After making a diagnosis of cancer, clinicians have a number of treatment options. Most of these involve coordinating multiple attacks on the tumor using an arsenal of cancer-killing therapies. Chemotherapy, where toxic drugs are used to specifically kill cancer cells, is a very powerful weapon in this arsenal. It is extremely effective in treating some cancers, such as testicular cancer and Hodgkin’s Disease, but works poorly in other cancer types. Although the reasons for these different responses are complex, one of the known limitations for solid tumors is that sometimes killer drugs injected into the bloodstream are not delivered efficiently to the tumor tissue, and even if they do reach their target, are not retained long enough to administer their lethal hit.

Professor Lisa Coussens and her coworkers, based at the University of California San Francisco Medical Center, have now discovered a way of enhancing drug delivery to tumors: using the cancer’s own architecture to bring about its downfall. Solid tumors need a good blood supply in order to grow, and the blood vessels nourishing the tumors are frequently disorganized and leaky, allowing drugs to leach into the tumor. However, this useful property is counteracted by high tissue pressure within the tumor itself, which creates a barrier for drug uptake. Coussens’ team have found a way of tipping the balance in favor of the blood vessels. Using a mouse model of cancer, they show that blocking the action of a signaling molecule called ALK5 makes tumor blood vessels even leakier for a short period of time, and this window of leakiness can be used to “open up” the tumor for more efficient delivery of drugs.

Coussens’ discovery has exciting implications. Blocking the ALK5 pathway may not only make chemotherapy far more effective in multiple cancers, but could also aid in efficient delivery of the many other therapies that rely on the bloodstream to carry them into a tumor. Further, ALK5 blockade could assist in diagnosis as well as treatment; the imaging molecules used to light up tumors so that they can be seen by scanners might also be able to get in more easily if ALK5 were inactivated at the time of scanning. Together, these benefits may lead to more accurate diagnosis and a far more hopeful prognosis for sufferers of previously intractable solid cancers.

For the first time, scientists have succeeded in growing empty particles derived from a plant virus and have made them carry useful chemicals.

The external surface of these nano containers could be decorated with molecules that guide them to where they are needed in the body, before the chemical load is discharged to exert its effect on diseased cells. The containers are particles of the Cowpea mosaic virus, which is ideally suited for designing biomaterial at the nanoscale.

“This is a shot in the arm for all Cowpea mosaic virus technology,” says Professor George Lomonosoff of the John Innes Centre, one of the authors on a paper to be published in Small.

Scientists have previously tried to empty virus particles of their genetic material using irradiation or chemical treatment. Though successful in rendering the particles non-infectious, these methods have not fully emptied the particles.

Scientists at the John Innes Centre discovered they could assemble empty particles from precursors in plants and then extract them to insert chemicals of interest. Scientists at JIC and elsewhere had also previously managed to decorate the surface of virus particles with useful molecules.

“But now we can load them too, creating fancy chemical containers,” says lead author Dr Dave Evans.

“This brings a huge change to the whole technology and opens up new areas of research,” says Prof Lomonossoff. “We don’t really know all the potential applications yet because such particles have not been available before. There is no history of them.”

One application could be in cancer treatment. Integrins are molecules that appear on cancer cells. The virus particles could be coated externally with peptides that bind to integrins. This would mean the particles seek out cancer cells to the exclusion of healthy cells. Once bound to the cancer cell, the virus particle would release an anti-cancer agent that has been carried as an internal cargo.

Some current drugs damage healthy cells as well as the cancer, leading to hair loss and other side effects. This technology could deliver the drug in a more targeted way.

“The potential for developing Cowpea mosaic virus as a targeted delivery agent of therapeutics is now a reality,” says Dr Evans.

Another weapon in the arsenal against cancer: Nanoparticles that identify, target and kill specific cancer cells while leaving healthy cells alone.

Led by Carl Batt, the Liberty Hyde Bailey Professor of Food Science, the researchers synthesized nanoparticles shaped something like a dumbbell made of gold sandwiched between two pieces of iron oxide. They then attached antibodies, which target a molecule found only in colorectal cancer cells, to the particles. Once bound, the nanoparticles are engulfed by the cancer cells.

To kill the cells, the researchers use a near-infrared laser, which is a wavelength that doesn’t harm normal tissue at the levels used, but the radiation is absorbed by the gold in the nanoparticles. This causes the cancer cells to heat up and die.

“This is a so-called ’smart’ therapy,” Batt said. “To be a smart therapy, it should be targeted, and it should have some ability to be activated only when it’s there and then kills just the cancer cells.”

The goal, said lead author and biomedical graduate student Dickson Kirui, is to improve the technology and make it suitable for testing in a human clinical trial. The researchers are now working on a similar experiment targeting prostate cancer cells.

“If, down the line, you could clinically just target the cancer cells, you could then spare the health surrounding cells from being harmed that is the critical thing,” Kirui said.

Gold has potential as a material key to fighting cancer in future smart therapies. It is biocompatible, inert and relatively easy to tweak chemically. By changing the size and shape of the gold particle, Kirui and colleagues can tune them to respond to different wavelengths of energy.

Once taken up by the researchers’ gold particles, the cancer cells are destroyed by heat just a few degrees above normal body temperature while the surrounding tissue is left unharmed. Such a low-power laser does not have any effect on surrounding cells because that particular wavelength does not heat up cells if they are not loaded up with nanoparticles, the researchers explained.

Using iron oxide which is basically rust as the other parts of the particles might one day allow scientists to also track the progress of cancer treatments using magnetic resonance imaging, Kirui said, by taking advantage of the particles’ magnetic properties.

A new method of growing arteries could lead to a “biological bypass” – or a non-invasive way to treat coronary artery disease, Yale School of Medicine researchers report with their colleagues in the April issue of Journal of Clinical Investigation.

Coronary arteries can become blocked with plaque, leading to a decrease in the supply of blood and oxygen to the heart. Over time this blockage can lead to debilitating chest pain or heart attack. Severe blockages in multiple major vessels may require coronary artery bypass graft surgery, a major invasive surgery.

“Successfully growing new arteries could provide a biological option for patients facing bypass surgery,” said lead author of the study Michael Simons, M.D., chief of the Section of Cardiology at Yale School of Medicine.

In the past, researchers used growth factors – proteins that stimulate the growth of cells – to grow new arteries, but this method was unsuccessful. Simons and his team studied mice and zebrafish to see if they could simulate arterial formation by switching on and off two signaling pathways – ERK1/2 and P13K.

“We found that there is a cross-talk between the two signaling pathways. One half of the signaling pathway inhibits the other. When we inhibit this mechanism, we are able to grow arteries,” said Simons. “Instead of using growth factors, we stopped the inhibitor mechanism by using a drug that targets a particular enzyme called P13-kinase inhibitor.”

“Because we’ve located this inhibitory pathway, it opens the possibility of developing a new class of medication to grow new arteries,” Simons added. “The next step is to test this finding in a human clinical trial.”

According to a new study, men employed in occupations with potential exposure to high levels of sunlight have a reduced risk of kidney cancer compared with men who were less likely to be exposed to sunlight at work. The study did not find an association between occupational sunlight exposure and kidney cancer risk in women. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the study is the largest case-control study of kidney cancer to investigate the association with occupational sunlight exposure. The study, however, did not include information on non-occupational sunlight exposure and does not address directly whether sunlight exposure can help prevent kidney cancer.

Research suggests that vitamin D, which is obtained from sun exposure, some foods, and from supplements, may help prevent some cancers. Vitamin D is metabolized and most active within the kidneys. Because both the incidence of kidney cancer and the prevalence of vitamin D deficiency have increased over the past few decades, Sara Karami, PhD, of the National Cancer Institute in Rockville, MD, and her colleagues designed a study to explore whether occupational sunlight exposure is associated with kidney cancer risk.

The study included 1,097 patients with kidney cancer and 1,476 individuals without cancer from four Central and Eastern European countries. Demographic and lifetime occupational information was collected through in-person interviews and occupational sunlight exposure indices were estimated based on industry and job titles. The investigators observed a 24 percent to 38 percent reduction in kidney cancer risk with increasing occupational sunlight exposure among male participants in the study. No association between occupational sunlight exposure and kidney cancer risk was observed among females in the study.

The findings suggest that sunlight exposure may affect kidney cancer risk, although the authors have no explanation for the apparent differences in risk between men and women. They offer several hypotheses for the observed differences. Biological or behavioral differences between men and women may play a role. For example, hormonal differences may influence the body’s response to sunlight exposure, females may have a higher tendency to use sunscreen on a regular basis, and men may be prone to working outdoors while shirtless. It is also possible that the observed gender differences in risk were due to confounding by other unmeasured kidney cancer risk factors, such as recreational sunlight exposure and physical activity levels.

While this study’s findings raise the possibility of a link between sunlight exposure and kidney cancer risk, “they clearly need to be replicated in other populations and in studies that use better estimates of long-term ultraviolet exposure and vitamin D intake,” said Dr. Karami.

The frequency of post-operative complications following surgery for liver cancer is associated with a hospital having a low volume of liver surgery. Investigators at The Cancer Institute of New Jersey (CINJ) are presenting that finding at the 63rd Annual Society of Surgical Oncology Symposium taking place this week in St. Louis. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

Previous analyses of state and national databases have documented institutional volume-related death rates at low-volume hospitals for this type of surgery; however, a causal relationship has not been determined. In this current study, the team analyzed 9,289 cases between 1998 and 2007 from the Nationwide Inpatient Sample database. Patients were more than 18 years old and underwent elective surgical removal of a portion of their liver due to malignancy. A threshold of 20 annual liver surgeries was used in each hospital to separate low-volume facilities from high-volume facilities. Investigators reviewed postoperative complications such as sepsis and hemorrhaging, as well as problems with the liver, lungs, heart, and bladder. Also taken into account were socio-demographic factors such as age, gender and race among other variables.

What they found was that patients at low-volume hospitals experienced at least one of the analyzed postoperative complications more often than at high-volume facilities. Specifically, hemorrhagic, septic and lung complications were more likely to occur at low-volume institutions. However, overall, the rate of liver complications was lower at these facilities. When mortality was analyzed, it was found that patients who underwent liver cancer surgery at low-volume hospitals were 1.4 times as likely to die as patients who had the procedure at a high-volume institution.

Christopher J. Gannon, MD, surgical oncologist at CINJ and assistant professor of surgery at UMDNJ-Robert Wood Johnson Medical School, is the lead investigator. “This new data is significant in that it could be utilized in low-volume facilities to investigate systems problems once complications occur. This information also has benefit for high-volume hospitals, as it could also be used in centralizing liver cancer care,” he noted.

Cholangiocarcinoma (CCA), a bile duct cancer, is one of the major cancers in Northeast Thailand. This cancer is difficult to diagnose and has high metastatic and mortality rates. Overexpression of Met, a hepatocyte growth factor (HGF) receptor, has frequently been found in CCA and is correlated with progression of this type of cancer. HGF/Met activation induces a variety of cellular processes, including cell scattering, invasion and proliferation. Although a number of studies have been reported regarding the correlation between Met expression and CCA, the molecular mechanisms by which HGF induces CCA invasion are not completely understood.

A research article published in the World Journal of Gastroenterology addresses this problem. The research team led by Dr. Suthiphongchai T from Mahidol University used two CCA cell lines overexpressing Met, KKU-M213 and HuCCA-1, to study the role of Met in CCA invasion by activating the Met pathway with HGF. HGF strongly induced invasion and motility of the two CCA cell lines and concomitantly altered E-cadherin localization from membrane to cytosol, but did not affect the levels of secreted MMP-2, MMP-9 or uPA.

Signaling pathways responsible for HGF-induced invasion were further investigated. HGF induced ERK and PI3K/Akt pathways of both CCA cell lines but with different kinetic profiles. HGF induced sustained ERK activation in the KKU-M213 cell line, but transient ERK activation in HuCCA-1 cells. Using specific inhibitors of PI3K and ERK pathways, it was shown that HGF-induced invasion of KKU-M213 was strongly inhibited by both inhibitors, while that of HuCCA-1 was strongly inhibited by PI3K inhibitor but only weakly inhibited by ERK inhibitor. Thus, the signaling pathways responsible for HGF-induced invasiveness of the two CCA cell lines were different, in that PI3K pathway was common for both cell lines, whereas the role of ERK1/2 was likely to be dependent on the duration of ERK1/2 activation.

These results provided more information on the understanding of the signaling mechanisms responsible for HGF-induced CCA invasiveness, which may be helpful for identifying better targets for CCA therapy and for designing appropriate therapeutic strategy to suit each individual patient.

Research published in the March edition of the Journal of Thoracic Oncology (JTO) explored the importance of a patient’s outlook as it relates to health behavior and health status. Researchers focused on lung cancer patients and discovered that those who exhibited an optimistic disposition experienced more favorable outcomes than those with a pessimistic disposition.

Previous research into how the body communicates with the mind has demonstrated a connection between pessimistic outlook and negative health behaviors. The examination of a possible relationship between patient outlooks and survivorship in oncology populations is a relatively new and provocative area of investigation, and such studies have yielded mixed results. Some suggest that having a pessimistic personality before receiving a cancer diagnosis might be predictive of survival time and immune function; whereas, others have not found such an association. This newly released study builds on the existing research to gain knowledge specifically toward the effect of attitudes on lung cancer patients.

Utilizing the Optimism – Pessimism scale (PSM) of the Minnesota Multiphasic Personality Inventory (MMPI), the study investigators identified pessimistic and non-pessimistic or optimistic personality styles among patients. Researchers performed a retrospective evaluation of 534 adults diagnosed with lung cancer who had completed a MMPI about 18 years before receiving their lung cancer diagnosis between 1997 and 2006. Patients (both women and men) classified as having an optimistic attitude survived an average of six months longer compared with the patients with a pessimistic attitude. Five-year survival rates for the two groups were 32.9 percent for non-pessimists and 21.1 percent for pessimists. Furthermore, the relationship was independent of smoking status, cancer stage, treatment, comorbidities, age and gender.

Median survival:

* Overall 14.8 months

* Non-pessimistic 19.2 months

* Pessimistic 13.1 months

Five-year survival:

* Overall 27.8%

* Non-pessimistic 2.9%

* Pessimistic 21.1%

“This six-month potential benefit related to an optimistic attitude is more impressive when one considers that the median survival time for this patient population with lung cancer is less than one year,” explains the study’s lead investigator Paul Novotny, MS of the Mayo Clinic. “Despite limitations, the results may provide insights for advancing patient care in cognitive therapy, one of the many treatment dimensions. This may ultimately aid in enhancing current approaches to patient care, such that clinicians may improve survival not only by developing new medical treatments but also by targeting patient’s psychosocial characteristics most likely to negatively affect cancer treatment decisions and ultimate outcomes.”

A study published on bmj.com today reports that the longer women wait for radiotherapy after breast cancer surgery, the more chance there is of local recurrence.

Starting radiotherapy as soon as possible will minimize this risk according to the authors.

The reasonable generally accepted interval between cancer surgery and radiotherapy is four to six weeks. Evidence on the effect of waiting times in patients with breast cancer is unclear.

In order to find out more, researchers from the United States, Canada and Japan investigated the link between interval to radiotherapy and recurrence of breast cancer.

A total of 18,050 national cancer records were analyzed. The data were from women aged 65 or older who were diagnosed with early stage breast cancer during 1991-2002. All women received breast conserving surgery and radiotherapy, but not chemotherapy.

Data from the 2000 US population census was used to identify demographic information. Women were monitored for an average of five years.

The findings indicated that starting radiotherapy more than six weeks after surgery was linked to a modest but significant increase in local recurrence. In the study, more than one in four women (30 percent) started radiotherapy after this time. A total of 734 (4 percent) experienced a local recurrence at five years.

Additional investigation showed a continuous relation between time to radiotherapy and local recurrence. This suggests that initiating radiation therapy as soon as possible could minimize local recurrence risk.

Longer periods before undergoing radiotherapy were also found among Black and Hispanic women and among women who lived outside the southern states of the US. The rates of breast conserving surgery were higher, suggesting limitations in capacity of radiation delivery.

The continuous relationship between the start of radiotherapy and local recurrence suggests that there is no “secure” threshold in terms of waiting time. Therefore, the authors recommend that radiotherapy should be started as soon as possible.

The researchers comment that the cost of increasing capacity to consistently ensure short waiting times could be important. This would need to be evaluated in return with the small absolute benefit in local recurrence. The authors conclude that it appears appropriate to consider this is a price to pay, given the recognized negative impact of local recurrence on overall survival, and the large numbers of women treated with radiotherapy for breast cancer.

In an associated editorial, Ruth Jack and Lars Holmberg from King’s College London say that minimizing delay improves outcomes; therefore investment and planning are needed.

They comment that healthcare providers need to evaluate where probable delays are occurring. Then they should make certain that these are reduced. In addition, they should ensure equal opportunities in accessing good care. On the other hand, they point out that if significant investment is required, the modest effects seen in this study would have to be weighed against other opportunities and priorities in cancer care.

“Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis”

A survey of parents who had a child die of cancer found that one in eight considered hastening their child’s death, a deliberation influenced by the amount of pain the child experienced during the last month of life, report Dana-Farber Cancer Institute researchers in the March issue of Archives of Pediatrics & Adolescent Medicine.

The study, the first to explore this sensitive area, suggests that many parents worry that their children will suffer from uncontrollable pain, and that some parents might consider that an early death would be preferable. The researchers say the findings underscore the importance of managing patients’ pain, and of communicating with parents about the tools available for easing progressive pain.

“The problem is that conversations about these family worries may not always happen,” said senior author Joanne Wolfe, MD, MPH, Division Chief of Pediatric Palliative Care at Dana-Farber and Director of Palliative Care at Children’s Hospital Boston. “Parents may not have the opportunity to express these feelings and considerations, and as clinicians, we may not be adequately enabling sufficient opportunity for them to talk about their concerns.”

Wolfe, along with first author Veronica Dussel, MD, MPH, a Dana-Farber research fellow, undertook the research to gain an understanding of why some parents would consider a measure as extreme as intentionally ending a child’s life.

The researchers interviewed 141 parents of children who had died of cancer and were treated at Dana-Farber, Children’s Hospital, or Children’s Hospitals and Clinics of St. Paul and Minneapolis, Minn.

The scientists queried parents about their behaviors and feelings leading up to their child’s death and at the time the survey was conducted, which was a year or more after the death. The parents were also presented with hypothetical vignettes involving a terminally ill child with uncontrolled excruciating pain or who was in an irreversible coma.

One in eight (13 percent) of parents had considered asking caregivers about the possibility of ending their child’s life, though only 9 percent reported having such a discussion. Five parents, or 4 percent, had requested that their child’s death be hastened, and 3 parents said it had been carried out, using morphine. Wolfe commented, however, that “this may not reflect what actually happened, because morphine is used in increasing doses to manage worsening pain without the intent or the effect of ending life.”

In response to the hypothetical vignettes, 50 percent of parents said they endorsed hastening death in situations of uncontrollable pain or if the child was in an irreversible coma. Parents were 40 percent more likely to approve hastening death for a child experiencing extreme pain than for a terminally ill child in a coma.

Wolfe said it is important to keep the findings in perspective. Only five parents reported having talked about hastening their child’s death, and 19 said they considered it. Wolfe said it is her experience that parents are comforted by having conversations about pain management and that most are reassured by knowing what will be done to ease their child’s suffering.

“We’ve come a long way, because we have a good palliative and supportive care program for children with cancer,” said Wolfe, who is also an assistant professor of pediatrics at Harvard Medical School.

But she acknowledged, “I can never promise that their child will be pain free. We still have quite a way to go in figuring out the best way to ease suffering at the end of life.” The gap exists in part, Wolfe said, because this area is not one given high priority for research funding agencies.