This randomized controlled trial compared low ligation versus high ligation of the inferior mesenteric artery during laparoscopic anterior resection for rectal cancer. The primary outcome was genitourinary dysfunction assessed through validated questionnaires and uroflowmetry at 1 and 9 months postoperatively. Results showed that both techniques resulted in impaired genitourinary function, though low ligation led to less worsening of symptoms over time. There were no significant differences in secondary outcomes like complications or oncological adequacy between the groups. In summary, low ligation of the inferior mesenteric artery better preserved genitourinary function after surgery without compromising other outcomes.

1. Journal Club
Low Ligation of Inferior Mesenteric Artery in Laparoscopic
Anterior Resection for Rectal Cancer Reduces
Genitourinary Dysfunction
Results From a Randomized Controlled Trial (HIGHLOW Trial)
Dr . Mutaz al makhamrah
Surgical oncology fellow
KHCC
Surgical oncology department

2. Article
Low Ligation of Inferior Mesenteric Artery in Laparoscopic
Anterior Resection for Rectal Cancer Reduces
Genitourinary Dysfunction
Results From a Randomized Controlled Trial (HIGHLOW Trial)
Giulio M. Mari, MD, Jacopo Crippa, MD,y Eugenio Cocozza, MD,z Mattia Berselli, MD,z
Lorenzo Livraghi, MD,z Pierluigi Carzaniga, MD,§ Francesco Valenti, MD, Francesco Roscio, MD, PhD,jj
Giovanni Ferrari, MD, Michele Mazzola, MD, Carmelo Magistro, MD, Matteo Origi, MD,
Antonello Forgione, MD, Walter Zuliani, MD,yy Ildo Scandroglio, MD,zz Raffaele Pugliese, MD,§§
Andrea T. M. Costanzi, MD, and Dario Maggioni, MD
Ann Surg. 2019 Jun;269(6):1018-1024. doi: 10.1097/SLA.0000000000002947.

3. Background:
The criterion standard surgical approach for rectal cancer is
LAR & TME. The level of artery ligation remains an issue related to functional
outcome, anastomotic leak rate, and oncological adequacy.
Retrospective studies failed to provide strong evidence in favour of one
particular vascular approach and the specific impact on GU function is poorly
understood

4. Surgical Technique
High Ligation
The opening of the peritoneum proceeds cephalad, from the IMA toward the
duodenojejunal angle of Treitz, and the mesenteric root is incised 1 cm below the
inferior margin of the pancreas. The aortomesenteric window is opened wide and
the inferior mesenteric vessels are exposed. The IMA is ligated and divided 2 cm
from its origin. The inferior mesenteric vein is ligated and divided below the
pancreatic margin.
Low Ligation
The peritoneum is opened from the presacral space, proceeding upward and then
laterally toward the sigmoid colon. The left colic artery is identified and preserved
while the superior hemorrhoidal artery is ligated. Apical lymph nodes are
dissected from the superior aspect of the IMA without reaching the aortic plane
with a standardized approach that all participating surgeons were trained for
meant to leave the inferior portion of the origin of the IMA intact.

5. The Right View of the Relationship Between the Root of THE IMA and the
Autonomic Nerve Plexuses Around It.
1, inferior mesenteric plexus; 2,
abdominal aortic plexus; 3, lumber splanchnic nerves; 4, the right
trunk of SHP; 5, the left trunk of SHP; 6. the right ascending
branches to IMP; 7, communicating branches of bilateral trunks
of SHP; 8, presacral nerves; 9, sympathetic trunk; 10, the left
descending branches to SHP; 11, inferior mesenteric artery;
12, left colic artery. Green arrowhead, mesocolon; yellow
arrowhead, anterior renal fascia
The Left View of the Relationship Between the Root of the IMA and
the Autonomic Nerves Around It.
1, abdominal aortic plexus; 2, inferior mesenteric
plexus; 3, lumber splanchnic nerves; 4, the left trunk of SHP; 5,
presacral nerve; 6, the right trunk of SHP; 7, sympathetic trunk;
8, the left descending branches to SHP; 9, inferior mesenteric
artery; 10, left colic artery. a, the distance between the origin
of THE IMA and the left descending branches to SHP; b, the
distance between the origin of the left colic artery and the left
descending branches to SHP. Green arrowhead, mesocolon;
yellow arrowhead, anterior renal fascia

7. Methods:
• Patients treated in 6 Italian non academic hospitals;
• Age >18 years
• BMI >30
• American Society of Anaesthesiologists grade of I, II, or III;
• scheduled to undergo elective laparoscopic LAR & TME;
• no evidence of metastatic disease.
• Exclusion criteria were prior surgery on the abdominal aorta and computed
tomography–proven arteriosclerosis of the IMA and its branches.
• The study was conducted in accordance with the principles of the Declaration of
Helsinki and according to the CONSORT statement.
• The medical ethics review board of each participating hospital approved the study
protocol.
• The protocols for this study were previously published and this trial was registered
under the ClinicalTrials.gov Identifier NCT02153801.

9. Design:
• The HIGHLOW study is a randomized, multicentre controlled
trial.
• In case of LL, preservation of the left colic artery had to be
proven by pathological examination demonstrating the absence
of the left colic artery in the specimen.
• Randomization was balanced for sex and neoadjuvant
chemoradiation therapy assuming that the large majority of
patients would receive radiation therapy preoperatively.
• All participating surgeons performed at least 20 laparoscopic
procedures per year during the previous 5 years.

10. outcomes :
The primary end-point was the incidence of postoperative GU dysfunction
compared with preoperative baseline assessment.
Standardized questionnaires were provided preoperatively and 1 and 9 months
postoperatively using
1. The International Index which are :(International Index of Erectile Function (IIEF),
International Consultation on Incontinence Questionnaire(ICIQ) , International
Prostatic Symptoms Score(IPSS), and Female Sexual Function)
2. Objective measurements of uroflowmetry and ultrasound measured post-void
residual volumes were also performed.
3. Quality of life (QOL) was assessed using the Gastrointestinal Quality of Life Index
(GIQLI) questionnaire.
The timing of evaluation was chosen by the authors outside a routine follow-up
course. Early onset of GU impairment after surgery was investigated at 1 month post-
operatively.
Acute peripheral nervous lesions can take up to 6 months to heal . Therefore, an
interval of 8 months from the first postoperative evaluation was chosen to allow
healing of transient lesions and better assessment of chronic impairment

11. The International Index:(ICIQI)
The ICIQ-UI Short form provides
a score ranging from 0-21.
With a higher score indicating
greater severity of symptoms.
The "self-diagnostic" portion of
the questionnaire is not given a
score.

12. The International Index:(IPSS)

13. The International Index:(IIEF)

14. The International Index:(IIEF)

15. The International Index:(FSFI)

16. The International Index:(FSFI)

17. Uroflowmetry:
Uroflowmetry is the measurement of voided urine (in millilitres)
per unit of time (in seconds).
The important elements of the test are voided volume (which
should be >150 mL), maximum flow rate (Qmax), and the curve
of the flow (which should be bell shaped).
In men, a Qmax >15 mL/s is considered normal, whereas a
Qmax <10 mL/s is considered abnormal.
normal values in females are described as a Qmax between 20
and 36 mL/s.

18. outcomes :
Secondary endpoints included
• Anastomotic leakage :Anastomotic leak was determined by the presence of
a radiologically endoscopically, or surgically proved fistula or as the
presence of a subclinical leak observed by endoscopic examination 30 days
after surgery, and were graded according to the method proposed by the
International Study Group of Rectal Cancer in 2010
• The oncological outcomes: were assessed by number of retrieved lymph
nodes and quality of the mesorectum, according to the Quirke classification
• Disease-free survival, overall survival, local recurrence, and distant
metastasis development was assessed 1 year postoperatively and will be
yearly assessed for both groups for 5 years

19. Quirke classification

20. Statistical Analysis:
The primary end-point measure was evaluated using
Fisher exact test (1-sided).
The difference in the incidence of GU dysfunction was evaluated using
the Mann-Whitney U test and the t test.
McNemar test was used to evaluate changes in questionnaire results
overtime.
Statistical analysis was performed in accordance with the intention-to-
treat principle.
All statistical analyses were performed using the statistical software
Statistical Package for the Social Sciences (SPSS) software (version 22,
SPSS, Chicago, IL)

21. Sample Size Calculation
The required total sample size of 212 patients (drop-out
estimated rate of 5%) enables a 2-tailed Fisher exact test applied
to 2 cohorts of 100 patients each to have 84.45 power in estimating a 20%
difference in the incidence of GU dysfunction (a = 0.05, b =
0.1555).
The 20% estimated difference was chosen based on a 40%
GU dysfunction incidence reported in the literature

22. Data Collection:
Individual data were collected using MS Office Access
(Microsoft Corp, Redmond, WA) database by one physician for
each hospital and referred to a central research staff that monitored
and secured all included data for each institution.
Patients filled out questionnaires during pre- and postoperative physical
examinations.
Uroflowmetry and ultrasound measurement of post-void bladder
volume were performed by the urologists of each institution
colonoscopies were performed by the endoscopists of each institution.
Histopathological examinations were performed by the pathologists
of each institution.

23. RESULTS:
 Between June 2014 and December 2016, 214 patients were
randomly assigned to high ligation (HL) or LL of IMA during
laparoscopic LAR&TME
Trial flow diagram. LAR & TME,
low anterior resection with total
mesorectal excision.
there were similarities
between all reviewed
factors between groups.
There were, however,
significant differences in
the distribution of stage I
(LL 60 vs HL 44) and stage
III cancers (LL 19 vs HL 31).
Eighteen patients were
excluded from the final
analysis

26. clavien dindo classification

27. RESULTS
Primary Outcome
GU function was impaired in both groups.
 One hundred percent of the analysed patients completed
the questionnaires about urinary function and performed
the uroflowmetric examination
(196/196)
 Fifty-seven percent of the analysed patients (112/196)
completed the questionnaires about sexual function.
 IPSS score significantly worsened in both groups after
surgery without returning to the preoperative level even
at 9 months postoperative.
 Time of flow was significantly worsened in both groups at
9 months postoperative compared to baseline.

30. RESULT
Secondary Outcome
 The conversion rate was similar between groups [10.8% HL vs 9.7%
LL, not significant (n.s.).
 There were no statistically significant differences in terms of blood
loss, surgical times, and postoperative complications between
groups.
 The overall complication rate was also similar in both groups
(27.9% HL vs 30% LL, n.s.).
 In particular, there was no difference in the anastomotic leak rate
(8.1% HL vs 6.7% LL, n.s.), although it was slightly better in the LL
group.
 Local recurrence rates 1 year postoperative were 0% in both
groups.

32. CRITICAL ANALYSIS:
 Strength:
• investigate GU function and QOL by using
international validated questionnaires, and this
adds significance to the validity of results
• this trial could be a good proposal for a
standardized GU function evaluation after rectal
surgery by using questionnaires and flowmetric
analysis to include both subjective and objective
evaluations.
• By investigating GU function as primary outcome
, this RCT represents an important shift toward
more patient centred outcomes studies in the
field of colorectal cancer surgery.
• In this study, uroflowmetric testing and
ultrasound measurement of bladder remnant
volume, affected by patient compliance,
combined with patient questionnaires, allowed
to more precisely evaluate the degree of
impairment of urinary function in patients.
 Weakness and limitation:
• A possible association between the result of
questionnaires related to urinary function and
uroflowmetric parameters has not been
investigated statistically
• In this study, uroflowmetric testing and
ultrasound measurement of bladder remnant
volume, affected by patient compliance.
• it should be recognized that the study was
underpowered for comparing anastomotic leak
between LL and HL group , Sample size
calculation was tailored for GU function
impairment and not for the incidence of
anastomotic leak
• Like defecatory function(matsuda et al), GU
function is also controlled by several complex
factors; it is therefore difficult to specifically
evaluate factors influencing GU function.

33. CRITICAL ANALYSIS:
 Strength
• this is the only randomized powered
trial evaluating GU function after
laparoscopic LAR&TME.
 Weakness and limitation
• There was no significant difference in terms of the
development of metastatic disease. In the HL group, 11.9%
versus 8.4% of patients, however, had lung or liver
metastatic disease at 1 year follow-up. The reason for this
difference could be the unequal distribution of pathological
stages between groups. Stage III disease was more
common in the HL group, which is associated with the
earlier development of metastatic disease
• No patient developed local recurrence at 1 year post
operative. This positive result correlates with the more than
90% TME completeness according to Quirke classification
of both groups. This aspect of the surgical specimen is
associated with the quality of the surgical technique
• nonhomogeneous distribution of tumor stages between
groups could represent a limitation in the evaluation of the
primary outcome and, to a greater extent, comparison of
the oncological outcome between groups

34. CRITICAL ANALYSIS:
 Weakness and limitation
• In the erectile disfunction
questioner not all patient did
the questioner and the
female not included
• In (GIQLI) there is significant p
value in preoperative in tow
groups (LL),(HL) …..

36. Conclusion:
In conclusion, low ligation of the IMA in LAR &TME results
in better GU function preservation without affecting initial oncological
outcomes.
HL does not seem to increase the anastomotic leak
rate.
Future study tailored to evaluate this issue should be planned.

37. Group discussion

38. Thank you