Target Cancer

[Michael Scally MD]

Cancer mortality often results from metastatic disease and is not the direct effect of the primary tumor. With advances in cancer treatment, control of the primary tumor can be managed by multimodal therapy; however, metastatic disease is frequently refractory to the same therapeutic approaches. Thus, identification of biomarkers that could accurately predict future metastasis from the state of the primary tumor would be invaluable for guiding therapy.

Currently, determination of the likelihood of developing metastatic disease is based on morphological and histological criteria such as the size of the primary tumor, local invasion, tumor differentiation together with vascular and capsular invasion, and the presence of cancer cells in lymph nodes. Although these criteria put many patients in a very high-risk category for metastatic disease, a significant number of them do not develop metastatic spread. On the other hand, patients with favorable conventional prognostic factors may still develop metastasis.

Researchers have found a compound that tumors make when they are likely to spread, and said they hope to use to it predict which patients are most at risk of dying from their cancers.


Lee TK, Murthy SRK, Cawley NX, et al. An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers. The Journal of Clinical Investigation. Journal of Clinical Investigation -- An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-?N) that drives metastasis. mRNA encoding CPE-?N was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-?N was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9) — which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-?N in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-?N mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-?N induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients.

 

[Michael Scally MD]

Re: OnLine First

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the tumor microenvironment. Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.


Hanahan D, Weinberg Robert A. Hallmarks of Cancer: The Next Generation. Cell 2011;144(5):646-74. http://download.cell.com/pdf/PIIS0092867411001279.pdf?intermediate=true

This illustration encompasses the six hallmark capabilities originally proposed in our 2000 perspective. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark.

 

[Michael Scally MD]

Studies Question Cancer Treatment's Cost-Effectiveness

According to a study in the Journal of Clinical Oncology, humanized monoclonal antibody "bevacizumab (Avastin) is not cost-effective for patients with advanced ovarian cancer." Data suggested that the "so-called incremental cost-effectiveness ratio for the drug is in excess of $400,000 per patient." Meanwhile, another study in the same issue found that bevacizumab "modestly slowed progression in women with metastatic breast cancer." The researchers reviewed data from the "Gynecologic Oncology Group 218 study," reported last year at the American Society of Clinical Oncology meeting, and found that progression-free survival went "from 10.3 months for the standard regimen to 11.2 months when bevacizumab was added" and to 14.3 months when the maintenance therapy was also included.


Hensley ML. Big Costs for Little Gain in Ovarian Cancer. Journal of Clinical Oncology. http://jco.ascopubs.org/content/early/2011/03/07/JCO.2010.34.0489.full.pdf


Cohn DE, Kim KH, Resnick KE, O'Malley DM, Straughn JM. At What Cost Does a Potential Survival Advantage of Bevacizumab Make Sense for the Primary Treatment of Ovarian Cancer? A Cost-Effectiveness Analysis. Journal of Clinical Oncology. At What Cost Does a Potential Survival Advantage of Bevacizumab Make Sense for the Primary Treatment of Ovarian Cancer? A Cost-Effectiveness Analysis

Purpose To determine whether the addition of bevacizumab to paclitaxel and carboplatin for the primary treatment of advanced ovarian cancer can be cost effective.

Methods A cost-effectiveness analysis compared the three arms of the Gynecologic Oncology Group (GOG) 218 study (paclitaxel plus carboplatin [PC], PC plus bevacizumab [PCB], and PCB plus bevacizumab maintenance [PCB+B]). Actual and estimated costs of treatment plus the potential costs of complications were established for each strategy. Progression-free survival (PFS) and bowel perforation rates were taken from recently reported results of GOG 218. Sensitivity analysis was performed for pertinent uncertainties in the model. Incremental cost-effectiveness ratios (ICERs) per progression-free life-year saved (PF-LYS) were estimated.

Results For the 600 patients entered onto each arm of GOG 218 at the baseline estimates of PFS and bowel perforation, the cost of PC was $2.5 million, compared with $21.4 million for PCB and $78.3 million for PCB+B. These costs led to an ICER of $479,712 per PF-LYS for PCB and $401,088 per PF-LYS for PCB+B. When the cost of bevacizumab was reduced to 25% of baseline, the ICER of PCB+B fell below $100,000 per PF-LYS. ICERs were not substantially reduced when the perforation rate was equal across all arms.

Conclusion The addition of bevacizumab to standard chemotherapy in patients with advanced ovarian cancer is not cost effective. Treatment with maintenance bevacizumab leads to improved PFS but is associated with both direct and indirect costs. The cost effectiveness of bevacizumab in the adjuvant treatment of ovarian cancer is primarily dependent on drug costs.

 

[Michael Scally MD]

Coffee Consumption And Risk Of Cancers

Coffee is one of the most widely consumed beverages in the world, with a yearly world average consumption of 1.1 kg per capita, which reaches 4.5 kg in industrialized countries. More recently, coffee consumption has been associated with reductions in the risk of several chronic diseases, including type 2 diabetes mellitus, Parkinson’s disease and hepatocellular disease. Among them, the relationship between coffee drinking and cancer risk holds great interest. Roasted coffee is a complex mixture of more than a thousand chemicals. Many constituents in it could potentially alter cancer risk through several biological mechanisms. Coffee is the major source of caffeine which has been reported to both stimulate and suppress tumors, depending upon the species and the phase of administration. There are two specific diterpenes in coffee, cafestol and kahweal, which produce biological effects compatible with anticarcinogenic properties, including the induction of phase II enzymes involved in carcinogen detoxification, specific inhibition of the activity of phase I enzyme responsible for carcinogen activation and stimulation of intracellular antioxidant defence mechanisms. Polyphenols are an important ingredient in coffee, such as lignan phytoestrogens and flavonoids and polyphenols are found to exhibit anticarcinogenic properties in several studies. Caffeic acid has the ability to inhibit DNA methylation in cultured human cancer cells and is associated with inactivation of various pathways involved in the tumorigenic process, including cell cycle regulation, inflammatory and stress response and apoptosis. Coffee is also a major source of the chlorogenic acid that contributes to its antioxidant effect. Intake of chlorogenic acid has been shown to reduce glucose concentrations in rats and intake of quinides, degradation products of chlorogenic acid, increases insulin sensitivity. Chronic hyperinsulinemia and insulin resistance are confirmed markers of high risk for some cancer sites.

Over the last 4 decades, a number of epidemiologic studies (over 500 papers) have estimated the associations between coffee consumption and cancer occurrence at various sites. However, their results were inconsistent. In 2007, the World Cancer Research Fund (WCRF) conducted a comprehensive analysis of diet and cancer, using a more standardized approach to review the evidence. This report addressed the significant relationships between coffee and risk of pancreatic and kidney cancer. In fact, epidemiologic studies have been published relating coffee intake to cancers of 11 different organ sites. Data from case-control studies may be subject to recall bias with respect to coffee consumption and selection bias with respect to the control group. Additional prospective cohort studies excluding those biases would be more useful to see coffee-cancer associations. In this report, researchers systematically reviewed and performed a meta-analysis of prospective cohort studies to quantitatively assess the association between coffee intake and cancer risk in human. Because of the high consumption of coffee, even small effects on cancer occurrence in persons could have a large impact on public health.


Yu X, Bao Z, Zou J, Dong J. Coffee consumption and risk of cancers: a meta-analysis of cohort studies. BMC Cancer 2011;11(1):96. http://www.biomedcentral.com/content/pdf/1471-2407-11-96.pdf

BACKGROUND: Coffee consumption has been shown to be associated with cancer of various sites in epidemiological studies. However, there is no comprehensive overview of the substantial body of epidemiologic evidence.

METHODS: We searched MEDLINE, EMBASE, Science Citation Index Expanded and bibliographies of retrieved articles. Prospective cohort studies were included if they reported relative risks (RRs) and corresponding 95% confidence intervals (CIs) of various cancers with respect to frequency of coffee intake. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with 1 cup/day increment of coffee consumption.

RESULTS: 59 studies, consisting of 40 independent cohorts, met the inclusion criteria. Compared with individuals who did not or seldom drink coffee per day, the pooled RR of cancer was 0.87 (95% CI, 0.82-0.92) for regular coffee drinkers, 0.89 (0.84-0.93) for low to moderate coffee drinkers, and 0.82 (0.74-0.89) for high drinkers. Overall, an increase in consumption of 1 cup of coffee per day was associated with a 3% reduced risk of cancers (RR, 0.97; 95% CI, 0.96-0.98). In subgroup analyses, we noted that, coffee drinking was associated with a reduced risk of bladder, breast, buccal and pharyngeal, colorectal, endometrial, esophageal, hepatocellular, leukemic, pancreatic, and prostate cancers.

CONCLUSIONS: Findings from this meta-analysis suggest that coffee consumption may reduce the total cancer incidence and it also has an inverse association with some type of cancers.

 

[Michael Scally MD]

Scientific Progress Spurs Research Into Record Number of Cancer Medicines
http://finance.yahoo.com/news/Scientific-Progress-Spurs-bw-763381909.html?x=0&.v=1
http://www.phrma.org/sites/default/files/1000/medicinesindevelopmentcancer2011_0.pdf

Source: PhRMA
April 5, 2011

WASHINGTON--(BUSINESS WIRE)-- A record 887 medicines for various of cancers are in clinical trials or awaiting Food and Drug Administration (FDA) review—well over double the number in the pipeline just six years ago, according to a report unveiled today by the Pharmaceutical Research and Manufacturers of America (PhRMA).

When PhRMA released its first accounting of medicines in development for cancer in 1988, only 65 were recorded. The numbers over the next decade grew gradually. As recently as 2005, there were fewer than 400 medicines in development for cancer.

“Unprecedented insights into how cancer cells develop, grow and spread are providing new targets and new ways of attacking the disease,” said John J. Castellani, PhRMA’s president and CEO, explaining the increase. “Rapidly advancing technologies and the commitment of researchers to follow new clues are providing hope.”

One promising development is the increased understanding about the many ways a tumor can protect and feed itself by co-opting the body’s own mechanisms, for example by reducing the efficacy of the immune system and by proliferating the growth of blood vessels, said Garry Neil, M.D., corporate vice president of science and technology at Johnson & Johnson. Dr. Neil is also chair of PhRMA’s Science and Regulatory Affairs Executive Committee.

Other remarkable new developments in cancer research include a better understanding of the key role that cancer stem cells play in resistance to chemotherapy, and the interplay between cancer cells and the supporting tissue that surround them, said Scott Waldman, M.D., Ph.D., of the Kimmel Cancer Center.

Biomarkers, Waldman added, are increasing researchers’ ability to predict and to understand the body’s response to new therapies. [related video] Dr. Waldman was recognized this year by the PhRMA Foundation for his breakthrough work on colorectal cancer.

He and Dr. Neil also pointed to advanced gene sequencing that is revealing the genetic basis of cancer and leading to opportunities for personalized medicine. Not only has genetic sequencing become available to many more researchers, but it has advanced into “next generation” and “multiplexed deep sequencing.”

Combination therapies, which were so successful in fighting HIV/AIDS, also represent an important step in cancer treatment, said Dr. Neil.

“As we develop the ability to block, with precision, the drivers of tumor growth, we must also block the escape mechanisms facilely used by these cells,” Neil said. Regulatory agencies, he added, are recognizing the need to simplify the testing of multiple medicines in development in order to realize this potential breakthrough.

Although five-year survival rates have increased across cancers since 1975—and have increased dramatically for breast, prostate, colon, rectum and lung cancer—the disease remains a leading cause of death.

Asked where we now stand in the battle against cancer, Dr. Neil quoted Winston Churchill, speaking in the late fall of 1942: “This is not the end. It is not even the beginning of the end…”

However, against a backdrop of new tools and a scientifically-based set of rules, Dr. Neil added, “We are hopefully moving to the beginning of the end for many cancers.”‹

 

[Michael Scally MD]

Cellular Respiration and Carcinogenesis. Apte, Shireesh; Sarangarajan, Rangaprasad (Eds.). 2009. http://xa.yimg.com/kq/groups/16749867/83122657/name/Cellular+Respiration+and+Carcinogenesis.pdf

Cellular Respiration and Carcinogenesis informs the reader about both basic and recent research in the field of cellular respiration and the effects of its dysfunction, alteration or attenuation on the development of cancer. This masterfully compiled text by leading experts in the field, offers the reader a fundamental understanding about how oxygen sensing and/or availability, programmed cell death, immune recognition and response and glucose metabolism are intimately linked with the two major mechanisms or pathways of cellular respiration; oxidative phosphorylation and glycolysis. The editors and contributing authors proficiently and unequivocally address the effects of dysfunction of the mitochondrial oxidative phosphorylation/glycolysis (cellular respiration) mechanisms and pathways on the development of cancer. While it remains true that there are no universal truths in cancer, Cellular Respiration and Carcinogenesis opens the dialogue that the etiology of cancer can usually be associated with and significantly attributed to the failure of one or multiple pathways of oxidative phosphorylation to normally burn fuel to generate energy, vis-à-vis the Warburg hypothesis. Keeping with its cutting-edge nature, Cellular Respiration and Carcinogenesis provides the first glimpse of cautionary evidence based counterbalance to the recent and rapidly proliferating notion that utilization of fuel primarily via glycolysis is a hallmark of cancer development.

Page 158: As an example of using a metabolic approach to provide therapeutic benefit, we will discuss the performance of one compound, dichloroacetate, in detail. There are two overall goals: first, to slow or inhibit high-rate glycolysis, and the second, to block fatty acid oxidation at several key enzymatic steps.

 

[Michael Scally MD]

New Cancer Drugs Reach Patients Sooner In The United States Than In Europe

Roberts SA, Allen JD, Sigal EV. Despite Criticism Of The FDA Review Process, New Cancer Drugs Reach Patients Sooner In The United States Than In Europe. Health Affairs. Despite Criticism Of The FDA Review Process, New Cancer Drugs Reach Patients Sooner In The United States Than In Europe

The US Food and Drug Administration is often criticized as inefficient compared to its European counterpart, the European Medicines Agency. This criticism is especially common in the field of oncology, where severely ill patients have few therapeutic options. We conducted a direct drug-to-drug comparison of the two regulatory agencies’ approvals of new oncology drugs. We found that contrary to public assertions, the median time for approval for new cancer medicines in the United States was just six months—and that these new anticancer medicines are typically available in the United States before they are in Europe. Our findings reinforce the need for strong financial and public support of the Food and Drug Administration, so that such medicines can continue to be made available speedily to patients in need.

 

[Michael Scally MD]

How Bright Promise in Cancer Testing Fell Apart
http://www.nytimes.com/2011/07/08/health/research/08genes.html

July 7, 2011
By GINA KOLATA

When Juliet Jacobs found out she had lung cancer, she was terrified, but realized that her hope lay in getting the best treatment medicine could offer. So she got a second opinion, then a third. In February of 2010, she ended up at Duke University, where she entered a research study whose promise seemed stunning.

Doctors would assess her tumor cells, looking for gene patterns that would determine which drugs would best attack her particular cancer. She would not waste precious time with ineffective drugs or trial-and-error treatment. The Duke program — considered a breakthrough at the time — was the first fruit of the new genomics, a way of letting a cancer cell’s own genes reveal the cancer’s weaknesses.

But the research at Duke turned out to be wrong. Its gene-based tests proved worthless, and the research behind them was discredited. Ms. Jacobs died a few months after treatment, and her husband and other patients’ relatives are suing Duke.

The episode is a stark illustration of serious problems in a field in which the medical community has placed great hope: using patterns from large groups of genes or other molecules to improve the detection and treatment of cancer. Companies have been formed and products have been introduced that claim to use genetics in this way, but assertions have turned out to be unfounded. While researchers agree there is great promise in this science, it has yet to yield many reliable methods for diagnosing cancer or identifying the best treatment.

Instead, as patients and their doctors try to make critical decisions about serious illnesses, they may be getting worthless information that is based on bad science. The scientific world is concerned enough that two prominent groups, the National Cancer Institute and the Institute of Medicine, have begun examining the Duke case; they hope to find new ways to evaluate claims based on emerging and complex analyses of patterns of genes and other molecules.

So far, the Food and Drug Administration “has generally not enforced” its regulation of tests created by individual labs because, until recently, such tests were relatively simple and relied heavily on the expertise of a particular doctor, said Erica Jefferson, a spokeswoman for the agency. But now, with labs offering more complex tests on a large scale, the F.D.A. is taking a new look at enforcement.

Dr. Scott Ramsey, director of cancer outcomes research at the Fred Hutchison Cancer Center in Seattle, says there is already “a mini-gold rush” of companies trying to market tests based on the new techniques, at a time when good science has not caught up with the financial push. “That’s the scariest part of all,” Dr. Ramsey said.

Doctors say the heart of the problem is the intricacy of the analyses in this emerging field and the difficulty in finding errors. Even well-respected scientists often “oversee a machine they do not understand and cannot supervise directly” because each segment of the research requires different areas of expertise, said Dr. Lajos Pusztai, a breast cancer researcher at M. D. Anderson Cancer Center at the University of Texas. As a senior scientist, he added, “It’s true for me, too.”

The Duke case came right after two other claims that gave medical researchers pause. Like the Duke case, they used complex analyses to detect patterns of genes or cell proteins. But these were tests that were supposed to find ovarian cancer in patients’ blood. One, OvaSure, was developed by a Yale scientist, Dr. Gil G. Mor, licensed by the university and sold to patients before it was found to be useless.

The other, OvaCheck, was developed by a company, Correlogic, with contributions from scientists from the National Cancer Institute and the Food and Drug Administration. Major commercial labs licensed it and were about to start using it before two statisticians from M. D. Anderson discovered and publicized its faults.

The Duke saga began when a prestigious journal, Nature Medicine, published a paper on Nov. 6, 2006, by Dr. Anil Potti, a cancer researcher at Duke University Medical Center; Joseph R. Nevins, a senior scientist there; and their colleagues. They wrote about genomic tests they developed that looked at the molecular traits of a cancerous tumor and figured out which chemotherapy would work best.

Other groups of cancer researchers had been trying to do the same thing.

“Our group was despondent to get beaten out,” said Dr. John Minna, a lung cancer researcher at the University of Texas Southwestern Medical Center. But Dr. Minna rallied; at the very least, he thought, he would make use of this incredible discovery to select drugs for lung cancer patients.

First, though, he asked two statisticians at M. D. Anderson, Keith Baggerly and Kevin Coombes, to check the work. Several other doctors approached them with the same request.

Dr. Baggerly and Dr. Coombes found errors almost immediately. Some seemed careless — moving a row or a column over by one in a giant spreadsheet — while others seemed inexplicable. The Duke team shrugged them off as “clerical errors.”

And the Duke researchers continued to publish papers on their genomic signatures in prestigious journals. Meanwhile, they started three trials using the work to decide which drugs to give patients.

Dr. Baggerly and Dr. Coombes tried to sound an alarm. They got the attention of the National Cancer Institute, whose own investigators wanted to use the Duke system in a clinical trial but were dissuaded by the criticisms. Finally, they published their analysis in The Annals of Applied Statistics, a journal that medical scientists rarely read.

The situation finally grabbed the cancer world’s attention last July, not because of the efforts of Dr. Baggerly and Dr. Coombes, but because a trade publication, The Cancer Letter, reported that the lead researcher, Dr. Potti, had falsified parts of his résumé. He claimed, among other things, that he had been a Rhodes scholar.

“It took that to make people sit up and take notice,” said Dr. Steven Goodman, professor of oncology, pediatrics, epidemiology and biostatistics at Johns Hopkins University.

In the end, four gene signature papers were retracted. Duke shut down three trials using the results. Dr. Potti resigned from Duke. He declined to be interviewed for this article. His collaborator and mentor, Dr. Nevins, no longer directs one of Duke’s genomics centers.

The cancer world is reeling.

The Duke researchers had even set up a company — now disbanded — and planned to sell their test to determine cancer treatments. Duke cancer patients and their families, including Mrs. Jacobs’s husband, Walter Jacobs, say they feel angry and betrayed. And medical researchers see the story as a call to action. With such huge data sets and complicated analyses, researchers can no longer trust their hunches that a result does — or does not — make sense.

“Our intuition is pretty darn poor,” Dr. Baggerly said.


This article has been revised to reflect the following correction:

Correction: July 7, 2011

An earlier version of this post misstated Dr. Steven Goodman's affiliation at Johns Hopkins University. He is a professor of oncology, pediatrics, epidemiology and biostatistics, not the director of oncology biostatistics.

 

[Michael Scally MD]

A 62-year-old woman with a history of well-controlled hypertension presents for routine follow-up. She is asymptomatic and feels well. She has jogged 3 miles 3 times weekly for years, with no recent change in exercise tolerance. She has a 30-pack-year history of cigarette smoking but stopped smoking 10 years ago. There is no personal or family history of cancer.

Physical examination is normal. She read a recent study that found a benefit to screening for lung cancer with computed tomography and inquires whether you think screening is appropriate for her. What should you recommend?


Silvestri GA. Screening for Lung Cancer: It Works, but Does It Really Work? Annals of Internal Medicine 2011:E-364. Screening for Lung Cancer: It Works, but Does It Really Work?

After the publication of the NLST (National Lung Screening Trial) results, physicians will be faced with whether to begin ordering low-dose computed tomography (LDCT) of the chest to screen for lung cancer in patients with a history of tobacco use. Despite the encouraging reduction in deaths observed by using LDCT in the NLST study population, recommending adoption of lung cancer screening in general practice is premature.

Lessons learned from prostate and breast cancer screening should remind us that the reductions in deaths expected with screening are unfortunately not as readily achievable as initially believed. Further, the potential harms of false-positive findings on chest computed tomography are very real. The morbidity and even mortality associated with invasive diagnostic testing and surgical resection due to false- and true-positive findings on computed tomography are likely to increase when the approach taken in the NLST is applied in non–specialty care settings and among the population at highest risk, namely, those with smoking-related comorbid conditions. Although the NLST results are perhaps encouraging, they do not tell us enough that we can be sure that patients who undergo LDCT in an attempt to find early-stage lung cancer will have more benefit than harm.


Jett JR, Midthun DE. Screening for Lung Cancer: For Patients at Increased Risk for Lung Cancer, It Works. Annals of Internal Medicine 2011:E-367. Screening for Lung Cancer: For Patients at Increased Risk for Lung Cancer, It Works

Screening for lung cancer is not currently recommended, even in persons at high risk for this condition. Most patients with lung cancer present with symptomatic disease that is usually at an incurable, advanced stage. The recently reported NLST (National Lung Screening Trial) showed a 20% decrease in deaths from lung cancer in high-risk persons undergoing screening with low-dose computed tomography of the chest compared with chest radiography.

The high-risk group included in the trial comprised asymptomatic persons aged 55 to 74 years, with smoking history of at least 30 pack-years. Screening with low-dose computed tomography detected more cases of early-stage lung cancer and fewer cases of advanced-stage cancer, confirming that screening has shifted the stage of cancer at diagnosis and provides more persons with the opportunity for curative treatment. Although computed tomography screening has risks and limitations, the 20% decrease in deaths is the single most dramatic decrease ever reported for deaths from lung cancer, with the possible exception of smoking cessation. Physicians should offer computed tomography screening for lung cancer to patients who fit the high-risk profile defined in the NLST.

 

[Michael Scally MD]

New Method for Detecting Lung Cancer Unveiled

Worldwide and in the United States, lung cancer is the most common cause of cancer-related death. In the U.S., more than 221,000 people will be newly diagnosed with lung cancer in 2011, and more than 155,000 people will die from the disease this year.

In a new article published in Nature Nanotechnology, biological engineers and medical scientists at the University of Missouri reveal how their discovery could provide a much earlier warning signal.

MU researchers used blood plasma samples to detect a change in a specific small ribonucleic acid (microRNA) molecule that is often elevated in lung cancer patients. The scientists put an extract of blood plasma through a protein-based nanopore, which is a tiny hole in a thin membrane that is just big enough for a single molecule to pass through. By applying an ionic current to the nanopore, the scientists measured changes in the current that occur when the microRNA molecule associated with lung cancer is present.


Wang Y, Zheng D, Tan Q, Wang MX, Gu L-Q. Nanopore-based detection of circulating microRNAs in lung cancer patients. Nat Nano;advance online publication. Nanopore-based detection of circulating microRNAs in lung cancer patients : Nature Nanotechnology : Nature Publishing Group

MicroRNAs are short RNA molecules that regulate gene expression, and have been investigated as potential biomarkers because their expression levels are correlated with various diseases. However, detecting microRNAs in the bloodstream remains difficult because current methods are not sufficiently selective or sensitive. Here, we show that a nanopore sensor based on the ?-haemolysin protein can selectively detect microRNAs at the single molecular level in plasma samples from lung cancer patients without the need for labels or amplification of the microRNA. The sensor, which uses a programmable oligonucleotide probe to generate a target-specific signature signal, can quantify subpicomolar levels of cancer-associated microRNAs and can distinguish single-nucleotide differences between microRNA family members. This approach is potentially useful for quantitative microRNA detection, the discovery of disease markers and non-invasive early diagnosis of cancer.


Wangyu Z, XiaoGuang L, JianYing H, DongDong C, Yanyan H, YongKui Z. Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study. BMC Cancer 2011;11(1):393. Abstract | Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study

Background Lung cancer is the leading cause of cancer-related deaths worldwide. Early detection is considered critical for lung cancer treatment. MicroRNAs (miRNAs) have shown promise as diagnostic and prognostic indicators. This study was to identify specific miRNAs with diagnostic and prognostic value for patients with lung cancer, and to explore the correlation between expression profiles of miRNAs and patient survival.

Methods Gene expression of members of the miR-183 family (miR-96, miR-182, and miR-183) were examined in 70 paired samples from lung cancer patients (primary cancer and non-cancerous tissues and sera), as well as 44 serum samples from normal volunteers and lung cancer cell lines by quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR). The correlation between the expression of miRNAs in tissues, sera, and patient overall survival were also examined by log-rank and Cox regression analysis.

Results Expression levels of members of the miR-183 family in lung cancer tumor and sera were higher than that of their normal counterparts. The miR-96 expression in tumors was positively associated with its expression in sera. Log-rank and Cox regression analyses demonstrated that high expression of tumor and serum miRNAs of the miR-183 family were associated with overall poor survival in patients with lung cancer.

Conclusions Our results suggest that the expressions of miR-96, miR-182, and miR-183 in tumor and sera may be considered potential novel biomarkers for the diagnosis and prognosis of lung cancer.

 

[tariq456]

I am too much long thread here

 

[cvictorg]

Cancer care in the U.S. versus Europe: Is more necessarily better?

Science-Based Medicine Cancer care in the U.S. versus Europe: Is more necessarily better?

 

[Michael Scally MD]

Gaziano J, Sesso HD, Christen WG, et al. Multivitamins in the Prevention of Cancer in Men: The Physicians' Health Study II Randomized Controlled Trial. JAMA. 2012;():1-10. JAMA Network | JAMA: The Journal of the American Medical Association | Multivitamins in the Prevention of Cancer in MenThe Physicians' Health Study II Randomized Controlled TrialMultivitamins in the Prevention of Cancer in Men

Context Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality.

Objective To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men.

Design, Setting, and Participants A large-scale, randomized, double-blind, placebo-controlled trial (Physicians' Health Study II) of 14 641 male US physicians initially aged 50 years or older (mean [SD] age, 64.3 [9.2] years), including 1312 men with a history of cancer at randomization, enrolled in a common multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011.

Intervention Daily multivitamin or placebo.

Main Outcome Measures Total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points.

Results During a median (interquartile range) follow-up of 11.2 (10.7-13.3) years, there were 2669 men with confirmed cancer, including 1373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (multivitamin and placebo groups, 17.0 and 18.3 events, respectively, per 1000 person-years; hazard ratio

---

, 0.92; 95% CI, 0.86-0.998; P = .04). There was no significant effect of a daily multivitamin on prostate cancer (multivitamin and placebo groups, 9.1 and 9.2 events, respectively, per 1000 person-years; HR, 0.98; 95% CI, 0.88-1.09; P = .76), colorectal cancer (multivitamin and placebo groups, 1.2 and 1.4 events, respectively, per 1000 person-years; HR, 0.89; 95% CI, 0.68-1.17; P = .39), or other site-specific cancers. There was no significant difference in the risk of cancer mortality (multivitamin and placebo groups, 4.9 and 5.6 events, respectively, per 1000 person-years; HR, 0.88; 95% CI, 0.77-1.01; P = .07). Daily multivitamin use was associated with a reduction in total cancer among 1312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56-0.96; P = .02), but this did not differ significantly from that among 13 329 men initially without cancer (HR, 0.94; 95% CI, 0.87-1.02; P = .15; P for interaction = .07).

Conclusion In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.

 

[Michael Scally MD]

Choi YJ, Li X, Hydbring P, et al. The Requirement for Cyclin D Function in Tumor Maintenance. Cancer Cell 2012;22(4):438-51. ScienceDirect.com - Cancer Cell - The Requirement for Cyclin D Function in Tumor Maintenance

D-cyclins represent components of cell cycle machinery. To test the efficacy of targeting D-cyclins in cancer treatment, we engineered mouse strains that allow acute and global ablation of individual D-cyclins in a living animal. Ubiquitous shutdown of cyclin D1 or inhibition of cyclin D-associated kinase activity in mice bearing ErbB2-driven mammary carcinomas triggered tumor cell senescence, without compromising the animals’ health. Ablation of cyclin D3 in mice bearing Notch1-driven T cell acute lymphoblastic leukemias (T-ALL) triggered tumor cell apoptosis. Such selective killing of leukemic cells can also be achieved by inhibiting cyclin D associated kinase activity in mouse and human T-ALL models. Inhibition of cyclin D-kinase activity represents a highly-selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues.

 

[Michael Scally MD]

Weeks JC, Catalano PJ, Cronin A, et al. Patients' Expectations about Effects of Chemotherapy for Advanced Cancer. New England Journal of Medicine 2012;367(17):1616-25. MMS: Error

BACKGROUND - Chemotherapy for metastatic lung or colorectal cancer can prolong life by weeks or months and may provide palliation, but it is not curative.

METHODS - We studied 1193 patients participating in the Cancer Care Outcomes Research and Surveillance (CanCORS) study (a national, prospective, observational cohort study) who were alive 4 months after diagnosis and received chemotherapy for newly diagnosed metastatic (stage IV) lung or colorectal cancer. We sought to characterize the prevalence of the expectation that chemotherapy might be curative and to identify the clinical, sociodemographic, and health-system factors associated with this expectation. Data were obtained from a patient survey by professional interviewers in addition to a comprehensive review of medical records.

RESULTS - Overall, 69% of patients with lung cancer and 81% of those with colorectal cancer did not report understanding that chemotherapy was not at all likely to cure their cancer. In multivariable logistic regression, the risk of reporting inaccurate beliefs about chemotherapy was higher among patients with colorectal cancer, as compared with those with lung cancer (odds ratio, 1.75; 95% confidence interval [CI], 1.29 to 2.37); among nonwhite and Hispanic patients, as compared with non-Hispanic white patients (odds ratio for Hispanic patients, 2.82; 95% CI, 1.51 to 5.27; odds ratio for black patients, 2.93; 95% CI, 1.80 to 4.78); and among patients who rated their communication with their physician very favorably, as compared with less favorably (odds ratio for highest third vs. lowest third, 1.90; 95% CI, 1.33 to 2.72). Educational level, functional status, and the patient's role in decision making were not associated with such inaccurate beliefs about chemotherapy.

CONCLUSIONS - Many patients receiving chemotherapy for incurable cancers may not understand that chemotherapy is unlikely to be curative, which could compromise their ability to make informed treatment decisions that are consonant with their preferences. Physicians may be able to improve patients' understanding, but this may come at the cost of patients' satisfaction with them.

 

[Michael Scally MD]

Hudson B, Zarifeh A, Young L, Wells JE. Patients' Expectations of Screening and Preventive Treatments. The Annals of Family Medicine 2012;10(6):495-502. Patients' Expectations of Screening and Preventive Treatments

PURPOSE - An informed decision to accept a health care intervention requires an understanding of its likely benefit. This study assessed participants' estimates of the benefit, as well as minimum acceptable benefit, of screening for breast and bowel cancer and medication to prevent hip fracture and cardiovascular disease.

METHODS - Three general practitioners sent questionnaires to all registered patients aged 50 to 70 years. Patients agreeing to participate in the study were asked to estimate the number of events (fractures or deaths) prevented in a group of 5,000 patients undergoing each intervention over a period of 10 years, and to indicate the minimum number of events avoided by the intervention that they considered justified its use. The proportions of participants that overestimated each intervention's benefit were calculated, and univariate and multivariable analyses of predictors of response were performed.

RESULTS - The participation rate was 36%: 977 patients were invited to participate in the study, and 354 returned a completed questionnaire. Participants overestimated the degree of benefit conferred by all interventions: 90% of participants overestimated the effect of breast cancer screening, 94% overestimated the effect of bowel cancer screening, 82% overestimated the effect of hip fracture preventive medication, and 69% overestimated the effect of preventive medication for cardiovascular disease. Estimates of minimum acceptable benefit were more conservative, but other than for cardiovascular disease mortality prevention, most respondents indicated a minimum benefit greater than these interventions achieve. A lower level of education was associated with higher estimates of minimum acceptable benefit for all interventions.

CONCLUSION - Patients overestimated the risk reduction achieved with 4 examples of screening and preventive medications. A lower level of education was associated with higher minimum benefit to justify intervention use. This tendency to overestimate benefits may affect patients' decisions to use such interventions, and practitioners should be aware of this tendency when discussing these interventions with patients.

 

[BBC3]

OR.... You could just get a Laborado Retriver as a pet and best friend and acknowldege that his sence of smell OUTWEIGHT medical science and pay attention to the day he starts licking you mouth PROFUSELY as if he were eating shit off the ground or hitten a dead squirrel carcus. Then is you were astute enough, you could hazzard to gamble there is DEAD tissue in your lungs and note the problem. THE TRICK would then be convincing BC/BS as it would have been detected FAR before current conventional medical scinece could have ever, or confirmed by their standards... LOL and serious.

Just tell em yut dog referred ya...

New Method for Detecting Lung Cancer Unveiled

Worldwide and in the United States, lung cancer is the most common cause of cancer-related death. In the U.S., more than 221,000 people will be newly diagnosed with lung cancer in 2011, and more than 155,000 people will die from the disease this year.

In a new article published in Nature Nanotechnology, biological engineers and medical scientists at the University of Missouri reveal how their discovery could provide a much earlier warning signal.

MU researchers used blood plasma samples to detect a change in a specific small ribonucleic acid (microRNA) molecule that is often elevated in lung cancer patients. The scientists put an extract of blood plasma through a protein-based nanopore, which is a tiny hole in a thin membrane that is just big enough for a single molecule to pass through. By applying an ionic current to the nanopore, the scientists measured changes in the current that occur when the microRNA molecule associated with lung cancer is present.


Wang Y, Zheng D, Tan Q, Wang MX, Gu L-Q. Nanopore-based detection of circulating microRNAs in lung cancer patients. Nat Nano;advance online publication. Nanopore-based detection of circulating microRNAs in lung cancer patients : Nature Nanotechnology : Nature Publishing Group

MicroRNAs are short RNA molecules that regulate gene expression, and have been investigated as potential biomarkers because their expression levels are correlated with various diseases. However, detecting microRNAs in the bloodstream remains difficult because current methods are not sufficiently selective or sensitive. Here, we show that a nanopore sensor based on the ?-haemolysin protein can selectively detect microRNAs at the single molecular level in plasma samples from lung cancer patients without the need for labels or amplification of the microRNA. The sensor, which uses a programmable oligonucleotide probe to generate a target-specific signature signal, can quantify subpicomolar levels of cancer-associated microRNAs and can distinguish single-nucleotide differences between microRNA family members. This approach is potentially useful for quantitative microRNA detection, the discovery of disease markers and non-invasive early diagnosis of cancer.


Wangyu Z, XiaoGuang L, JianYing H, DongDong C, Yanyan H, YongKui Z. Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study. BMC Cancer 2011;11(1):393. Abstract | Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: a case control study

Background Lung cancer is the leading cause of cancer-related deaths worldwide. Early detection is considered critical for lung cancer treatment. MicroRNAs (miRNAs) have shown promise as diagnostic and prognostic indicators. This study was to identify specific miRNAs with diagnostic and prognostic value for patients with lung cancer, and to explore the correlation between expression profiles of miRNAs and patient survival.

Methods Gene expression of members of the miR-183 family (miR-96, miR-182, and miR-183) were examined in 70 paired samples from lung cancer patients (primary cancer and non-cancerous tissues and sera), as well as 44 serum samples from normal volunteers and lung cancer cell lines by quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR). The correlation between the expression of miRNAs in tissues, sera, and patient overall survival were also examined by log-rank and Cox regression analysis.

Results Expression levels of members of the miR-183 family in lung cancer tumor and sera were higher than that of their normal counterparts. The miR-96 expression in tumors was positively associated with its expression in sera. Log-rank and Cox regression analyses demonstrated that high expression of tumor and serum miRNAs of the miR-183 family were associated with overall poor survival in patients with lung cancer.

Conclusions Our results suggest that the expressions of miR-96, miR-182, and miR-183 in tumor and sera may be considered potential novel biomarkers for the diagnosis and prognosis of lung cancer.

 

[Michael Scally MD]

Duane SF. What a Difference a Letter Can Make. Journal of Clinical Oncology 2012;30(33):4171-2. What a Difference a Letter Can Make

I learned an important life lesson recently from a sixth-grade student: a letter from your mom can make all the difference.

All too often, oncologists find themselves in the difficult position of sitting across from a dying patient who is also the mother or father of young children, discussing end-of-life care. In my practice, such conversations usually involved young women with metastatic breast cancer. When the delicate topic of the patient's children was broached, tears were inevitable. There is perhaps no greater sadness than that of a mother who is about to leave her children behind forever.

After allowing time for the patient to cry and to say whatever she felt up to saying, I often talked gently about ways that I hoped might help my patient and her children cope a little bit better with such an unthinkable loss. One idea that I sometimes suggested was for the patient to write letters to each of her children to open on special occasions in the future, after the patient was gone—letters for certain birthdays, graduation, or a wedding day. Despite making this recommendation, to me the act of writing such letters had always seemed impossible. And I also often wondered how these letters would be received by the child—would the communications from a long-gone parent be eagerly anticipated and prized, or would they instead be dreaded, summoning ghosts and painful memories of a desperately sad time? Whenever I imagined that future birthday or wedding day, I could see an image of the letter being opened and read, but my thoughts were unable to go any further.

Enter the sixth grader who taught me just how important those letters can be to the recipient.

I was asked to attend a support group for kids who had lost a loved one. This group is open to sixth through eighth graders and meets weekly in a local junior high school. The two group facilitators had been inundated with medical questions from the students, and the counselors asked me to attend one of the group meetings to help answer some of these queries. I accepted, but I had some reservations about talking with junior high school students, especially as it has been almost half a century since I was that age myself.

I arrived at the meeting early and was led to a room that was near the school principal's office. The room was large and stark, making it seem more suited for detention than for baring one's heart. The kids filed in slowly; eventually, six students comprised the group. They looked so young as they talked about band practice, compared homerooms, and speculated about this evening's basketball game. “So, are you the doctor?” one boy eagerly asked. “Yes,” I said, knowing that my gray hair and necktie had likely already answered his question.

The facilitators began by asking each student to introduce themselves and briefly recount the story of their loved one's death. Cancer was the common theme. Questions quickly followed. Initially, these questions were easy, straightforward ones that I had answered many times before. How did the cancer get to my mom's brain? Why does chemotherapy make a person so sick? But soon the questions began to cover more uncomfortable matters. What does it mean that I dream about my dad? Is it OK that I am mad at God for taking my mom? It quickly became clear to me that these kids had been forced to grow up faster than children should, and they were demonstrating maturity and wisdom well beyond their years.

One young boy grew quiet, and the counselor noted his bowed head looking down. “Are you OK?” she asked. His soft response was, “It's just not fair. Sometimes it makes me so angry that my mom had to die.” The counselor repositioned herself, now sitting next to the boy with her arm around him. (There are uncelebrated heroes on this earth, and I realized that I was witnessing one of them in action). “What do you do when you feel this way?” she asked him.

He looked up, paused briefly and said, “I read my mom's letter. I was reading it just now.” He volunteered, “Would you like to see it?” After a few questions from the group leaders probing whether it would be OK, we collectively asked the boy to share the letter.

He explained that his mom died of cancer when he was 5 years old and she had written this letter just before her death. He had not been given the letter until he was 8. Now, he keeps a copy of his mother's letter on his smart phone, along with her picture.

He showed us what the letter looked like and then started to read it. It was clear from the sound of his voice that he had read it many times before. The letter was brief, encouraging, sad, loving—and obviously deeply treasured by the boy. He shared with us that whenever he feels really down or angry, he rereads his mother's letter. “Reading it always makes me feel better, more relaxed. I feel connected to my mom.” As he pocketed his phone, I could see a noticeable change in his expression and his posture—calmer and more settled. Fortified by his mom's courageous letter, the young man now appeared ready to move ahead, both with the rest of his day and with the rest of his life.

A deep uneasiness stayed with me for days following this experience. My thoughts bounced back and forth between my previous conversations with dying parents and what I'd heard that afternoon from the group of young students. I felt a great sadness reflecting on the profound losses that they had experienced, and yet what kept resurfacing was appreciation of the courage and resilience that I had witnessed. So, bravo to that dying mother who somehow found the courage to write a critical letter to her 5-year-old son. Bravo, too, to that resilient young man, whose mother is now memory, but who is using her words to help him find his way in life, just as she had hoped he would. What a difference a letter can make.

 

[Michael Scally MD]

Scott AM, Allison JP, Wolchok JD. Monoclonal antibodies in cancer therapy. Cancer Immun 2012;12:14. Monoclonal antibodies in cancer therapy

Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumors in the last 20 years. The initial combining of serological techniques for cancer cell surface antigen discovery with hybridoma technology led to a series of landmark clinical trials that paved the way for new generation antibodies and subsequent clinical success. Optimization of anti-tumor immune responses through Fc modifications has also made a major contribution to clinical efficacy. The modulation of immune system interplay with tumor cells through targeting of T cell receptors has emerged as a powerful new therapeutic strategy for tumor therapy and to enhance cancer vaccine efficacy. This commentary will provide an overview of the history of antibody identification of tumor surface antigens, antigenic targets suitable for antibody-based therapy, antibody mechanisms of action, and recent successes of antibodies in the clinic.

 

[Michael Scally MD]

Galon J, Franck P, Marincola FM, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 2012;10(1):205. http://www.translational-medicine.com/content/pdf/1479-5876-10-205.pdf

Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy.

Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification.

It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization.

In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).