What are car T cell therapies in cancer treatment, and why is there so much buzz about it nowadays?


For a long time, the cancer treatment universe was restricted to 4 modalities, in particular Surgery, Radiation, Chemotherapy and Targeted Drug Treatments. Of late, we have seen the expansion of a fifth front in the fight against cancer, called Immunotherapy. Researchers have been endeavoring to create approaches to prepare the human immune system to battle cancer cells, similar to how they eliminate germs in trifling issues such as the common cold.

When we become ill with the common cold, our immune system attacks the infectious germs and executes them, viably curing us. What is at work here are a sort of cells present in our blood called T-cells. T-cells have the one of a kind capacity to recognize affected cells, lock on to them and kill them.

In a CAR T-cell treatment, a patient’s T-cells are designed, so that they attach themselves to cancer cells and destroy them. Such T-cells are extracted from the patient’s own blood, and are built in a lab to identify particular proteins (or antigens) present inside cancer cells. Then, once these cells increase in adequate numbers, they are infused once more into the patient’s circulation system. Once in the body, they start targeting cancer cells.

The utilization of Car T-cell treatments had been constrained to clinical trials till recently. In these trials, numerous patients in advanced stages of cancer have encountered positive outcomes. Numerous such trials included patients experiencing advanced ALL (Acute Lymphoblastic Leukemia) with limited treatment alternatives. Most patients experienced 100% remission, and remained this way for prolonged periods of time. Comparable promising outcomes have been seen in the case of lymphoma patients. Some of these treatments have been approved for treatment in certain leukemias and few solid tumours.

While the symptoms of such medicines can be perilous, the medical science has developed practical protections against such impacts, with supportive treatments. Car T-cell treatments appear to have immense potential, however given the dynamic nature of cancer mutations, further investigation is required to standardize it and make it accessible to patients all around. Numerous labs around the globe are right now testing these treatments not only for blood cancer but also solid tumors, such as pancreatic and brain tumours. Given the measure of intrigue the field has produced among scientists around the world, it is likely that the following decade will be transformative in characterizing the cancer treatment paradigm.

 

Early-Stage Lung Ca: Better OS with Surgery?


Lobectomy seems to offer better long-term outcomes over radiotherapy, yet the latter is still gaining ground

An ongoing debate in the lung cancer community is whether patients with early-stage disease benefit more from surgery or from stereotactic body radiation therapy (SBRT). Radiation oncologists are certainly on board with SBRT in inoperable patients, and there is some data to back up that assertion, as highlighted in this ASCO Reading Room articlefrom last year.

Meanwhile, thoracic surgeons seem to be moving away from lobectomy, and have stumped for less aggressive surgical approaches, such as wedge resection and segmentectomy.

But any discourse gets that much livelier when there’s someone who is willing to offer a third opinion. Researchers at two University of California branches took on that monkey-wrench role with their study in U.S. veterans that compared lobectomy with SBRT — and decided that surgery was the winner. In an interesting twist, the authors are affiliated with radiation oncology — and not surgery — departments at their respective institutions.

“Our data suggest that the more aggressively we treat early lung cancer, the better the outcome,” noted Alex Bryant, of the University of California, San Diego, in a statement. “This study is one of the best-powered and detailed analyses to date and suggests that lobectomy is still the preferred treatment of this disease for most patients.”

Surgery Scores

Bryant and his colleagues identified early-stage non-small cell lung cancer (NSCLC) patients from the VA Informatics and Computing Infrastructure (VINCI). He described VINCI as “an extremely rich source of health information” from which the authors were able to gather detailed data related to a large, nationwide group of veterans.

The study population ultimately consisted of a little over 4,000 patients (97% male) who were diagnosed with clinical T1 or T2a (<5 cm in greatest dimension), N0 (no regional lymph node metastasis), M0 (no distant metastasis), biopsy-proven NSCLC. The diagnoses took place between Jan. 1, 2006 and Dec. 31, 2015.

Patients were treated definitively with either surgery or radiation. Those with a history of prior malignancy, those with a missing cause of death, those treated more than 6 months after diagnosis, and those with missing covariates were excluded. Covariates derived from VINCI were tumor size, tumor grade, histology, patient age, sex, race, and tobacco history. Having these data makes the registry particularly unique, Bryant noted.

“Factors such as these are often not available and have not been consistently addressed in previous studies, which sets this study apart.”

In terms of the procedures themselves, SBRT was defined as the delivery of one to five daily fractions of radiation directed at the lung (mean biologically equivalent dose of 124 Gy10), while the surgical groups were divided into lobectomy and sublobar resection. The latter included wedge and segmental resection; video-assisted thoracoscopic surgery and open surgeries were combined for this analysis.

The authors compared cancer-specific survival among patients receiving lobectomy, sublobar resection, or SBRT with univariable and multivariable competing risk analyses.

The unadjusted analysis revealed higher immediate post-procedural mortality in the surgery groups versus the SBRT group. While multivariable analysis that looked at long-term survival found higher cancer-specific mortality for SBRT compared with lobectomy (subdistribution hazard ratio 1.45, 95% CI 1.09-1.94, P=0.01), there was no survival difference between SBRT and sublobar resection (subdistribution HR 1.25, 95% CI 0.93-1.68, P=0.15).

“Despite the higher postoperative mortality risk, the lobectomy group had the lowest unadjusted risk of all-cause mortality at 5 years,” the authors wrote. “In the lobectomy group, the unadjusted 5-year overall survival [OS] was 70%, followed by sublobar resection at 56% and SBRT at 44%.”

In addition, the multivariable Cox proportional hazards model showed that SBRT was tied to a 38% increased risk of all-cause mortality versus lobectomy (HR 1.38, 95% CI 1.08-1.78, P=0.01).

There was no significant difference in OS between the SBRT and sublobar groups (HR 1.17, 95% CI 0.90-1.53, P=0.85), and there were no significant differences between groups when evaluating noncancer mortality based on univariable or multivariable analysis. There also was no difference in OS or cancer-specific survival between patients who received wedge versus segmental resection (P>0.09 in all unadjusted and adjusted analyses).

Finally, the authors noted that for every 10 Gy increase in biologically equivalent radiation dose, the risk of cancer-related death decreased by 7% (subdistribution HR 0.93, 95% CI 0.86-1.00, P=0.06).

A Resolution?

In spite of the perioperative mortality risks linked with surgery, lobectomy improved survival compared with SBRT in the long term, the researchers concluded. So did the group make the ultimate mic drop in favor of lobectomy? Not quite.

As one MedPage Today reader commented, SBRT is generally reserved for patients who are poor candidates for surgery. But a number of trials designed to compare SBRT with surgery in early-stage disease — STARS, ROSEL, RTOG 1021 — were shuttered early because of poor accrual.

“The probable reason that earlier prospective randomized trials failed to accrue was because surgeons who had operable stage I patients would not consider SBRT, and patients who were not surgical candidates didn’t qualify for randomization in the failed studies,” the reader pointed out.

That leaves the lung cancer community anticipating results from two recently launched trials — VALOR and STABLE-MATES.

The JoLT-Ca Sublobar Resection (SR) Versus Stereotactic Ablative Radiotherapy (SAbR) for Lung Cancer (STABLE-MATES) trial aims to recruit 258 patients at more than 30 institutions, and has an estimated primary completion date of December 2021.

STABLE-MATES’ principal investigator, Robert Timmerman, MD, of UT Southwestern Medical Center in Dallas, explained in a statement that the “two therapies [surgery and SABR] are both fiercely competitive, like thoroughbreds in a race. Yet when not competing on the track, they reside together in a stable enjoying each other’s company — ready and eager to be called on for the next challenge.”

Meanwhile, the currently recruiting Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy (VALOR) trial will compare the two modalities in 670 patients at 16 VA centers. The estimated primary completion date is September 2027.

VALOR co-principal investigator Drew Moghanaki, MD, MPH, of the VCU Massey Cancer Center in Richmond, VA, noted in a statement: “There is a lot of research that suggests stereotactic radiotherapy might be just as effective as surgery for lung cancer, or even better. Currently, more than 90% of lung cancers that are caught at an early stage can be controlled with this non-surgical treatment. We know it is often safer than surgery and, for this reason, cancer researchers now question whether surgery is still the optimal treatment for lung cancer.”

He added, however, that while this new treatment approach is promising, there has as yet been no successful comparison of stereotactic radiotherapy with surgery in a head-to-head trial to know how well it works in the long-term: “There are many oncologists who believe stereotactic radiotherapy might be the best way to treat lung cancer. But, until a study like the VALOR trial is completed we will not know what is the best treatment for all of our lung cancer patients.”

More on Surgery

Other recent research has also evaluated ways to refine lung cancer surgery:

  • Two investigators at Houston Methodist Hospital reported on the “five on a dice” port placement and technique to allow for minimal assistance during lobectomy
  • An Italian team explained why the technique for video-assisted thoracoscopic surgery (VATS) lymphadenectomy was the same as that of thoracotomy in early-stage lung cancer
  • Another group of Italian researchers found that VATS lobectomy for locally advanced-stage NSCLC was safe and effective in appropriately selected patients, ensuring perioperative results similar to those obtained in early-stage tumors
  • Japanese researchers reported on two patients in whom salvage VATS lobectomy was feasible after SBRT

The study by Bryant’s group was supported by the National Institutes of Health. Bryant disclosed no relevant relationships with industry; one co-author disclosed support from EMD Serano.

The VALOR trial is funded by the Veterans Affairs Cooperative Studies Program.

Broccoli Extract Can Rid Your Body of Cancer-Causing Chemicals and Fight Oral Cancer


It’s no surprise that cruciferous vegetables – such as broccoli, cabbage, and garden cress – are good for our health. Now, a new study demonstrates how broccoli sprout extract activates a gene that detoxifies carcinogens in the body, serving to prevent cancer recurrence in people who have encountered head and neck cancer.

The study, published in the journal Cancer Prevention Research, was led by Dr. Julie Bauman, co-director of the University of Pittsburgh Medical Center (UPMC) Cancer Center in Pennsylvania.

According to the Centers for Disease Control and Prevention (CDC), each year in the United States, over 30,000 new cases of oral cancer are diagnosed, and there are over 8,000 deaths due to oral cancer. The survival rate for such cancers is quite low, with a 5-year survival rate of about 50 percent.

“With head and neck cancer, we often clear patients of cancer only to see it come back with deadly consequences a few years later,” says Dr. Bauman.

Methods of treating oral cancers include surgery, radiation, and chemotherapy, but they can be disfiguring and costly. Repeated exposure to carcinogens is the greatest risk factor for head and neck cancer. Cruciferous vegetables have a high concentration of sulforaphane; previous research has shown it can protect people against environmental carcinogens.

 Dr. Bauman notes that previous attempts to develop drugs to reduce the risk of head and neck cancer recurrence “have been inefficient, intolerable in patients and expensive. That led us to ‘green chemoprevention’ – the cost-effective development of treatments based upon whole plants or their extracts.”

Lab, mice, and human studies have been successful

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To further investigate, Dr. Bauman and colleagues first treated human head and neck cancer cells with different doses of sulforaphane, as well as a control. They then compared them with healthy throat and mouth cells.

Results showed that the sulforaphane encouraged both cell types to increase levels of a protein that turns on specific genes that induce carcinogen detoxification, protecting cells from cancer. Next, in a small preclinical trial, for several days, 10 healthy volunteers drank or swished juice mixed with broccoli sprout extract.

Not only did the study subjects have no significant problems tolerating the extract, but the lining of their mouths also showed that the same protective genetic pathway was activated in their mouths. The researchers say this means the sulforaphane was absorbed and focused on at-risk tissue.

In a further experiment, the researchers used mice to see how the extract worked in those predisposed to head and neck cancer. Results showed that the mice that received the extract developed fewer tumors, compared with those that did not.

In light of the successful studies, Dr. Bauman and her colleagues have initiated a larger clinical trial in humans who have previously been cured of head and neck cancer. The participants are currently taking capsules with broccoli seed powder.

The researchers write:


”Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC [head and neck squamous cell carcinoma].”

Watch the video discusion. URL:https://youtu.be/QTA-BMAYaxQ

 

Spice Beats Chemo, Radiation, Surgery for Brain Cancer, Studies Suggest


Increasingly, science is validating the therapeutic value of spices to prevent and treat disease, including for conditions as serious as lethal brain cancer. 

Modern medical science is finally catching up to the wisdom of our distant ancestors. Spices, for instance, were once traded along ancient spice routes throughout Asia, Northeast Africa, and Europe, as highly precious commodities; some of them were so prized for their life-saving properties they were literally worth their weight in gold. Only in the past few decades have the traditional folkloric uses of these powerful plant extracts undergone validation via pre-clinical and clinical research. The results are nothing short of amazing, especially when it comes to providing hope for conditions that conventional treatment not only does not have anything to offer, but may actually worsen.

There are a number of driving factors behind the increasing interest innatural substances as drug alternatives, one of which is the fact that a large number of popular over-the-counter and prescribed drugs are extremely dangerous, don’t work as advertised (ineffective), and are exorbitantly over-priced (e.g. Some patented chemotherapy agents can cost 4,000 times more than gold by weight!). To the dismay of the medical industrial complex, the public is growing increasingly aware of these facts. Indeed, it’s a problem hard to ignore when correctly prescribed drugs have been estimated to take over 100,000 lives each year in the U.S. alone.

Turmeric is one of the most powerfully healing spices known, and yet its use is still mostly relegated to an FDA-approved food coloring agent, instead of the safe, effective, affordable, and easily accessible remedy for the prevention and treatment of disease that is is. In total, we have identified research on its potential value in preventing and treating over 800 different conditions, with cancers — dozens of them — being the most thoroughly researched aspect of its healing properties.

Recently, research has surfaced revealing it may help to combat one of the most lethal forms of cancers: glioblastoma. 

Glioblastoma is a particularly fast-growing and deadly form of brain cancer which, despite aggressive therapies, is associated with survival rates that rarely surpass two years. Given the poor prognosis, and the serious dangers linked to chemotherapy, surgery, and radiation, natural solutions are beginning to be taken more seriously by the conventional medical establishment. Indeed, two recently published studies provide compelling evidence that turmeric/curcumin may be a viable option in preventing and treating this deadly brain disease.

The first study, published in the journal Medical Oncology titled, “Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma,” looked at a total of 19 in vitro (test tube) and five in vivo (animal) studies on the turmeric extract curcumin and its ability to combat glioblastoma.

Their literature review produced the following findings:

“A total of 19 in vitro and five in vivo studies were analyzed. All of the studies indicated that curcumin decreased glioblastoma cell viability through various pathways (i.e. decrease in prosurvival proteins such as nuclear factor κB, activator protein 1, and phosphoinositide 3 kinase, and upregulation of apoptotic pathways like p21, p53, and executor caspase 3). Curcumin treatment also increased animal survival compared with control groups.”

The authors concluded:

“Curcumin inhibits proliferation and induces apoptosis in certain subpopulations of glioblastoma tumors, and its ability to target multiple signaling pathways involved in cell death makes it an attractive therapeutic agent. As such, it should be considered as a potent anticancer treatment. Further experiments are warranted to elucidate the use of a bioavailable form of curcumin in clinical trials.”

From these studies alone, we can not yet draw definitive conclusions about whether or not curcumin will work the same way in humans; nor did the cited research address the problem of the relatively poor bioavailability of curcumin extracts. Moreover, in the case of brain tumors, the delivery of curcumin to the brain is hard to ascertain or prove for obvious reasons (you would have to cut open the brain or use toxic fluorescent dyes and brain scans).

Despite these limitations, a new study published in the journal Nutrition and Cancer and titled, “Intratumoral Concentrations and Effects of Orally Administered Micellar Curcuminoids in Glioblastoma Patients,” provides evidence that it is possible to get physiologically relevant doses of curcumin into glioblastoma tumors of patients via oral delivery methods.  The study used human subjects to determine the bioavailability of a combination of so-called micellar (water dispersible) curcuminoids. Specifically, the study participants were administered 70 mg of the curcuminoid combination 3 times a day for 4 days prior to surgical resection (removal) of their respective brain tumors. Tumor and blood samples were taken during surgery and analyzed for total curcuminoid concentrations, and (31) P magnetic resonance spectoscropic imaging was performed before and after curcuminoid consumption.

They found that curcumin was absorbed into the tumors. The results were reported as follows:

“Ten (of 13) patients completed the study. The mean intratumoral concentration of curcumin was 56 pg/mg of tissue (range 9-151), and the mean serum concentration was 253 ng/ml (range 129-364). Inorganic phosphate was significantly increased within the tumor (P = 0.034). The mean ratio of phosphocreatine to inorganic phosphate decreased, and the mean intratumoral pH increased (P = 0.08) after curcuminoid intervention.”

The study concluded:

“Oral treatment with micellar curcuminoids led to quantifiable concentrations of total curcuminoids in glioblastomas and may alter intratumoral energy metabolism.”

Taken together, these two studies clear the path for a better understanding of how and why turmeric extracts may help combat treatment refractory glioblastoma.

Additionally, because it is known that cancer malignancy and resistance to treatment is due to cancer stem cells, and that glioma stem cells are present in glioblastoma cancers, turmeric extract is clearly superior in that it targets this particular subpopulation of radioresistant and chemoresistant cells that conventional treatments do not. In fact,chemotherapy and radiotherapy have been shown to actually enrich cancer stem cell populations. This means these treatments may actually increase glioblastoma malignancy and can accelerate the death of patients.  

For more information on natural glioblastoma interventions, as well as likely risk factors and causes (e.g. SV40 from vaccines),  take a look at our glioblastoma research portal. You’ll find commonly available and recognized foods, plants, and phytocompounds listed there, such as:

  • Cannabinoids

  • Olive Oil

  • Berberine

  • Genistein

  • Carrot

  • Sulforaphane

  • Green Tea

  • Lysine

  • Vitamin C

The Immunologic Effects of Surgery: Spurring Tumor Growth


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Richard Whelan, MD

Richard Whelan, MD, is director of surgical oncology and colon & rectal surgery at Mount Sinai St. Luke’s Roosevelt Hospital, in New York City. He was one of the first surgeons in New York to perform laparoscopic colectomy and helped develop hand-assisted minimally invasive surgical (MIS) techniques. Since 1996, he has directed a basic science and clinical research lab that has shown surgical procedures can cause temporary changes in a patient’s blood composition, changes that may promote the growth of cancer tumor deposits. General Surgery News spoke with Dr. Whelan after a presentation he gave at the 2016 Minimally Invasive Surgery Symposium.

Q. What inspired you to start looking at immunologic effects of surgery?

A. In 1996, laparoscopic surgery was becoming popular, but not in colorectal surgery because of fears about port-site tumors. We began by comparing laparoscopic with open surgery, looking at the effects on the physiology of the body. We also used tumor models in mice to look at port-site tumors and began to notice that major surgery affected the way tumors grew. We weren’t the first to notice this effect: There’s a body of literature that extends way earlier that shows surgical trauma somehow stimulates tumor growth. Since 1996, we focused on trying to find more information about these surgical trauma–related cancer effects.

Q. You’ve also studied this in humans?

A. We made the jump to human research in the 1990s, which confirmed what others had noted, namely, that surgery causes immunosuppression. If you do major surgery, you’ll get immunosuppressed for a brief time. It could be less than a week or a couple of days longer, but this seems to have an effect on how tumor cells behave for a while.

Q. Is there a difference between the effect of laparoscopic and open operations?

A. Ten years ago or so, we realized, in regard to blood compositional changes, open and laparoscopic surgery are very similar in regard to the way they affect tumor growth after surgery. We initially hoped that laparoscopy would be associated with a cancer survival benefit, but that just has not been borne out clinically. The laparoscopic and open methods probably are very similar in regard to the effects they have on proteins in the bloodstream.

Q. What are those effects?

A. When you do a major operation on somebody and you check the blood proteins that affect inflammation, you see changes that last anywhere from two to four days. Some of them last just 12 hours. These are real changes that you can detect if you measure cytokines and inflammatory markers, but they tend to disappear pretty quickly. This is the case with classic trauma markers such as interleukin-6 or C-reactive protein. They resolve pretty quickly. We stumbled on the fact that there’s another group of changes that last up to five weeks. We believe these more persistent changes are of more concern. If the proteins in question have the capacity to affect tumor growth, then they might stimulate the growth of residual tumor deposits or circulating tumor cells in the first month after the operation to remove the primary cancer. If you have an effect that lasts for five weeks, the chance of it stimulating tumor growth would be much greater. We’ve found the levels of vascular endothelial growth factor (VEGF), which is a very well-known protein, were elevated right after surgery and continued to rise. They peaked two weeks after surgery and were elevated for up to four weeks. That was a surprise because no one had ever shown that surgery had effects you could detect in the bloodstream that would persist that long.

Q. And there are changes that extend beyond VEGF?

A. We’ve found a total of 14 proteins that share this pattern of being elevated for three to five weeks after surgery. All of those proteins affect angiogenesis. Proteins that promote angiogenesis that are elevated for a long period of time after surgery might stimulate new blood vessel formation in existing tumor deposits, resulting in tumor growth. This could be a problem in patients who have a cancer removed but have some small, unknown metastases left behind.

Q. Do we see evidence of this outside of test tubes?

A. There are data in the literature about patients who show up with a liver cancer and a colon cancer at the same time. A number of studies show 25% to 35% of patients who first have surgery for a colon cancer will have marked growth in preexisting liver lesions or will develop new liver metastases in the three- to four-month interval before the liver resection is done [J Gastrointest Surg2008;12:1391-1398]. There’s also a study that looked at PET scans done before and after surgery in similar patients with simultaneous colon cancer and liver metastases. They found that those patients who had the colon tumor resected first, on repeat PET imaging a few months later, showed significantly increased FDG (18F-fluorodeoxyglucose) uptake [Surgery 2005;137:246-249]. The point is there is clinical evidence that when do you an operation like colectomy in someone who has liver metastases, it can stimulate the growth of those tumors.

Q. What’s the end goal for your research?

A. We want to prove to doctors and patients that we need to do some kind of anticancer treatment during that first month after and perhaps just before surgery. Most chemotherapy is started, at the earliest, one month after surgery. Most often in the United States, it’s six to eight weeks. We believe that we have shown that the first month may be a dangerous time period for cancer patients. Our lab is devoted to explaining and understanding the oncologic effects of surgery. We’re trying to find agents that are safe to take immediately before and after surgery that can slow tumor growth during this period when there may be stimuli to grow faster. The problem is that you cannot give something that will interfere with wound healing; thus, the drug must kill tumor cells but not inhibit healing.

Q. Have you found anything?

A. In the past, we gave immunomodulators perioperatively that showed some promise [Eur J Surg Oncol 2007;33:1169-1176]. Now, we’re doing a study wherein two antioxidants, one found in green tea and the other in milk thistle, are given to patients for a week before and three weeks after cancer surgery. We’ve checked these agents in animals and showed that they do inhibit growth, to some extent. Of note, they have also been shown not to inhibit wound healing in mice; therefore, they should be safe to take after surgery. This is an FDA-approved Phase I trial.

Q. Why do some changes after surgery last only a few days and others for weeks?

A. That’s a question we’re trying to answer this year. We think the source of all these proteins is the healing wounds. Angiogenesis is a critical part of the healing process and plays a key role in the tissue remodeling that occurs for over a month after surgery. We just presented a poster at the 2016 American Society of Colon and Rectal Surgeons annual meeting that showed that blood levels of eight angiogenesis-promoting proteins were significantly elevated after MIS colorectal resection during the month after surgery. Of note, the study also showed that wound levels of the same proteins were between six and 50 times higher than the blood levels. So, it looks like the extra protein is being made in the wounds and is then spilling into the bloodstream.

The wound is an area of intense growth, and the conditions that a wound needs to heal turn out to be the same conditions that a cancer needs to grow. If you look at a healing wound under a microscope and you look at a cancer, it’s hard to tell them apart. The difference is that the cells in a healing wound know to stop dividing when the tissue gap is filled. In a cancer, the cells keep growing. To put these findings in perspective, once the anesthesia-related changes and immediate effects of trauma have resolved two to five days after surgery, a second set of blood protein elevations occur that are related to wound healing. The wounds contain very high levels of these proteins. These blood protein changes render the blood proangiogenic. In patients with residual tumor deposits, these conditions may stimulate new blood vessel formation in the tumors that allow cancer growth. These findings, perhaps, explain why it now is standard practice not to remove the primary tumor in patients who have unresectable metastases, unless they are bleeding or obstructed. In the past, the primary tumor was routinely removed to reduce the tumor burden and then chemotherapy given. Results with chemotherapy alone are superior to those after primary resection followed by chemotherapy. The bottom line is that surgery is a double-edged sword, and there are times when it is best left in the scabbard.

Q. But you’ve said this effect of elevated blood proteins isn’t in all patients?

A. What we’ve reported is the mean or average levels for groups of patients. For all the proteins in question, the average late post-op levels are significantly elevated compared with mean pre-op blood levels. However, if you look at each patient, it turns out that maybe 25% to 40% of patients have a big increase, whereas other patients have modest increases or no elevation at all. We are currently in the process of trying to identify the characteristics of patients with big increases. If we can figure out who those patients are, we could perhaps modify the way in which we treat these patients.

Q. Based on the evidence now, what do you recommend surgeons do to minimize the negative effects of surgery?

A. The easy answer is that on our website we have a section on perioperative therapies. They’re holistic things, chemopreventive things: green tea and silibinin (milk thistle). Also cimetidine, an ulcer drug that is believed to suppress T cells that inhibit the immune response to tumors. There are data from four or five small clinical studies suggesting that perioperative cimetidine may improve cancer outcomes. We encourage our patients to consider taking one or several of these agents while they are waiting for surgery and for a month after surgery.

Q. What’s the take-home message for general surgeons about your research?

A. Surgery has many effects and most of them are good, but we’ve found something that may be a detrimental one. What this information does is gives me pause before I operate on a cancer patient. I want to make sure that there’s no option to give chemotherapy alone or before surgery. It’s important that we don’t rush into surgery without thinking of the possible ramifications. Also, we need to find safe and effective anticancer agents that can be given perioperatively.

A Patient-Centered Solution To Simultaneous Surgery


The practice of concurrent, or simultaneous, surgery has largely been hidden from public knowledge until recently, and current guidelines regulating the practice fall short in protecting and serving patients in crucial ways. Simultaneous surgery occurs when one surgeon, with the help of assistants, performs two surgeries on two different patients in different operating rooms at the same time. A series of articlespublished last year in The Boston Globe propelled the practice into public consciousness. In response to the ensuing outcry the American College of Surgeons revised their guidelines with respect to simultaneous surgeries.

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The medical community hopes this will put the controversial matter to rest. The revised guidelines stress both informed patient consent and the necessity of ensuring that surgeons are present during “critical elements” of any surgery. Importantly, these guidelines leave the decision regarding what exactly constitutes “critical elements” completely in the hands of the operating surgeon. While I applaud the emphasis on informing patients, these guidelines are not nearly enough, and fall short in two crucial ways.

Truly Informed Consent

Informed consent has been the standard of care for American physicians for decades. Unfortunately, we continue to be surprisingly bad at it.

Recent research shows that only a small minority of patients—just 9 percent in one study—receive adequate information from their medical team to make truly informed decisions. I suspect that explaining to patients that their surgeon will be operating on other patients while the patient is undergoing his or her surgery will be even more difficult and less successful. Euphemisms, incomplete information, and oblique discussions will be the norm. This is an issue that deeply concerns patients: in one study, when patients were given a realistic scenario in which a resident would act as the operative surgeon without direct staff supervision, only 18 percent said they would give consent.

Additionally, the recommended timing of this discussion is completely absent from these guidelines. Telling patients on the day of their surgery—which is often when consent is obtained—that their surgeon will be absent from the operating room and busy working on different patients for parts of their procedure is terribly unfair. At that point, patients are emotionally prepared to proceed with surgery, work arrangements have been made, and family members are all assembled. This is not the time to present potentially disconcerting new information and ask patients to accept it.

When surgery is first discussed, surgeons should tell patients if they practice simultaneous surgery, and explain what this will mean in the operating room. Elective surgery schedules are typically developed weeks or months in advance of the surgery date, so forewarning patients promptly would give them adequate time to consider the idea and ask questions. It would also give them time to find another surgeon if they are uncomfortable with the practice of simultaneous surgery.

Defining Critical Elements

According to the American College of Surgeons guidelines, each surgeon should decide, acting in their sole discretion, which components of each surgery are “critical elements” worthy of their attendance in the operating room. Such a standard is subject to all sorts of confounding variables. A physician’s mood, the demands of the daily surgery schedule, or even the insurance status of a patient may affect how a surgeon views the critical parts of any one surgery. The fear this standard engenders is that what a surgeon considers to be “critical” in a procedure performed on his partner’s mother may be different from what is considered “critical” for the average patient operated on at the end of a long day.

Asking surgeons, by themselves, to define “critical” components of any patient’s surgery is completely upside down. Patients take all the risk and bear all the expense of a surgical procedure; therefore, they—through their payors or representatives—should define the standard for a surgeon’s participation in any patient’s surgery.

To use current parlance, the standard should be patient-centered, easily understood and discussed, and agreeable to the patients undergoing surgery. This type of standard would be identical to what we expect from other professionals. Lawyers, for instance, adhere to federal and state legal standards about how they practice and financial advisors adhere to fiduciary standards imposed upon them by regulators. These standards are easily understood, not just by professionals, but by everyone participating in the process — they are transparent and build trust between members of the public and the professionals who serve them. Because of such standards, Americans know exactly what they can expect in their dealings with these professionals.

Currently Medicare and other insurers fully reimburse for simultaneous surgery when the surgeon is present for only those parts of the procedure that that surgeon deems critically important. In order to reduce the influence of such subjective variables as time of day, the patient’s insurance status, or other demands upon members of the operative team, this decision should not be left to the surgeon. Instead, payers or other patient representatives should be the ones defining which elements of a surgery are critical, and patients should know exactly what to expect while unconscious in the operating room.

For example, CMS might expect a surgeon to be in the operating room from the time she moves beyond the subcutaneous tissues until only these tissues are left to close. Everyone in the operating room would understand such a standard and know what to expect, including the surgeon, assistants, the anesthesiologist, operating room nurses, and, most importantly, the patient who places his life in the care of others.

Justice Benjamin Cardozo said it well in 1914 in the case that made informed consent the law of the land: “Every human being of adult years and sound mind has a right to determine what shall be done with his own body,” and this extends to the right to make judgments over who shall perform surgery and under what conditions. A patient-centered, transparent standard for simultaneous surgery is surely the way forward. It will increase patient trust in their operating team and keep the team on the same page; it will simplify informed consent discussions for patients; and it will ensure that all patients know exactly what to expect when they are unconscious and vulnerable. Payers and regulators, working with the medical community, should adopt such standards expeditiously.

Antibiotics vs. surgery for appendicitis: Critique of a meta-analysis


A meta-analysis can be useful when looking at a topic that has been studied by several different groups of investigators. The pooling of data from different published papers can sometimes bolster a conclusion about the effectiveness of a treatment.

However, a meta-analysis is only as good as the studies it includes, and the biases of those performing the meta-analysis can color the results.

Last month, a meta-analysis concerning antibiotics vs. surgery for the treatment of uncomplicated acute appendicitis by investigators from Nottingham University Hospitals was published in the World Journal of Surgery.

The authors concluded that “antibiotic therapy represents a safe, efficacious and viable treatment option for the treatment of uncomplicated acute appendicitis.” I disagree.

Five randomized trials involving 1430 subjects were included in the meta-analysis. After one year of follow-up, the efficacy of treatment for those receiving antibiotics was 62.2% compared with those undergoing appendectomy whose treatment efficacy was 88%. Depending on the inclusion or exclusion of a particularly weak study there was said to be a 39-52% risk reduction for complications in the antibiotic group.

This meta-analysis has so many problems that it is hard to know where to start.

Would you let a robot perform your surgery by itself?


This is the Smart Tissue Autonomous Robots, known as STAR, in action.

Robots have become the norm in numerous industries, taking over repetitive tasks that humans aren’t necessarily needed for — or want to do — such as the production of cars and electronics.

One step up the technological spectrum is artificial intelligence, where robots are now making informed decisions based on the tasks they’re presented with, highlighted by the burgeoning field ofdriverless cars.
As we get used to the idea of machines producing our goods, we’re slowly coming around to them making decisions for us, but would you put your life in their hands? More specifically, would you let a robot perform surgery on you?

Better than a human surgeon

Performing heart surgery without touching the heart

The idea might scare you, but scientists are making it happen — and doing it safely — as shown in a recent study by surgeons at Children’s National Medical Center in Washington.
The team showed for the first time that a supervised autonomous robot could perform soft-tissue surgery, stitching together a pig’s bowel during open surgery — and doing so better than a human surgeon.
“This smart, intelligent technology will tell you how to (conduct surgery) optimally,” said Peter Kim, associate surgeon in chief at the hospital and project lead on the Smart-Tissue Autonomous Robot, or STAR. “This is not to replace surgeons tomorrow but provide collective experiences of how things should be done.”
Kim argues that developing robots in this way can ensure all patients receive the best care, regardless of which surgeon is available when they are in need of it. “Wouldn’t it be nice that whenever or wherever you need surgery, it’s done by the best surgeon?”
 Surgeons monitor an operation performed by the Smart-Tissue Autonomous Robot (STAR).

Scientists have discovered a new body part.


Scientists have discovered a new ligament in the human knee, which seems to play an important role in patients who suffer ligament injuries and their knees continue to ‘give way’ even after treatment.

The discovery was made by orthopaedic surgeons Dr Steven Claes and Professor Dr Johan Bellemans of the University Hospitals Leuven, who have been conducting research for the last four years into serious anterior cruciate ligament (ACL) injuries.

They studied 41 cadaveric knees using macroscopic dissection techniques to examine why some patients continue to suffer the pivot shift, where the knee gives way during physical activity.

ACL tears are common among athletes and those who play sports such as basketball and football.

Dr Claes and Dr Bellemans followed on from the work of French surgeon Paul Ferdinand Segon in 1879, who penned an article that suggested an additional ligament may exist on the anterior of the knee.

Orthopedic surgeons find a new ligament that may explain why knees ‘give

Their research, published in the Journal of Anatomy, shows the new ligament now known as the anterolateral ligament (ALL) was present in all but one of the 41 knees.

Subsequent research shows that pivot shift of the knee in patients with an ACL tear is caused by an injury in the ALL ligament.

The study concluded: “Given its structure and anatomic location, the ALL is hypothesized to control internal tibial rotation and thus to affect the pivot shift phenomenon, although further studies are needed to investigate its biomechanical function.”

Dr Claes and Professor Bellemans are currently working on a surgical technique to correct ALL injuries, which could be ready within the next seven years.

The secret language of surgery.


There are many voices in the operating theatre, and sometimes the most important are those that don’t use words at all.
Heart surgery

For a newcomer, the operating theatre is an overwhelming place. Sound is all around: beeps, alarms, the noise of people moving. Speech, when it surfaces, uses an alien language peppered with abbreviations and jargon. Photograph: Sean Smith/Guardian

The first time I took part in an operation I had no idea what was going on. As a new medical student I hadn’t learned the language of surgery. I didn’t even know there was a language of surgery. A few years later, as a surgeon myself, this language had become second nature and I didn’t even know I was using it.

Of course there are many voices in the operating theatre. They don’t always say what they mean or mean what they say. And sometimes the most important voices are those that don’t use words at all.

For several years I’ve been leading research projects that investigate how people communicate during surgery. At Medicine Unboxed in Cheltenham, I’m going to explore how to read some of these surgical voices and make sense of what they say.

Of course the story starts with the patient. What happens to their voice during surgery? At first glance, it seems to have disappeared altogether, especially if the operation needs a general anaesthetic. In the anaesthetic room the patient gradually relinquishes autonomy, leaving behind their personhood and their power to speak for themselves as powerful drugs make them unconscious.

But they haven’t stopped communicating. Speech mutates into a language of the unconscious body. Functions that we take for granted and scarcely notice – our heart beating, our lungs breathing, our blood circulating – are represented by wavy lines on a screen or the beep of a machine. Words have turned into traces, and the voice of the anaesthetised patient has become transformed.

Throughout the operation the surgical team monitors this wordless commentary, this constant unconscious broadcast of the body. Any variation – a change in rhythm, a subtle inflection of pitch – will put the team on high alert. The team has become fluent in the language of unconsciousness.

When the operation is over, when the wound is closed and the dressings are in place, the anaesthetist disconnects these machines and hands back the power of speech.

Reading voices

In the operating theatre, different voices are in play. At the centre is the scrub team – those who operate on the body itself. Around them are other members of the group – equally important but differently so – and all have different voices.

The surgeon’s voice is often muted, soft, muffled by a mask. Intended for the scrub team only, it may be inaudible beyond. Voices spread out in ripples from the scrub team: requests for instruments, instructions to others in the theatre. The anaesthetist, the operating department practitioner, the runner nurse – all have their ways of speaking, their vocabularies, their own vocal fingerprint.

The voices you hear depend on where you’re standing. Like conversation at a party, there are ebbs and flows, natural rhythms and patterns. Often you can’t make out the words, but you have to interpret the many meanings within this soundscape of surgery and recognise when they involve you. You develop new sensitivities, new ways of reading what is said.

What do these voices convey? Some are the voices of people talking in ordinary words. But others are different. Some are distorted voices, pulled out of shape by their peculiar setting. Some are transformed voices, expressed through machines instead of words. And some are silent voices, conveying their message by what they do not say.

Reading voices isn’t easy. For a newcomer, the operating theatre is an overwhelming place. Sound is all around: beeps, alarms, the noise of people moving. Sometimes music. And speech, when it surfaces, uses an alien language, peppered with abbreviations and jargon.

Once you get used to it, you can tell how things are going the instant you step in. If all is well, there’s a general buzz of conversation, movement, activity. But if things are going badly, you sense the tension without even knowing how. The most eloquent voice of all is the voice of silence: the voice that says ‘we’ve got a problem here and we all need to focus on fixing it’.

In my conversation at Medicine Unboxed, I hope to unpick some of these ideas, exploring what’s different about surgical voices and what they can and cannot say.