Promissory Notes, Demonstrations for the First Time, and Other Claims in Scientific Research

There seems to be a need for some investigators to claim priorities and/or suggest clinical relevance or potential clinical usefulness of an agent or therapy based upon limited experiments or studies in a small number of animals, tissues, or cells. I have called this a promissory note, which is inferred at the end of an abstract or an article. Much of the time there have been no clinical studies to suggest the possibility of this usefulness. Two examples that stand out in the literature in the recent past are the following. Seino et al. (1) say in their conclusions that “these results provide the basis for a novel therapeutic modality in which an unfavorable apoptotic process can be inhibited without affecting a favorable response for liver regeneration; this would be relevant to the clinical treatment of acute and chronic liver diseases as well as to some inflammatory disorders with hypercytokenemia such as sepsis.” These conclusions were made on the basis of a mutant in mice in which there was Fas-association protein with death domain (FADD) deletion. The number of animals studied was not mentioned. Another example is an article about increased NFκB activity that mediates increased cox-2 expression after trauma. The authors write, “Given the reported immunosuppressive properties of PGE2, NFκB may provide a potential molecular target to reverse trauma induced immunosuppression” (2). These statements were based on a study of 12 mice, six in a control group and six in the traumatized group. These are examples, I believe, of investigators overstating their case and going well beyond the data of their study. I reviewed papers presented and published in the Surgical Forum from a recent meeting of the American College of Surgeons, and I found over 10 that had promissory notes. Examples from this and from other publications are shown in Table 1. Recent editions of the journals Shock, Archives of Surgery, Annals of Surgery, The American Journal of Surgery, and abstracts from other programs contain examples of promissory notes. These examples include “interleukin (IL) ____ may have potential clinical benefits in the therapy and management of intra-abdominal infection and sepsis,” “These results suggest that ____ may be useful as a vaccine for the prevention of gram negative bacterial infection,” “Since ____ improves cardiovascular hepatocellular function, this agent may be a useful adjunct to fluid resuscitation after trauma in hemorrhagic shock,” “IL-____ appears to play an active role in the postinjury immune response making it an attractive therapeutic target in attempts to control hyperinflammatory provoked organ injury,” “Our findings indicate a potential prophylactic and therapeutic role for this substance during SIRS,” and “These biologic effects suggest ____ as a promising candidate for the treatment of sepsis in humans.” Many other examples could be given.Table 1: Examples of promissory notes (all suggest therapy)Others claim priorities such as “this is the first demonstration that NFκB-dependent chemoresistance may be overcome in pancreatic cancer” (3), “to our knowledge, this is the first direct evidence that alveolar instability contributes to lung injury” (4), “these results constitute the first demonstration of GV and GX PLA2 mRNA and proteins in human PMNs” (5), “Our results demonstrate for the first time that PTEN expression in the colon is limited to differentiated colonocytes” (6), or “The data demonstrate for the first time a positive association of Fas-ligand with male gender and multiple organ failure” (7). Do these authors think that the Nobel Committee will find these claims important in their reviews? Others emphasize timing: immediate, on the horizon, in the future, in the distant future, and its a light at the end of the tunnel. These studies are all interesting, worthwhile, and important. They provide good information about many disease processes. They should be reported. However, they may never come into clinical usefulness or may never even be evaluated in clinical trials. Why, then, do investigators who studied 30 rats suggest that their results could be clinically useful? Do they believe that by so saying or writing this that it makes their contribution more important? Are they expected to do this by granting agencies? Does the National Institutes of Health (NIH) expect clinical relevance in grant applications? Do journals expect that? There was a recent flurry of excitement about the agents that block angiogenesis factor that were reported by Dr. Judah Folkman and his group. Dr. Folkman is a respected surgeon and an excellent investigator. Newspapers and other media, however, blew his report into the possibility of a clinical cure for cancer. He was quoted in his usual modest way saying, “If you have a mouse with cancer, I think we can cure it”. The media, in trying to create news and excitement, created what is better called “hype” and produced unreasonable expectations. Lay people have their expectations raised. Many with difficult or hopeless problems or situations are looking for some hope. It is unfair to people and fellow scientists to stretch the data into clinical relevance. Moldawer wrote an accurate fair qualifier for programmed cell death in sepsis that serves as an example. He wrote, “Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of apoptosis may represent an appropriate therapeutic target for the septic patient” (8). All of us who have done research know the excitement about results in our animal laboratories. Many, if not most, of these results never came into clinical usefulness. I love research, but I abhor stretching the results of otherwise good research to suggest clinical relevance. Research seeks the truth—what happens in biologic phenomena? Animal models will provide interesting and worthwhile information even though this information is not clinically relevant. In fact, few animal models provide information about therapy in patients unless the disease occurs naturally in animals, such as cowpox. It is difficult to develop therapy solely based on animal studies other than for toxicity studies. Examples of these include agents that I personally studied along with my fellow investigators years ago in our animal laboratory. We studied low molecular weight Dextran to prevent sludging of blood in the microcirculation with shock, clinical Dextran to provide oncotic pressure, phenoxybenzamine (dibenzyline, an α-adrenergic blocking agent) to prevent the excessive vasoconstriction of shock, tris-hydroxymethyl-aminomethane to correct intracellular acidosis (THAM), 2-3 diphosphoglycerate 2-3 (DPG) to improve oxygen unloading in the capillary bed, polarizing solutions, steroids for septic shock, white blood (large amounts of ringer's lactate solution), buffers, and so forth. Several of these agents did go through some clinical evaluation, but none of them ever became accepted treatment of injured or sick patients (9–11). Examples of encouraging early animal and tissue studies that have not been found worthwhile in clinical studies are the use of matrix metalloproteinase inhibitors (MMPIs) in cancer. Coussens, et al. (12) wrote, “For at least 30 years, MMPIs have been heralded as promising targets for cancer therapy.” Preclinical studies testing the efficacy of MMP suppression in tumor models were so compelling that synthetic MMP inhibitors were rapidly developed and routed into human clinical trials. The results of these trials have been disappointing. Perhaps it would be better to be species specific about the recommendations in an abstract or in an article. For example, Seifert and Oesser (13) conclude, “these results show that fibronectin is an essential protein which is decreased in severe infection and can be substituted and improve the mortality rate in peritonitis of rats.” This species specificity could be used, for example, in the following “taken together, these data suggest that inhibition of IL-4 or the IL-4 signal transducer stat-6 may provide a novel approach to ameliorating immune suppression and the associated mortality encountered in polymicrobial sepsis (in mice)” (14). There are many other examples where species specificity in rats or mice may help the reader. For example, in saying that a particular approach may be a useful adjunct for the treatment of trauma victims, it would be important to point out that these trauma victims were rats, not patients. There are many hedge words that are used, such as a potential strategy or target for therapy, a new therapeutic concept or approach, a potential molecular target, a promising potentially useful adjunct, such and such may prove beneficial, it suggests that it may be efficacious in patients, and novel and safe adjuncts. “It may represent a new therapeutic strategy for treating gram-negative sepsis” happened to be from a study of cultured hepatocytes. Another example is “these data suggest that pentoxifylline may be a possible candidate as future therapy for acute pulmonary dysfunction. Further studies in human patients are necessary” (15). I have been told that that NIH and perhaps the Medical Research Council of Canada expect research proposals to describe some potential clinical relevance. The application form for an RO-1 grant for research from the NIH contains the following requirement: “Please complete this section on background and significance. Briefly sketch the background leading to the present application, critically evaluate existing knowledge and specifically identify the gaps that the project intends to fill. State concisely the importance and health relevance of the research described in this application by relating the specific aims to the broad, long-term objectives. Two to three pages are recommended.” I have been told, also, that members of study sections of the NIH recommend funding of grants that evaluate potential clinical relevance and that this should be considered in their review process. However, in a recent review of the NIH peer review overhaul by former director Harold Varmus and others, nothing was said about clinical relevance (16). Significance was important for the science, but not necessarily clinical significance. Does the study address an important problem? In the approach, are the conceptual framework, design, and methods of analysis, adequately developed? Is there innovation and does the project use novel concepts? Is the investigator appropriately trained? Does the scientific environment in which the work will be done contribute to the probability of success? A carefully controlled animal study with one perturbation and one agent being evaluated may provide statistically significant results. If this perturbation produces a mortality of 50% and the agent has a modest influence to decrease mortality to 20%, this could be a statistically significant result. However, this is a long way from clinical relevance. There are also biologic conundrums or puzzles in the complexity of information. An example is tumor necrosis factor that if given intravenously or if endotoxin is given intravenously, produces deleterious effects. These effects can be blocked by antibodies (17). However, if TNF is blocked by an antibody in an animal model of peritonitis, the mortality of the animals is greatly increased (18). Boehm et al. (19) found that sFas-ligand was not elevated in the serum of septic ICU patients (a human ELISA), whereas Sigel et al. (20) found that Fas-ligand concentrations were increased in critically ill patients and were higher in men and in those with MOF (ELISA kit for Fas-ligand). Were these differences due to different methodologies or the patients? Also, Fleck et al. (21) found that increased levels of soluble Fas were present in the sera of patients with sepsis. What do these differences mean in terms of apoptosis and human infection? There are many other examples of such conundrums, too much, too little, too soon, too late, good in this circumstance, and bad in that. There is also a big problem of biologic simplicity in investigating separately the many individual factors involved in infection, sepsis, inflammation, and injury (reductionist biology). This is contrasted with the biologic complexity of human disease and injury. There are also great genetic variations in patients. We all perform precise animal experiments that may or may not be relevant to imprecise or clinical variable problems. Also, because many diseases require specific treatment such as antibiotics for infection, bowel resection for perforated diverticulitis, and so forth, a proposal for a nonspecific agent should be for adjuvant therapy. This would seem much more realistic. Finally, do investigators insert a promissory note at the end of the abstract or in the discussion section of their experimental study because they truly believe that this could be clinically relevant and important, or is it because they are expected to? I do not know the answer to this. I suspect it may be a bit of both. We would all like to speculate about the far-reaching effects of our research. I am sure that these possibilities drive investigators in study sections of the NIH, and some of this can be good. What is the answer, then, to promissory notes? I believe that we should avoid suggestions or recommendations that go beyond the data. We should be species specific. We will learn a lot about diseases and mechanisms in the process. Eventually, therapy will improve. Let the results speak for themselves. A satisfactory suggestion is that in the future, continued studies and clinical evaluation may lead to improvements in patient care. In Table 2, I list some promissory notes from the literature that I find more acceptable. A colleague compared an example from Table 1, “may lead to the development of new strategies to prevent MOF” with one from Table 2, “may provide further insight into the pathogenesis of post-injury MOF.” He asked, “What is the difference?” The example from Table 1 is prevention of a clinical entity, therapy, which may or may not ever happen. The Table 2 example, further insight, promotes understanding—a scientific endeavor to help clarify a clinical situation but not therapy. The Table 1 example would be more acceptable to me if it read, “may lead to a better understanding of MOF.” Some readers may think that I am nit picking. I believe that the use of hedge words such as potential, could be useful, may offer, can be considered, a novel approach, and may represent are not the same as “further studies may lead to novel strategies for therapy.” Suggesting clinical studies may give someone an idea for further research. Authors should consider what is acceptable—scientifically reasonable—and what is hype.Table 2: Examples of promissory notes which I find more acceptable (understanding, insight, suggest further studies, etc.)

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