Annals of Surgery

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Annals of Surgery Journal Club
Interactive resource for surgery residents and surgeons to discuss and critically evaluate articles published in Annals of Surgery selected by a monthly guest expert who will review an article each month, offer questions and respond to reader's comments.
Tuesday, December 1, 2015

Moderator:Erik G. Van Eaton, MD

Schreiber MA, McCully BH, Holcomb JB, et al. Transfusion of Cryopreserved Packed Red Blood Cells is Safe and Effective After Trauma. Ann Surg. 2015;262:426-433.

This double-blinded study randomized 256 stable trauma patients across five US Level I trauma centers who needed red blood cell transfusion to receive one of three red cell transfusion products: liquid packed red blood cells (LPRBCs) that were young (≤ 14 storage days), or that were old (> 14 storage days), or cryopreserved packed red blood cells (CPRBCs). The primary outcome variable was differences in thenar eminence tissue oxygenation measured by near-infrared spectroscopy (StO2%). Secondary outcome variables included biochemical markers of impaired red blood cell function; measures of hemolysis and coagulation; systemic concentrations of inflammatory mediators; and clinical outcomes such as acute renal failure, infection, pulmonary embolism, mortality, etc.

About the Author

Dr. Erik G. Van Eaton is an Associate Professor of Surgery at the University of Washington School of Medicine in Seattle, Washington. There, he serves as a trauma and critical care surgeon in the Division of Trauma, Critical Care, and Burns. He completed his General Surgery Residency at the University of Washington, and his Surgical Critical Care Fellowship at Harborview Medical Center in Seattle, Washington. He is also an Adjunct Associate Professor in the Department of Biomedical Informatics and Medical Education. The recipient of a National Institutes of Health Ruth L. Kirschstein National Research Service Award for research in biomedical health informatics, Dr. Van Eaton developed a process for delivering trauma and critical care algorithms and protocols to clinical users at the bedside; a system for integrating morbidity and mortality event monitoring into the electronic medical record; and a computerized rounding and sign-out software system that changed the ways in which clinicians communicate about and manage their patients.

The authors found no differences among the three groups in demographics or injury severity. There was no difference in the change in thenar eminence tissue oxygenation among the three groups. There was a significant increase in free hemoglobin in the old LPRBC group but not among the other groups. IL-2 levels were higher 12 hours after transfusion in the cryopreserved packed red blood cells group compared to the other groups. There were no differences among the groups in measures of coagulation or clinical outcomes. The authors concluded, “Transfusion of CPRBCs is as safe and effective as transfusion of young and old LPRBCs and provides a mechanism to deliver PRBCs in a wide variety of settings.”


  1. The authors chose thenar eminence near-infrared spectroscopy StO2% as the primary outcome for this study. For what physiologic outcome is this a surrogate end point? What other objective metrics could you use as surrogates for that outcome?
  2. Is this a traditional comparative study, an equivalence study, or a noninferiority study? How does the type of study affect the null hypothesis and power analysis?
  3. The study did not achieve the target enrollment set by its power analysis. Do you think that affects the statistical results? Do you think it affects the authors' conclusions?
  4. This study intended to show that CPRBCs could be safely administered to trauma patients. Do you think it succeeded? Do you think it provides a solution to the challenges described by the authors regarding the RBC supply for trauma? If not, what questions do you think still need to be answered?
  5. If CPRBCs become widely available and indicated for use in trauma patients, do you think the patients in this trial are likely to be representative of those who will receive this therapy? If not, do you think repeating this study in those patients will yield different results? Why or why not?

Thursday, November 5, 2015

Moderator:Paul G. Gauger, MD

Adam MA, Pura J, Gu L, et al. Extent of Surgery for Papillary Thyroid Cancer Is Not Associated With Survival: An Analysis of 61,775 Patients. Ann Surg. 2014;260:601-607.

With a thoughtful and thorough analysis of a more contemporary cohort of papillary thyroid cancer patients in the NCDB, this study provides important considerations around the still unsettled question of whether or not a more extensive thyroid resection is associated with a clear survival benefit. The study made an excellent effort to isolate the effect of total thyroidectomy on patient survival by adjusting for patient comorbidities and tumor characteristics and concluded that no survival benefit could be demonstrated for patients with tumors between 1.0-4.0 cm who were treated with total thyroidectomy (compared to lobectomy). This multifactorial adjustment was important because more of the patients in the NCDB who were treated with total thyroidectomy had concerning tumor characteristics such as nodal disease, extrathyroidal extension, multifocal disease, distant metastases, etc. The authors' primary conclusion was preserved after multiple subgroup and sensitivity analyses. The conclusion does not agree with an important previous analysis of the same database (which was less-contemporary and adjusted for fewer factors) and also supports some other recent studies which have suggested equivalent survival influence between total thyroidectomy and lobectomy for some patients. This article is particularly timely considering the recent update to the American Thyroid Association treatment guidelines.

About the Author

Paul G. Gauger, MD, is the William J. Fry Professor of Surgery and Professor of Learning Health Sciences at the University of Michigan where he is Chief of the Division of Endocrine Surgery. He also serves as Program Director for the General Surgery residency.

The conclusion of the study seems most appropriately applied to patients with low or intermediate risk papillary thyroid cancers. There is some concern that over-application of this conceptual equivalence could meet with worsened long-term outcomes in patients who are treated with lobectomy for higher-risk tumors. Just because no survival advantage could be proven in a population-level database analysis does not mean that these are equivalent surgical options for all or even most of the individual patients encountered in surgical practice. This clinical equipoise should largely be reserved for decision-making in patients who have no concerning clinical features and after thorough pre-operative assessment which should include ultrasound assessment of the tumor, the entire thyroid, and the cervical node basins.

One Important limitation to the study is that survival was the primary measure analyzed as the NCDB does not track tumor recurrence or cause-specific mortality well. Therefore, there may be other very real advantages to total thyroidectomy which are not able to be ascertained in this study.

One thing that is clear from this important work is that as surgeons, we should be precise and fair in our pre-operative discussions with our patients. The rationale for total thyroidectomy may be sound and anchored by a number of advantages in facilitation of post-operative radioiodine scanning/treatment and long term surveillance. However, to lead our patients to think that we are extending their lives through more complete initial thyroid resection may not be an accurate or meaningful message.


  1. Some additional factors influence recommendations about extent of thyroid resection [e.g. age, large tumor size, and ultrasound suggestions of multifocal disease or extra-thyroidal extension (particularly in the posterior aspect)]. Will the conclusion of this study likely change your practice over time, or will it instead change the details of the discussions you have with your patients during pre-operative planning?
  2. Considering overall treatment strategies which prioritize complete elimination of detectable tumor burden, how would a more flexible surgical strategy around extent of thyroid resection likely be met by the endocrinology community as a whole?
  3. Although fundamentally and obviously important, overall survival may not the sole best metric for evaluating treatment strategies for this particular cancer. In a cancer such as PTC where long survival is the expectation for most patients, are there other advantages to total thyroidectomy besides survival that should take precedence in guiding this initial decision about extent of surgery?
  4. How will this study affect your decision about the necessity of completion thyroidectomy in a patient whose diagnosis of PTC is not made until after permanent histology of a lobectomy specimen? What if the patient has a low-risk PTC?

Friday, October 2, 2015

Moderator:Christopher L. Wolfgang, MD, PhD

Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261:12-17.

This month's Journal Club is a nicely executed study by Cristina Ferrone and her colleagues that addresses several important questions related to patients with Stage III pancreatic cancer treated with induction or neoadjuvant FOLFIRINOX. It is estimated that at the time of diagnosis 30% of patients with pancreatic cancer have localized tumors that are unresectable due to major vessel involvement (Stage III). Historically, these patients were treated with systemic therapy but the majority never made it to surgical resection. In part, this was due to the notoriously ineffective nature of the systemic therapy in terms controlling systemic disease and lack of response of the primary tumor. Recently, several more effective chemotherapy regimens such as FOLFIRINOX have shown improved efficacy in Stage IV disease. This has prompted the use of FOLFIRINOX in stage III patients in an attempt to better control micrometastatic disease, “sterilize” margins or downstage the tumor. Currently very little is known about selection of patients for surgical resection and the surgery-related outcomes of Stage III patients who underwent induction or neoadjuvant FOLFIRNOX treatment. This is the impetus for the manuscript in this month's journal club.

About the Author

Christopher L. Wolfgang, MD, PhD is the Chief of Hepatobiliary and Pancreatic Surgery at the Johns Hopkins Hospital and Professor of Surgery, Pathology and Oncology at Johns Hopkins University School of Medicine. He also is the Paul K. Neumann Professor of Pancreatic Cancer Research and a member of the Miller-Coulson Academy of Clinical Excellence. He obtained his medical degree from Temple University School of Medicine and residency training in General Surgery at Penn State Milton S. Hershey Medical Center. In addition, Dr. Wolfgang obtained a Ph.D. degree in Biochemistry, also from Temple University School of Medicine. Dr. Wolfgang has completed a research fellowship in surgical oncology from Penn State and a clinical fellowship in gastrointestinal surgery at Johns Hopkins.

Of the several interesting findings in this study I would like to focus on the two that I think are the most important. In the study 47 Stage III patients underwent exploration after receiving FOLFIRINOX. Among this cohort, 40 were able to undergo an oncological resection despite the fact that 62% were initially locally advanced and unresectable based on AHPBA/SSO/SSAT criteria. Moreover, the margin-negativity rate in this group was 92%. The FOLFIRNOX resulted in downstaging of 9 patients in this group but the post treatment CT continued to demonstrate unresectablity in the majority of patients. To confirm the staging determined by the tumor board, the study also had Andrew Warshaw, a senior experienced pancreatic surgeon, assess resectability in a blinded fashion. His observations were nearly identical to the tumor board. Taken together, these observations lead to the first major finding of the study and, that is, following FOLFIRINOX treatment a CT scan becomes less useful in determining resectability. The second important finding of this paper is an assessment of the biological activity of FOLFIRINOX. Only 35% of patients had regional lymph node metastases compared to 79% in the cohort not undergoing neoadjuvant therapy. In fact, all negative pathological features were less prevalent in the FOLFIRONOX group.
Others have confirmed many of the findings of this study in more recent manuscripts as outlined in a recent meta-analysis by Petrelli et al., 2015.1
Although the study is nicely done there are some limitations inherent to a retrospective analysis. This is not an intention to treat analysis, so it is not known how many Stage III patients were initially treated with FOLFIRNOX and never made it to exploration. In addition, the initial AHPBA/SSO/SSAT stage is reported for the cohort, but the post-treatment stage is not - only the extent of response. Finally we have no follow-up on disease specific survival to know if the pathological features in the FOLFIRINOX group translate into improved survival.


  1. If the CT scan does not accurately predict resectability follow FOLFIRINOX (and likely other aggressive regimens), what should be the criteria to explore a Stage III patient following treatment? Based on the findings of this paper, should the new criteria be anatomic? Extent of response? Performance status alone?
  2. Since a significant proportion of the FOLFIRINOX cohort also received external beam radiation, do you think that some of the effect may be more related to the radiation than the systemic therapy? Is chemoradiation possibly synergistic with FOLFIRINOX?
  3. Based on the biological activity of FOLFIRINOX in terms of nodal status, margin status and CT response rate, should we consider moving toward neoadjuvant therapy in all patients including Stage I/II resectable?
  4. What do you predict will be the correlation of pathological features with survival after neoadjuvant? Will the same pathological feature apply post-treatment? Put in another way, does a negative nodal status mean the same following treatment as it does in a chemo-naive patient?

1. Petrelli F, Coinu A, Borgonovo K, et al. FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies. Pancreas. 2015;44:515-521.

Monday, September 7, 2015

Moderator: Julie A. Margenthaler, MD

Prospective Study of Surgical Decision-making Processes for Contralateral Prophylactic Mastectomy in Women With Breast Cancer. Ann Surg. 2015 March 27 [epub ahead of print].

Parker et al. tackle the controversial topic of contralateral prophylactic mastectomy in this month's journal club article "Prospective Study of Surgical Decision-making Processes for Contralateral Prophylactic Mastectomy in Women with Breast Cancer." In 1991, the National Institute of Health Consensus Conference endorsed breast conserving therapy (BCT) as the preferred treatment of early-stage breast cancer. This endorsement was based on evidence demonstrating that women undergoing BCT for early stage breast cancer have equivalent survival outcomes compared to mastectomy. These findings led to the widespread use of BCT as the treatment for early stage breast cancer at major centers across the United States during the past two decades. More recently, however, physicians have noted, and studies have confirmed, increased rates of mastectomy and contralateral prophylactic mastectomy (CPM) for the treatment of breast cancer. The underlying reasons for this shift have been hotly debated in the past few years and have generated many retrospective reports.

About the Author

Julie A. Margenthaler, MD is the Director of Breast Surgical Services at Siteman Cancer Center and Associate Professor of Surgery and Director of the Breast Fellowship Program at Washington University School of Medicine in St. Louis, MO. She is a graduate of Southern Illinois University School of Medicine and completed her general surgery residency and breast fellowship at Washington University School of Medicine. Dr. Margenthaler is on the Board of the American Society of Breast Surgeons and a Councilor at Large for the Society of Surgical Oncology. Her research interests include breast cancer clinical outcomes and the development of novel imaging devices.

This paper is unique from other recent publications in that it is a prospective study examining the women's interest in contralateral prophylactic mastectomy (CPM) before and after their visit with the breast surgeon, and the perception of the appropriateness of CPM by the surgeon. The authors studied 117 women who were of average risk for breast cancer prior to their diagnoses. Prior to their first visit, 50% of women reported that they were moderately to extremely interested in CPM. However, only 10% of the women ultimately had CPM. Interestingly, only 43% of women reported that CPM had been discussed moderately to extensively with their surgeon, while surgeons reported this number to be 33%. In fact, surgeons reported that CPM was not discussed at all in 45% of visits. Cancer worry was the strongest factor associated with having a CPM.

There are some limitations to this study despite its prospective nature. The sample size is relatively small and it is difficult to determine whether the results are generalizable to other practice settings. There are likely factors not captured by the study that impact the final decision. For instance, 23% of women reported that they were likely to have a CPM following the visit with the surgeon, but only 10% actually did.

The importance of this study is that it provides a glimpse into the real-time decision-making of a patient who is considering CPM. It is clear from this study that the patient's perception of risk and the surgeon's ability to communicate that risk and the options for treatment are paramount in driving the rate of CPM for average-risk women. It also illustrates the need for systematic communication tools to guide these discussions.


  1. For average risk women with breast cancer, what is an acceptable CPM rate? Are there certain patient and/or tumor factors where this rate would be acceptably higher (young age at diagnosis, need for unilateral mastectomy for known disease, lobular histology, reconstructive symmetry)?
  2. Do you think that the individual surgeon's beliefs and practices impact the rate of CPM? Does surgeon sex, age, or level of training play a role?
  3. Cancer worry is a strong factor in the decision for CPM in this study and in previous retrospective studies. Do you think cancer worry decreases with CPM? What tools might we use to counsel women about cancer worry?

Thursday, August 6, 2015

Moderator: Karen Brasel, MD, MPH

Cooper Z, Courthwright A, Karlage A, et al. Pitfalls in Communication That Lead to Nonbeneficial Emergency Surgery in Elderly Patients With Serious Illness: Description of the Problem and Elements of a Solution. Ann Surg. 2014;260:949-957.

In this month's journal club article, “Pitfalls in Communication That Lead to Nonbeneficial Emergency Surgery in Elderly Patients With Serious Illness: Description of the Problem and Elements of a Solution”, Cooper et al provide a structure describing elements that lead to nonbeneficial emergency surgery in elderly patients with serious illness. This well-written manuscript provides a framework with which to conceptualize and potentially address the problem of nonbeneficial surgery. However, it is not a rigorous methodological review, but rather a well-referenced opinion piece. The lack of rigorous methodology leaves the assessment of the underlying factors open to bias; this is important as it has direct impact on whether the proposed solutions can be expected to be successful.

About the Author

Karen Brasel, MD, MPH, Professor of Surgery, is the General Surgery Residency Program Director at Oregon Health & Science University in Portland, Oregon.  Dr. Brasel received her medical degree from the University of Iowa, completed her surgical residency and master's degree in Public Health at the University of Minnesota, and her surgical critical care fellowship at the University of North Carolina. She serves on the Executive Committee of the American College of Surgeons Board of Governors, the American College of Surgeons Task Force on Surgical Palliative Care, and is a Director of the American Board of Surgery. Her research interests, funded by the Centers for Disease Control, include post-injury quality of life and functional outcomes, surgical palliative care, ethics and education.
The problem being addressed is the increased use of resources, particularly surgery unlikely to alter an elderly patient's clinical course, that occurs in elderly patients with serious illness. The authors identify surgeon, patient, surrogate, and systemic or structural factors as potential areas of communication pitfalls. Surgeon factors include inadequate time for conversation, inadequate training, and a belief that patients do not want to talk about death and dying. The authors provide evidence that training improves surgeon confidence and competence in these discussions, suggesting that one strategy to address the primary underlying problem would be to increase education for all surgeons, beginning with surgeons in training. This effort is being helped through efforts of SCORE, the ACS Task Force on Surgical Palliative Care, and the American Board of Surgery. Another difficulty that is common to both surgeon and patient is the difficulty in prognostication. Data that show patients who understand their prognosis, and have had prior discussions with healthcare providers about prognosis, seem to be supportive of the fact that lack of a long-term relationship between surgeon and patient may be part of the prognostication problem. However, providers who have a long-term relationship with a patient may actually be less able to accurately prognosticate due to their emotional investment with the patient. Use of standardized prognostic tools, such as the NSQIP risk calculator, provides much more accurate prognostic information. In at least one center, use of a threshold prognostic value for mortality in the elective setting triggers a palliative care consult, mandatory discussion about risks and benefits. This has reduced both mortality and nonbeneficial surgery; such an approach could potentially be modified for the urgent/emergent setting.

The biggest benefit of this review is the logical organization and the extensive reference list. It not only outlines potentially beneficial approaches to improve communication, but importantly outlines areas in which we have very little if any evidence on the outcomes that are of primary importance to our patients and their families.


  1. What evidence do the authors cite that surgeon education and training improves patient outcomes? What evidence would convince you to participate in an educational intervention?
  2. What information leads to inaccurate prognostication? How strong is the evidence supporting this information?
  3. Does an appropriately completed informed consent discussion lead to a decrease in nonbeneficial emergent surgery in elderly patients?
About the Author

Ronald B. Hirschl, M.D
Ronald B. Hirschl, M.D, is the Head of Pediatric Surgery at C.S. Mott Children’s Hospital at the University of Michigan. He is also a Director of the American Board of Surgery and Chair of the Pediatric Surgery Board. He is funded by the NIH to study long-term artificial lung support in Pediatric patients with chronic lung failure. Dr. Hirschl obtained his Masters of Science from the University of Michigan in Clinical Research Design and Statistical Analysis. He has been involved in a number of studies and trials on the topic of appendicitis.