Bryan M. Clary

The International Position on Laparoscopic Liver Surgery: The Louisville Statement, 2008

Objective:To summarize the current world position on laparoscopic liver surgery. Summary Background Data:Multiple series have reported on the safety and efficacy of laparoscopic liver surgery. Small and medium sized procedures have become commonplace in many centers, while major laparoscopic liver resections have been performed with efficacy and safety equaling open surgery in highly specialized centers. Although the field has begun to expand rapidly, no consensus meeting has been convened to discuss the evolving field of laparoscopic liver surgery. Methods:On November 7 to 8, 2008, 45 experts in hepatobiliary surgery were invited to participate in a consensus conference convened in Louisville, KY, US. In addition, over 300 attendees were present from 5 continents. The conference was divided into sessions, with 2 moderators assigned to each, so as to stimulate discussion and highlight controversies. The format of the meeting varied from formal presentation of experiential data to expert opinion debates. Written and video records of the presentations were produced. Specific areas of discussion included indications for surgery, patient selection, surgical techniques, complications, patient safety, and surgeon training. Results:The consensus conference used the terms pure laparoscopy, hand-assisted laparoscopy, and the hybrid technique to define laparoscopic liver procedures. Currently acceptable indications for laparoscopic liver resection are patients with solitary lesions, 5 cm or less, located in liver segments 2 to 6. The laparoscopic approach to left lateral sectionectomy should be considered standard practice. Although all types of liver resection can be performed laparoscopically, major liver resections (eg, right or left hepatectomies) should be reserved for experienced surgeons facile with more advanced laparoscopic hepatic resections. Conversion should be performed for difficult resections requiring extended operating times, and for patient safety, and should be considered prudent surgical practice rather than failure. In emergent situations, efforts should be made to control bleeding before converting to a formal open approach. Utilization of a hand assist or hybrid technique may be faster, safer, and more efficacious. Indications for surgery for benign hepatic lesions should not be widened simply because the surgery can be done laparoscopically. Although data presented on colorectal metastases did not reveal an adverse effect of the laparoscopic approach on oncological outcomes in terms of margins or survival, adequacy of margins and ability to detect occult lesions are concerns. The pure laparoscopic technique of left lateral sectionectomy was used for adult to child donation while the hybrid approach has been the only one reported to date in the case of adult to adult right lobe donation. Laparoscopic liver surgery has not been tested by controlled trials for efficacy or safety. A prospective randomized trial appears to be logistically prohibitive; however, an international registry should be initiated to document the role and safety of laparoscopic liver resection. Conclusions:Laparoscopic liver surgery is a safe and effective approach to the management of surgical liver disease in the hands of trained surgeons with experience in hepatobiliary and laparoscopic surgery. National and international societies, as well as governing boards, should become involved in the goal of establishing training standards and credentialing, to ensure consistent standards and clinical outcomes.

Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum

ObjectiveIn this study, the impact of preoperative chemotherapy and radiation on the histopathology of a subgroup of patients with rectal adenocarcinoma was examined. As well, survival, disease-free survival and pelvic recurrence rates were examined, and compared with a concurrent control group. Summary Background DataThe optimal treatment of large rectal carcinomas remains controversial; current therapy usually involves abdominoperineal resection plus postoperative chemoradiation; the combination can be associated with significant postoperative morbidity. In spite of these measures, local recurrences and distant metastases continue as serious problems. MethodsFluorouracil, cisplatin, and 4500 cGy were administered preoperatively over a 5-week period, before definitive surgical resection in 43 patients. In this group of patients, all 43 had biopsyproven lesions >3 cm (median diameter), involving the entire rectal wall (as determined by sigmoidoscopy and computed tomography scan), with no evidence of extrapelvic disease. The patients ranged from 31 to 81 years of age (median 61 years), with a male:female ratio of 3:1. A concurrent control group consisting of 56 patients (median: 62 years, male:female ration of 3:2) with T2 and T3 lesions was used to compare survival, disease-free survival, and pelvic recurrence rates. ResultsThe preoperative chemoradiation therapy was well tolerated, with no major complications. All patients underwent repeat sigmoidoscopy before surgery; none of the lesions progressed while patients underwent therapy, and 22 (51%) were determined to have complete clinical response. At the time of resection, 21 patients (49%) had gross disease, 9 (22%) patients had only residual microscopic disease, and 11 (27%) had sterile specimens. Of the 30 patients with evidence of residual disease, 4 had positive lymph nodes. In follow-up, 39 of the 43 remain alive (median follow-up = 25 months), and only 1 of the 11 patients with complete histologic response developed recurrent disease. Six of the 32 patients with residual disease (2 with positive nodes) have developed metastatic disease in follow-up (median time to diagnosis 10 months, range 3–15 months). Three of these patients with metastases have died (median survival after diagnosis of

Intrahepatic Cholangiocarcinoma: An International Multi-Institutional Analysis of Prognostic Factors and Lymph Node Assessment

PURPOSE To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. PATIENTS AND METHODS From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. RESULTS Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). CONCLUSION Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.

Simultaneous resections of colorectal cancer and synchronous liver metastases: A multi-institutional analysis

BackgroundThe safety of simultaneous resections of colorectal cancer and synchronous liver metastases (SCRLM) is not established. This multi-institutional retrospective study compared postoperative outcomes after simultaneous and staged colorectal and hepatic resections.MethodsClinicopathologic data, treatments, and postoperative outcomes from patients who underwent simultaneous or staged colorectal and hepatic resections at three hepatobiliary centers from 1985–2006 were reviewed.Results610 patients underwent simultaneous (n = 135) or staged (n = 475) resections of colorectal cancer and SCRLM. Seventy staged patients underwent colorectal and hepatic resections at the same institution. Simultaneous patients had fewer (median 1 versus 2) and smaller (median 2.5 versus 3.5 cm) metastases and less often underwent major (≥ three segments) hepatectomy (26.7% versus 61.3%, p < 0.05). Combined hospital stay was lower after simultaneous resections (median 8.5 versus 14 days, p < 0.0001). Mortality (1.0% versus 0.5%) and severe morbidity (14.1% versus 12.5%) were similar after simultaneous colorectal resection and minor hepatectomy compared with isolated minor hepatectomy (both p > 0.05). For major hepatectomy, simultaneous colorectal resection increased mortality (8.3% versus 1.4%, p < 0.05) and severe morbidity (36.1% versus 15.1%, p < 0.05). Combined severe morbidity after staged resections was lower compared to simultaneous resections (36.1% versus 17.6%, p = 0.05) for major hepatectomy but similar for minor hepatectomy (14.1% versus 10.5%, p > 0.05). Major hepatectomy independently predicted severe morbidity after simultaneous resections [hazard ratio (HR) = 3.4, p = 0.008].ConclusionsSimultaneous colorectal and minor hepatic resections are safe and should be performed for most patients with SCRLM. Due to increased risk of severe morbidity, caution should be exercised before performing simultaneous colorectal and major hepatic resections.

Selection of Patients for Resection of Hepatic Colorectal Metastases: Expert Consensus Statement

Surgical margin status has been shown to be important in long-term outcomes following resection of colorectal liver metastases. Multiple studies have shown that a negative resection margin decreases local recurrence rates and improves survival.1,62 In a study by Scheele et al.,63 the median survival of patients who underwent an R1 or R2 resection was only 14 months compared with 44 months for those who underwent an R0 resection. In a more recent study by Choti et al.,1 patients who had a positive microscopic resection margin had a median survival of only 24 months compared with 46 months for patients with a negative surgical margin. In this study, positive surgical margin status was associated with a 3.5 increase in relative risk of disease-specific death. Similarly, Pawlik et al.62 reported that a positive resection margin was associated with a significantly higher risk of surgical margin recurrence and decreased overall survival. Given the importance of a clear surgical margin, the question then arises as to what constitutes a minimally acceptable negative microscopic margin. Several earlier series concerning liver resection for hepatic colorectal metastases have reported that one should attain at least a 1-cm margin,64,65 and if not possible, this should be a relative contraindication to surgery.66 Cady et al.65 reported that a surgical margin less than 1 cm was associated with a significantly shorter disease-free survival. As a result, many centers adopted the “1-cm rule” as a minimal margin to obtain at the time of hepatic resection.67,68 These findings, however, have not been corroborated in multivariate regression analyses adjusted for other confounding risk factors.62 In fact, other investigators62,69 more recently reported that the actual width of the surgical margin has no effect on survival as long as the margin is microscopically negative. Altendorf-Hofmann and Scheele69 noted that while patients with a microscopically positive margin had a worse prognosis compared with patients who had a microscopically negative margin, survival was not associated with the width of the negative surgical margin. Similarly, Pawlik et al.62 noted that the width of a negative surgical margin did not affect survival, recurrence risk, or site of recurrence following hepatic resection of colorectal metastases. In this study, patients with a positive surgical margin had a higher overall risk of recurrence (51%) compared with patients who had a negative surgical margin (40%); however, patients with a negative margin—regardless of the width of the surgical margin—had similar overall recurrence rates. The 5-year survival rate was 17% for patients with a positive surgical margin compared with 64% for patients with a negative surgical margin. The width of the surgical margin did not significantly affect survival in patients with negative margins.62 In the past, resection of hepatic colorectal metastases was not attempted in patients who had more than three or four metastases, hilar adenopathy, metastases within 1 cm of major vessels such as the vena cava or main hepatic veins, or extrahepatic disease. Earlier studies that established certain clinicopathologic factors as being contraindications for surgery have subsequently been criticized on both clinical and methodologic grounds. Methodologically, these studies were problematic because only a small number of patients who actually met all the “exclusion” criteria were included in the analyses. Additionally, most early studies reported only univariate or log-rank analyses while failing to control for competing risk factors. Clinically, data are problematic because many of these early studies were carried out prior to the era when new, more active chemotherapy agents, as well as new techniques such as portal vein embolization (PVE) and radiofrequency ablation, were available. More recent studies demonstrate that patients with “traditional” adverse clinicopathologic factors can achieve long-term survival following hepatic resection and therefore should not be excluded from surgical consideration. This has therefore precipitated a shift in the definition of resectability from criteria based on the characteristics of the metastatic disease (tumor number, size, etc.) to new criteria based on whether a complete (margin-negative) resection of the liver lesion can be performed. Currently, hepatic colorectal metastases should be defined as resectable when it is anticipated that disease can be completely resected, two adjacent liver segments can be spared, adequate vascular inflow and outflow and biliary drainage can be preserved, and the volume of the liver remaining after resection (i.e., the “future liver remnant”) will be adequate (at least 20% of the total estimated liver volume).21,70 This definition of resectability represents a paradigm shift. Instead of resectability being defined by what is removed, decisions regarding resectability should now focus on what will remain following resection. Concern for the future liver remnant is particularly pertinent during preoperative evaluation of patients for an extended hepatectomy (resection of ≥ five liver segments), as some patients may be excluded from the benefit of a potentially curative resection because the anticipated liver remnant may be too small. In general, 20% of the total liver volume appears to be the minimum safe volume that can be left following extended resection in patients with normal underlying liver. CT or MRI can now provide an accurate, reproducible method for preoperatively measuring the volume of the future liver remnant.70 To avoid operating on patients with low-volume future liver remnants, any patient who fails to show compensatory hypertrophy as a result of tumor growth and who has a future liver remnant of less than 20% should be considered for PVE to induce hypertrophy of the contralateral liver lobe.71 Another factor that has almost universally been well accepted as a contraindication to liver resection is the presence of extrahepatic disease. In Adson’s38 initial report in 1984, he noted that no patient with extrahepatic disease survived beyond 5 years. As such, extrahepatic disease has long been regarded as an absolute exclusion criteria for hepatic resection. The advent of more effective systemic chemotherapy agents, as well as improvements in imaging modalities to more accurately identify the true extent of extrahepatic disease, has prompted some investigators to advocate for surgical resection for patients with extrahepatic disease. Elias et al.72 have reported that the 5-year survival rates following hepatectomy for hepatic colorectal metastases and simultaneous resection of extrahepatic disease with curative intent was 29%. As such, the presence of extrahepatic disease should not be considered an absolute contraindication to hepatic resection. However, patients with extrahepatic disease must be selected carefully. In general, resection should only be considered following documentation of stable/responsive disease after treatment with systemic chemotherapy in situations where complete (margin-negative) resection is feasible. Management of patients with simultaneous intra- and extrahepatic disease involves complex clinical decision making and therefore should be carried out in a multidisciplinary setting. Consensus Statement: 1. In patients undergoing liver resection for hepatic colorectal metastases, a positive surgical margin is associated with a higher local recurrence and worse overall survival and should be avoided whenever possible. 2. While a wide (> 1-cm) resection margin should remain the goal when performing a liver resection, an anticipated margin of less than 1 cm should not be used as an exclusion criterion for resection. 3. Assessment of resectability of hepatic colorectal metastases should focus on the ability to obtain a complete resection (negative margins). 4. The feasibility of hepatic resection should also be based on three criteria related to the remaining liver following resection: (1) the ability to preserve two contiguous hepatic segments, (2) preservation of adequate vascular inflow and outflow as well as biliary drainage, and (3) the ability to preserve adequate future liver remnant (> 20% in a healthy liver). 5. The presence of extrahepatic disease should no longer be considered an absolute contraindication to hepatic resection provided the patient is carefully selected and a complete (margin-negative) resection of both intra- and extrahepatic disease is feasible.

Sentinel Lymph Node Biopsy in the Management of Patients With Primary Cutaneous Melanoma: Review of a Large Single-institutional Experience With an Emphasis on Recurrence

ObjectiveTo analyze the authors’ experience with sentinel lymph node biopsy (SLNB) and the subsequent incidence and pattern of recurrence in patients with positive and negative nodes. Summary Background DataLymphatic mapping with SLNB has become widely accepted in the management of patients with melanoma who are at risk for occult regional lymph node metastases. Because this procedure is relatively new, the pattern of recurrence after SLNB is not yet clear. MethodsAll patients with primary cutaneous melanoma who underwent SLNB from 1991 through 1998 were identified from a prospective single-institution melanoma database. ResultsThree hundred fifty-seven consecutive patients with localized primary cutaneous melanoma who underwent SLNB were identified. The sentinel node was identified in 332 patients (93%) and was positive in 56 (17%). Fourteen percent of patients had developed a recurrence at a median follow-up of 24 months. The median time to recurrence was 13 months. The 3-year relapse-free survival rates for patients with positive and negative nodes were 56% and 75%, respectively. SLN status was the most important predictor of disease recurrence. The site of first recurrence in patients with negative and positive nodes was more commonly locoregional than distant. Reexamination of the SLN in 11 patients with negative nodes with initial nodal and in-transit recurrence showed evidence of metastases in 7 (64%). ConclusionsPatients with positive sentinel nodes have a significantly increased risk for recurrence. The early pattern of first recurrence for patients with negative and positive results is characterized by a preponderance of locoregional sites, similar to that reported in previous series of elective lymph node dissection. These data underscore the need for careful pathologic analysis of the SLN as well as a careful, directed locoregional physical examination in the follow-up of these patients.

Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.

AbstractBackground: The use of neoadjuvant preoperative chemoradiotherapy CRT for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer. Methods: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy EBRT; median, 4500 cGy with 5-flourouracil–based chemotherapy. Tumors were defined as potentially resectable PR, n = 53 in the absence of arterial involvement and venous occlusion and locally advanced LA, n = 58 with arterial involvement or venous occlusion by CT. Results: Five patients 4.5% were not restaged due to death n = 3 or intolerance of therapy n = 2. Twenty-one patients 19% manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors 53% and 11 patients with initially LA tumors 19% were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months. Conclusions: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant postoperative CRT.

Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

SummaryWe present a series of 8 patients (6 males, 2 females) with hepatocellular carcinoma (HCC) and glycogen storage disease type Ia (GSD Ia). In this group, the age at which treatment was initiated ranged from birth to 39 years (mean 9.9 years). All patients but one were noncompliant with treatment. Hepatic masses were first detected at an age range of 13–45 years (mean 28.1 years). Age at diagnosis of HCC ranged from 19 to 49 years (mean 36.9 years). Duration between the diagnosis of liver adenomas and the diagnosis of HCC ranged from 0 to 28 years (mean 8.8 years, SD=11.5). Two patients had positive hepatitis serologies (one hepatitis B, one hepatitis C). α-Fetoprotein (AFP) was normal in 6 of the 8 patients. Carcinoembryonic antigen (CEA) was normal in the 5 patients in which it was measured. Current guidelines recommend abdominal ultrasonography with AFP and CEA levels every 3 months once patients develop hepatic lesions. Abdominal CT or MRI is advised when the lesions are large or poorly defined or are growing larger. We question the reliability of AFP and CEA as markers for HCC in GSD Ia. Aggressive interventional management of masses with rapid growth or poorly defined margins may be necessary to prevent the development of HCC in this patient population.

In vivo selection of tumor-targeting RNA motifs

In an effort to target the in vivo context of tumor-specific moieties, a large library of nuclease-resistant RNA oligonucleotides was screened in tumor-bearing mice to identify candidate molecules with the ability to localize to hepatic colon cancer metastases. One of the selected molecules is an RNA aptamer that binds to protein p68, an RNA helicase that has been shown to be upregulated in colorectal cancer.

Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience.

ObjectiveTo examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma. Summary Background DataPreoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates. MethodsA retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil ± cisplatin and 4,500–5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival. ResultsMedian follow-up was 27 months, and mean age was 59 years (range 28–81). Mean tumor distance from the anal verge was 6 cm (range 1–15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival. ConclusionsNeoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.