health Coalition.
The Case
Save Canada's Public Health Care.
Save Canada's Public Health Care.
Phase 1: AZD1775 As Monotherapy/in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors
abstract:
Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors
Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient
tumor cells to DNA damage. This phase I study evaluated safety,
tolerability, pharmacokinetics, and pharmacodynamics
of oral AZD1775 as monotherapy or in combination
with chemotherapy in patients with refractory solid tumors.
Patients and Methods
In part 1, patients received a single dose of AZD1775 followed by 14
days of observation. In part 2, patients received AZD1775
as a single dose (part 2A) or as five twice per
day doses or two once per day doses (part 2B) in combination with one of
the
following chemotherapy agents: gemcitabine
(1,000 mg/m2), cisplatin (75 mg/m2), or carboplatin (area under the curve, 5 mg/mL⋅min). Skin biopsies were collected for pharmacodynamic assessments. TP53 status was determined retrospectively in archival tumor tissue.
Results Two hundred
two patients were enrolled onto the study, including nine patients in
part 1, 43 in part 2A (including eight
rollover patients from part 1), and 158 in part
2B. AZD1775 monotherapy given as single dose was well tolerated, and the
maximum-tolerated
dose was not reached. In the combination
regimens, the most common adverse events consisted of fatigue, nausea
and vomiting,
diarrhea, and hematologic toxicity. The
maximum-tolerated doses and biologically effective doses were
established for each
combination. Target engagement, as a predefined
50% pCDK1 reduction in surrogate tissue, was observed in combination
with
cisplatin and carboplatin. Of 176 patients
evaluable for efficacy, 94 (53%) had stable disease as best response,
and 17 (10%)
achieved a partial response. The response rate
in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33).
Conclusion AZD1775 was
safe and tolerable as a single agent and in combination with
chemotherapy at doses associated with target engagement.
Definition of WEE1 inhibitor AZD1775 - NCI Drug Dictionary
National Cancer Institute
- WEE1 inhibitor AZD1775
- A small molecule inhibitor of the tyrosine kinase WEE1 with potential antineoplastic sensitizing activity. AZD1775 selectively targets and inhibits WEE1, a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDK1, CDC2) to inactivate the CDC2/cyclin B complex. Inhibition of WEE1 activity prevents the phosphorylation of CDC2 and impairs the G2 DNA damage checkpoint. This may lead to apoptosis upon treatment with DNA damaging chemotherapeutic agents. Unlike normal cells, most p53 deficient or mutated human cancers lack the G1 checkpoint as p53 is the key regulator of the G1 checkpoint and these cells rely on the G2 checkpoint for DNA repair to damaged cells. Annulment of the G2 checkpoint may therefore make p53 deficient tumor cells more vulnerable to antineoplastic agents and enhance their cytotoxic effect. Check for active clinical trials using this agent. (NCI Thesaurus)
Addressing Administrative and Regulatory Burden in Cancer Clinical Trials: Summary of a Stakeholder Survey and Workshop Hosted by the ASCO/AACR
open access:
Addressing Administrative and Regulatory Burden in Cancer Clinical Trials: Summary of a Stakeholder Survey and Workshop Hosted by the American Society of Clinical Oncology and the Association of American Cancer Institutes
Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy
abstract:
Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy | Clinical Cancer Research
Purpose: Some forms of chemotherapy can enhance anti-tumor immunity through immunogenic cell death, resulting in increased T cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunological changes consistent with this possibility.
Methods: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n=90).
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