RNA Interference Technique Causes Toxicity in Mice

The idea of silencing aberrant gene expression by interfering with the RNA product after transcription holds promise in the field of cancer gene therapy. One possible technique under study for RNA interference is the delivery of short hairpin RNA strands (shRNA) that are complementary to the target aberrant RNA, by way of a viral vector. However, a study published in the May 25 Nature highlights the risk of unintentional inhibition of cellular microRNA (miRNA) by shRNA overexpression, which led to fatalities in mice.

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The investigators transfected mice with high doses of shRNA and found that the resulting toxicity was also high - 36 out of 49 shRNAs tested caused severe toxicity, and almost half of all shRNAs tested caused mortality within 2 months due to liver damage. This toxicity was not restricted to a particular shRNA sequence or target.

After further experiments to clarify the cause of the toxicity, the investigators found evidence of oversaturation of the endogenous shRNA processing machinery. This processing machinery is also needed by normal cellular miRNAs, which play an important role in the cell cycle and cellular development. The authors "therefore speculated that highly expressed 'toxic' shRNAs competed with miRNAs for intracellular processing, to such an extent that affected cells died."

Additional in vivo and in vitro experiments provided more evidence for this competition model, and identified a protein - nuclear karyopherin exportin-5 - that is likely a limiting factor in the shared processing pathway. The investigators caution that, in future use of shRNA, "monitoring and controlling intracellular shRNA levels is imperative for guaranteeing stable in vivo gene silencing while mitigating adverse effects."

Cryoablation for Small Renal Tumors Shows Promising Results

Results from the study of the largest cohort of patients who have been followed for at least 5 years after cryoablation for small renal tumors were presented on May 21 at the American Urological Association's annual meeting. Dr. Nicholas Hegarty, a clinical fellow at the Cleveland Clinic, reported the follow-up data from 60 patients in their study, which began accrual in September 1997.

In cryoablation, tumor tissue is frozen and destroyed using small probes during open or laparoscopic surgery, or percutaneously under local anesthetic, depending on the tumor location.

Out of 60 patients treated with cryoablation for a solitary sporadic renal lesion, only 3 developed local tumor recurrence. All three underwent nephrectomy and remained disease free after the second surgery, though one patient died from other causes while on dialysis. One additional patient presented with distant metastases 6 months after cryoablation, but the investigators believe that the patient likely had occult metastases at the time of initial treatment. Because of the indolent nature of the disease, patients in the cohort will continue to be followed to acquire long-term survival data.

Advantages of the technique for surgeons include relative ease in performing the procedure, explained Dr. Hegarty. "A surgeon familiar with laparoscopic surgery typically will be able to perform this," he said. "We do not need to expose the renal vasculature, we do not need to clamp it, and there is no complex reconstruction like in a partial nephrectomy."

MRI Screening Is Cost Effective for Some BRCA Carriers

Women who carry BRCA1 or BRCA2 mutations and undergo regular screening for early breast cancer have the option of mammography alone or with magnetic resonance imaging (MRI). Now researchers at Stanford University School of Medicine and the VA Palo Alto Health Care System have come up with a cost per quality-adjusted life-year (QALY) for each option. Their findings are published in the May 24 JAMA.

The researchers used a computer model with a simulated cohort of BRCA1/2 mutation carriers who were born in 1980 and followed them over their virtual lifetimes, beginning in 2005. The model incorporates a natural history of breast cancer based on SEER data. It also includes screening sensitivity, specificity, lead time, and overdiagnosis rates for MRI and mammography, as well as treatment outcomes.

The results showed that among women aged 25 to 69, the QALY for BRCA1 mutation carriers with the addition of MRI to annual mammography was $88,651, compared with $188,034 for BRCA2 carriers. The combination of MRI and mammography was more cost effective for women at specific ages: the QALY was lowest between the ages of 40 and 49 at $43,484 for BRCA1 carriers ($18,952 with mammography alone) and $111,600 for BRCA2 carriers ($28,421 with mammography alone).

The authors conclude that with a threshold of $100,000 per QALY gained, adding annual MRI is cost effective for BRCA1 carriers between the ages of 35 and 54, as well as for BRCA2 carriers with especially dense breasts, for whom mammography is insensitive. They note that in the future, digital mammography and chemoprevention could affect QALY for these groups.

Transfusions During Surgery Linked to Cancer-Related Mortality

Receipt of blood transfusions during surgery for renal cell carcinoma (RCC) and prostate cancer significantly increases the risk of a patient dying from the disease compared with patients who receive fewer or no transfusions, Mayo Clinic researchers reported last week.

At a minimum of 5 transfused units, prostate cancer patients had a threefold increased risk of cancer-related mortality at 5 years. In kidney cancer patients, however, there was a dose-specific response to blood transfusion, with increased risk seen after the transfusion of a single unit, and incrementally increased risk associated with additional transfused units.

Speaking at the annual meeting of the American Urological Association in Atlanta, Ga., last week, Dr. Jonathan C. Routh reported that, of the more than 2,400 patients with RCC who had surgery at Mayo, the 5-year survival rates were 51.7 percent for those who received a transfusion and 83.1 percent for those who did not. The more units transfused, he said, the greater the mortality risk. More than 7,500 patients were included in the study of patients with adenocarcinoma of the prostate.

In both studies, the increased mortality risk associated with transfusion persisted even when potentially confounding factors such as tumor size and the stage of the cancer were taken into account. "Though these were the largest series to date to examine this phenomenon, these were retrospective studies, so there may have been biases that we did not correct for," Dr. Routh said.

Nearly 150 similar studies covering multiple cancer types have been performed, with differing conclusions on a possible transfusion-associated effect, Dr. Routh explains. Several theories have been put forth to explain the increased risk.

"Our laboratory is looking at whether this might be a T-cell mediated phenomenon," he says. "We have some very interesting preliminary data, but at this point nothing concrete to report."

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