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Wednesday, October 26, 2016

Viewpoint: Estimating deaths due to medical error: the ongoing controversy and why it matters

open access
 Published Online First 12 October 2016 

One important reason for the widespread attention given to the 1999 US Institute of Medicine (IOM) report To Err Is Human1 lie in its estimate that medical error was to blame for 44 000–98 000 deaths each year in the US hospitals. This striking claim established patient safety as a public concern, strengthened the case for improving the science underlying safety and motivated providers, policymakers, payers and regulators to take safety seriously. Some did express disquiet about the validity of the figures cited,2 including one of the principal investigators of the two studies that provided the data for these estimates.3
A decade and a half later, Makary and Daniel4 attribute an even higher toll to medical error: 251 454 deaths in US hospitals per year, making, they say, medical error the third-leading cause of death in the USA. Unsurprisingly, this claim generated widespread coverage in multiple media channels. It also ignited scientific controversy about the basis of the estimate and the role of mortality as a patient safety indicator (PSI). In this paper, we address this controversy and why it matters. We propose that the new estimate is very likely to be wrong. Not only is it wrong, it risks undermining rather than strengthening the cause of patient safety.

The new paper is not a study

Though the paper by Makary and Daniel was widely cited as ‘a study’, it presented no new data nor did it use formal methods to synthesise the data it used from previous studies. The authors simply took the arithmetic average of four estimates since the publication of the IOM report, including one from HealthGrades,5 a for-profit company that markets quality and safety ratings, a report from the US Office of the Inspector General (OIG)6 and two peer-reviewed articles (table 1).7 ,8 The paper did not apply any established methodology for quantitative synthesis nor did it include a discussion either of the intrinsic limitations of the studies used or of the errors associated with the extrapolation process......

NICE recommends screening for Lynch syndrome

pharma news
October 24, 2016
In new draft guidelines, the Institute says that testing all people with colorectal cancer for the condition will help identify whether the patient's family may also be at increased risk of cancer.

(media) Tennessee: Rees Skillern Cancer Institute Achieves Full Membership To The Lynch Syndrome Screening Network - Chattanoogan.com


(platinum resistant) Lead Researcher Discusses Promising Antibody-Drug Conjugate for Ovarian Cancer (PF-06647020)

 October 25, 2016
Results from an expansion cohort of a preliminary clinical trial have shown encouraging activity for a novel antibody-drug conjugate in patients with heavily pretreated advanced ovarian cancer.

The antibody-drug conjugate, PF-06647020, targets the protein tyrosine kinase 7 (PTK7) in these patients. PTK7 has several functions in developmental biology, including Wnt signaling and planar cell polarity. The enzyme is overexpressed in a variety of human cancers, including ovarian, breast, colon, lung, gastric, and esophageal, as well as in acute myeloid leukemia.

Six of 22 evaluable patients in the current expansion cohort responded to PF-06647020, including 1 complete response, and an additional 12 patients had stable disease. Some responses were durable, ranging from 6 to 10 months’ duration.....

OncLive: Could you provide an overview of the data you presented at ESMO?

Sachdev: This is an initial phase I exploration of an antibody-drug conjugate molecule in the clinic. It started with the traditional dose escalation design which was for patients with advanced solid tumors. And then there were preplanned expansion groups for breast cancer, non–small cell lung cancer and ovarian cancer.

The data we presented were from the expansion group for ovarian cancer, specifically, platinum-resistant ovarian cancer patients. The data from the dose escalation part were actually presented at last year’s ESMO in 2015. And once we reached our recommended phase II dose, then the planned expansions were undertaken. So today, we presented data for the 27 patients who were in the ovarian cancer expansion arm.....

AstraZeneca’s Lynparza shows significant PFS benefit in ovarian cancer patients - (Pharma)

Pharmaceutical Business Review

Ovarian cancer risks for women (media/Cleveland Clinic interview)

Ovarian cancer risks for women

Psychological Stress and Chronic Illness Among (childhood) Survivors of Cancer

medical news
The authors do not seriously discuss whether these psychological issues are related to cancer diagnosis and treatment, and may themselves be causal factors of the noted physical ailments.

  1. Vuotto SC, Krull KR, Li C, et al. Impact of chronic disease on emotional distress in adult survivors of childhood cancer: a report from the childhood cancer survivor study. Cancer. 2016 Oct 20. doi: 10.1002/cncr.30348 [Epub ahead of print]
  2. Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the Childhood Cancer Survivor Study. J Clin Oncol. 2014;32:1218-1227.

(Italy) Is Ovarian Cancer Being Managed According to Clinical Guidelines

Background: In the northwestern Italian region of Piedmont, current statistics on hospitalizations show that surgical treatment for ovarian cancer (OC) is taking place in many small hospitals, as opposed to a more centralized approach. A population-based clinical audit was promoted to investigate whether OC is being managed according to clinical guidelines, identify determinants of lack of adherence to guidelines, and evaluate the association between adherence to guidelines and survival.
Patients and Methods: Residents diagnosed with OC in 2009 were identified in the regional hospital discharge records database. All hospitalizations within 2 years from diagnosis were reviewed. Patients were classified according to their initial pattern of care, defined as “with curative intent” (CIPC) if including debulking surgery aimed at maximal cytoreduction. Adherence to guidelines for surgery and chemotherapy and the effects of this adherence on OC survival were investigated with logistic regression and Cox models.
Results: The final study sample consisted of 344 patients with OC, 215 (62.5%) of whom received CIPC. Increasing age, comorbidities, and metastases were negatively associated with receiving CIPC. In the CIPC group, surgical treatment was adherent to guidelines in 35.2%, whereas chemotherapy was adherent in 87.8%. Surgical treatment that was adherent to guidelines [hazard ratio (HR), 0.72] and absence of residual tumor (HR, 0.55) were associated with better survival in the CIPC group, and chemotherapy that was adherent to guidelines was associated with a significant reduction in the risk of death (HR, 0.49).
Conclusions: Results support the need to reorganize the clinical pathway of patients with OC in the Piedmont Region and the need for better adherence to current guidelines.

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population


 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.

[Clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma: an analysis of 368 radical nephroureterectomy specimens].

abstract: (China)
[Clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma: an analysis of 368 radical nephroureterectomy specimens].

 Conclusions: Chinese UTUC reveals its unique epidemiology. UTUC more commonly occurs in women and has a similar incidence between the renal pelvic and ureteral carcinoma. Patients with history of renal transplantation are prone to detect UTUC through physical examination rather than hematuria.....

Differences in survival for patients with familial and sporadic cancer.


Family history of cancer is a well-known risk factor but the role of family history in survival is less clear. The aim of this study was to investigate the association between family history and cancer survival for the common cancers in Sweden. Using the Swedish population-based registers, patients diagnosed with the most common cancers were followed for cancer-specific death during 1991-2010. We used multivariate proportional hazards (Cox) regression models to contrast the survival of patients with a family history of cancer (individuals whose parent or sibling had a concordant cancer) to the survival of patients without a family history. Family history of cancer had a modest protective effect on survival for breast cancer (hazard ratio (HR) = 0.88) and prostate cancer (HR = 0.82). In contrast, family history of cancer was associated with worse survival for nervous system cancers (HR = 1.24) and ovarian cancer (HR = 1.20). Furthermore, the poorer survival for ovarian cancer was consistent with a higher FIGO stage and a greater proportion of more aggressive tumors of the serous type. The better survival for patients with a family history of breast and prostate cancer may be due to medical surveillance of family members. The poor survival for ovarian cancer patients with an affected mother or sister is multifactorial, suggesting that these cancers are more aggressive than their sporadic counterparts. 

Reimagining hospice care — for the living

Reimagining hospice care — for the living

November Index: International Journal of Gynecological Cancer

Current Issue (not an open access journal)

open access: Cutaneous metastases from adenocarcinoma of the ovary (breast cancer rash...)

open access - case report/review

Case report

A 24-year-old Hispanic woman presented with a 3-month history of painful, pruritic, progressive rash localized to both breasts. Her medical history was significant for refractory metastatic stage IIIB mucinous adenocarcinoma of the ovary diagnosed 10 months before appearance of the rash..... The patient was discharged home to hospice care and died 4 months after appearance of the rash.


Cutaneous metastasis is an uncommon manifestation of internal malignancy. Spread of a primary tumor to the skin typically occurs late in the course of disease but may be the presenting sign of underlying cancer.....
Our case is one example of the many unusual presentations of cutaneous metastatic ovarian cancer.

CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis


 Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival. We performed immunohistochemistry on 207 tumors [clear cell carcinoma (n=120), endometrioid carcinoma (n=49), and seromucinous tumors (n=38)], followed by two-color fluorescence in situ hybridization (n=88) and compared with ARID1A expression and hTERT promoter mutations in the same samples. Cyclin E1 overexpression and CCNE1 copy-number gain occurred in 23.3% and 14.8% of ovarian clear cell carcinomas, respectively, but they were not detected in any of the other endometriosis-related tumors. All cases with CCNE1 copy-number gain demonstrated an intense cyclin E1 immunoreactivity (P<0.001). Cyclin E1 overexpression was positively correlated with hTERT promoter mutations (P=0.01), but not with the loss of ARID1A expression. A multivariate analysis revealed that CCNE1 overexpression predicts poor overall survival, even after adjusting for stage and age. Specifically, CCNE1 overexpression and copy-number gain were both correlated with a poor outcome in patients with stage I disease. Moreover, the subset with CCNE1 overexpression and ARID1A retention demonstrated the worst outcome. Our findings suggest that gene copy-number gain and upregulation of CCNE1 occur in ovarian clear cell carcinoma and are associated with a worse clinical outcome, dictating the survival of early-stage patients, and that these molecular alterations are unique to clear cell carcinoma among different types of endometriosis-related ovarian neoplasms.Modern Pathology

When Clinical Care Depends on the Answer: The Challenges of Assessing Germline Cancer Gene Variants: Journal of Clinical Oncology: Vol 0, No 0

open access JCO

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening - changes Oct 21st



Evidence of Lack of Mortality Benefit Associated with Screening

Single-threshold cancer antigen 125 (CA-125) levels and transvaginal ultrasound (TVU)

There is solid evidence to indicate that screening women aged 55 to 74 years at average risk of developing ovarian cancer with the serum marker CA-125 (at a fixed threshold for a positive result of 35 U/mL) annually for 6 years and TVU for 4 years does not result in a decrease in ovarian cancer mortality, after a median follow-up of 14.7 years.
Magnitude of Effect: The ovarian cancer mortality rate was 3.8 deaths per 10,000 women in the screened group and 3.6 deaths per 10,000 person-years in the usual-care group, yielding a mortality rate ratio of 1.06 (95% confidence interval [CI], 0.87–1.30).[1]
  • Study Design: Evidence obtained from one randomized controlled trial.
  • Internal Validity: Good.
  • Consistency: One trial has evaluated the impact on mortality from ovarian cancer.
  • External Validity: Good.

Screening with TVU alone or with multimodal screening with CA-125 levels, assessed using the Risk of Ovarian Cancer Algorithm (ROCA), with TVU

Screening with TVU alone or with multimodal screening with CA-125 levels, assessed using the ROCA, combined with TVU in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) did not show a mortality benefit of screening with either approach based on a predetermined primary endpoint among women undergoing 7 to 11 screens and a median of 11.1 years of follow-up.[2]
Magnitude of Effect: Multimodal screening was associated with a nonsignificantly lower mortality than with no screening (15% lower mortality; 95% CI, -3% to 30%; P = .10). Ultrasound only screening also resulted in nonsignificantly lower mortality (11% lower mortality; 95% CI, -7% to 27%; P = .21).[2]
  • Screening complications were less than 1% for both TVU only and multimodality screening strategies.
  • Study Design: Evidence obtained from one randomized controlled trial.
  • Internal Validity: Good.
  • Consistency: One trial has evaluated the impact on mortality from ovarian cancer using this specific approach.
  • External Validity: Good—based on data from other studies assessing complementary endpoints.

Statement of Harms

Based on solid evidence, screening for ovarian cancer results in false-positive test results. Screened women had higher rates of oophorectomy and other minor complications such as fainting and bruising.
Magnitude of Effect:
  • Of screened women, 9.6% had false-positive results, resulting in 6.2% undergoing surgery. The surgical complication rate was 1.2% for all screened women.
  • Oophorectomy rates were 85.7 per 10,000 person-years among screened women and 64.2 per 10,000 person-years among usual-care women.
  • Minor complications with screening: 58.3 cases per 10,000 women screened with CA-125 and 3.3 cases per 10,000 women screened with transvaginal sonogram (TVS).
  • Study Design: Evidence obtained from one randomized controlled trial.
  • Internal Validity: Good.
  • Consistency: Not applicable (N/A).
  • External Validity: Good.
In the TVU-only arm of the UKCTOCS trial, there were 50 false-positive surgical procedures, and in the multimodality arm, there were 14 false-positive operations per 10,000 screens.[2]
In the general population, screening is targeted to postmenopausal women, and the major complications are related to surgery. Among younger women, the potential target group among BRCA1/2 mutation carriers, oophorectomy at younger than 45 years may increase mortality secondary to cardiovascular disease. Oophorectomy, if performed among younger women, may also reduce risk of estrogen receptor–positive breast cancers, which occur with elevated frequency among carriers of BRCA2 mutations.
  1. Buys SS, Partridge E, Black A, et al.: Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 305 (22): 2295-303, 2011. [PUBMED Abstract]
  2. Jacobs IJ, Menon U, Ryan A, et al.: Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 387 (10022): 945-56, 2016. [PUBMED Abstract]
  • Updated: October 21, 2016

Tuesday, October 25, 2016

Body weight changes in patients undergoing chemotherapy for ovarian cancer influence progression-free and overall survival | SpringerLink

Body weight changes in patients undergoing chemotherapy for ovarian cancer influence progression-free and overall survival 


The aim of this study was to evaluate whether body weight changes in patients undergoing chemotherapy for epithelial ovarian cancer (EOC) influence progression-free survival (PFS) and overall survival (OS).


An analysis of 190 patients diagnosed with ovarian cancer after first-line chemotherapy was conducted. Changes in body weight were assessed by comparing measurements at baseline to those of the third and sixth cycles of chemotherapy. PFS and OS were calculated with the Kaplan–Meier method and multivariate Cox model.


Significant reduction in body weight in advanced EOC was observed with no changes in early EOC. Significant differences in PFS were observed in advanced EOC patients that lost more than 5 % of their body weight (6 months), maintained weight (13 months), or gained more than 5 % of their body weight (15 months). Similarly, significant differences in OS were noted in advanced EOC at the following time points: 24.3, 42.4, and 66.2 months. No effect was reported for early EOC patients. The multivariate Cox analysis showed significant body weight changes from the first to the sixth chemotherapy cycle for PFS (HR = 0.97) and OS (HR = 0.94) as well as from the first to the third chemotherapy cycle for OS (HR = 0.93).


Body weight changes can be recognized as a prognostic factor for PFS and OS in advanced EOC patients undergoing chemotherapy. Weight loss is associated with poorer survival while weight gain improved outcomes.

open access: The epidemiologic status of gynecologic cancer in Thailand

JGO :: Journal of Gynecologic Oncology
 Fig. 1.
Top ten cancers in Thailand (female) (estimated), 2011 [4].

2. Ovarian cancer
The mean ovarian cancer incidence per annum is 6.0 per 100,000 females in 2011. Bangkok, Lamphun and Krabi province had the highest number of incidence comparing to other provinces (ASR=7.3), while the Northeastern region had the lowest number of new cases of ovarian cancer (ASR=4.4). The incidence of ovarian cancer increased from the age of 55 years onward. This shows that there is a later onset of the cancer compared to 1999 where the peak incidence was in the age group 40–65 [2]. The incidence can occur since very young age. Interestingly, the most common histological types of ovarian cancer in 2011 were serous carcinoma followed by mucinous carcinoma and endometrioid carcinoma. This showed a larger variation from the data in 1999 as the two most prevalent histological types were serous and mucinous cystadenocarcinoma [2]. The most common stage of ovarian cancer was local, followed by regional stage.