Are Metastatic Central Lymph Nodes (D3 volume) in right-sided Colon Cancer a Sign of Systemic Disease? A sub-group Analysis of an Ongoing Multicenter Trial.

OBJECTIVE: Assess outcomes of patients with right-sided colon cancer with metastases in the D3 volume after personalized surgery. BACKGROUND: Patients with central lymph node metastasis (D3-PNG) are considered to have a systemic disease with a poor prognosis. A 3-dimensional definition of the dissection volume allows the removal of all central nodes. MATERIALS AND METHODS: D3-PNG includes consecutive patients from an ongoing clinical trial. Patients were stratified into residual disease negative (D3-RDN) and residual disease positive (D3-RDP) groups. D3-RDN was further stratified into 4 periods to identify a learning curve. A personalized D3 volume (defined through arterial origins and venous confluences) was removed " en bloc" through medial-to-lateral dissection, and the D3 volume of the specimen was analyzed separately. RESULTS: D3-PNG contained 42 (26 females, 63.1 SD 9.9 y) patients, D3-RDN:29 (17 females, 63.4 SD 10.1 y), and D3-RDP:13 (9 females, 62.2 SD 9.7 y). The mean overall survival (OS) days were D3-PNG:1230, D3-RDN:1610, and D3-RDP:460. The mean disease-free survival (DFS) was D3-PNG:1023, D3-RDN:1461, and D3-RDP:74 days. The probability of OS/DFS were D3-PNG:52.1%/50.2%, D3-RDN:72.9%/73.1%, D3-RDP: 7.7%/0%. There is a significant change in OS/DFS in the D3-RDN from 2011-2013 to 2020-2022 (both P =0.046) and from 2014-2016 to 2020-2022 ( P =0.028 and P =0.005, respectively). CONCLUSION: Our results indicate that surgery can achieve survival in most patients with central lymph node metastases by removing a personalized and anatomically defined D3 volume. The extent of mesenterectomy and the quality of surgery are paramount since a learning curve has demonstrated significantly improved survival over time despite the low number of patients. These results imply a place for the centralization of this patient group where feasible.

The Use of a Vascular Roadmap at Surgery Evens out Surgeons Expectations on Operating Time, Blood Loss, Lymph Nodes Harvest and Operative Difficulty when Performing Right Colectomy with Extended D3 Mesenterectomy.

PURPOSE: To determine how individual vascular road-mapping impacts the surgeonsâ?? expectations in difficulty in D3 right colectomy for cancer, and compare these expectations to the results previously published. Aim/summary background data:Literature still lacks data on surgeons expectations using preoperative 3D roadmap of the vascular system. METHOD: Surgeons filled out a survey asking expectations about operation time, estimated blood loss, amount of lymph nodes harvested and difficulty. The patients were classified into 4 groups and 2 subgroups according to the crossing pattern of the ileocolic artery and the jejunal veins. SPSS was used for statistical analysis. Results: Twelve surgeons were included. Eight of them expected type 2 anatomy to be least time consuming while 11/12 indicated anatomy group 4 to be the most. Five surgeons expected low blood loss in group 2 anatomy patients while 10/12 expected higher blood loss in group 4 anatomy patients. Three anticipated that group 2 would generate the highest lymph node yield and while 2/12 surgeons expected the lowest in anatomy group 4. Eight surgeons perceived group 2 as the least challenging while 10/12 experienced group 4 as the most difficult. Compared to previously published results only group 4b operating time met surgeons expectations. CONCLUSION: Using a vascular roadmap at surgery evens out surgeons expectations in operation time, blood loss, lymph node harvested and difficulty. Comparing expectations to previously published data shows operating time in one anatomy group as the only factor where these expectations were met.

Visible Lymph Affluents in the D3 Volume: An MDCTA Pictorial Essay.

BACKGROUND: There seems to be a gap in knowledge of the anatomy of mesenteric lymphatics between the superior mesenteric nodes and the intestinal trunk. To our knowledge, these central lymph vessels were not hitherto systematically searched for, described, or morphometrically analyzed. Our aim was to identify those vessels on the routine multidetector computerized tomography angiography (MDCTA), performed prior to right colectomy for cancer, with extended mesenterectomy, central vascular ligation, and D3 lymphadenectomy. METHODS: A total of 420 MDCTA datasets were analyzed utilizing manual segmentation and 3D reconstruction, with the aid of image processing software Osirix, Mimics, and 3-matic. The 3D models and masks underwent a detailed topographic and morphometric analysis. RESULTS: Significant vascular-like structures, having neither origin nor termination on the blood vessels, were noted in 18 cases (4.3%) in the D3 volume. The dimensions of visible lymph vessels varied, their mean diameter was 1.81 ± 0.61 mm, and the mean length was 38.07 ± 22.19 mm. In the vast majority of cases, the lymph vessels were situated in front of the superior mesenteric artery (SMA), coursing either longitudinally cranially (13 cases) or transversely/obliquely to the left (5 cases). In all cases but one, the lymph vessel passed at the left-hand side of the middle colic artery. As for the course shape, in seven cases, the lymph vessel appeared highly serpiginous. CONCLUSIONS: The regular MDCTA can provide valuable information on mesenteric lymphatics and aid in surgical planning.

Establishing correlations between normal pancreatic and submandibular gland ducts.

BACKGROUND: The objectives of this study were to evaluate the relationship between ductal morphometry and ramification patterns in the submandibular gland and pancreas in order to validate their common fractal dimension. METHODS: X-ray ductography with software-aided morphometry were obtained by injecting barium sulphate in the ducts of post-mortem submandibular gland and pancreas specimens harvested from 42 adult individuals. RESULTS: Three cases were excluded from the study because of underlying pathology. There was a significant correlation between the length of the main pancreatic duct (MPD) and the intraglandular portion of the right submandibular duct (SMD) (r = 0.3616; p = 0.028), and left SMD (r = 0.595; p < 0.01), respectively, but their maximal diameters did not correlate (r = 0.139-0.311; p > 0.05). Both dimensions of the SMD showed a significant right-left correlation (p < 0.05). The number of MPD side branches (mean = 37) correlated with the number of side branches of left SMD, but not with the right one (mean = 9). Tortuosity was observed in 54% of the MPD, 32% of the right SMD, and 24% of the left SMD, with mutual association only between the two salivary glands. CONCLUSIONS: Although the length of intraglandular SMD and MPD correlate, other morphometric ductal features do not, thus suggesting a more complex relationship between the two digestive glands.

Re-interpreting mesenteric vascular anatomy on 3D virtual and/or physical models, part II: anatomy of relevance to surgeons operating splenic flexure cancer.

BACKGROUND: The splenic flexure is irrigated from two vascular areas, both from the middle colic and the left colic artery. The challenge for the surgeon is to connect these two vascular areas in an oncological safe procedure. MATERIALS AND METHODS: The vascular anatomy, manually 3D reconstructed from 32 preoperative high-resolution CT datasets using Osirix MD, Mimics Medical and 3-matic Medical Datasets, were exported as STL-files, video clips, stills and supplemented with 3D printed models. RESULTS: Our first major finding was the difference in level between the middle colic and the inferior mesenteric artery origins. We have named this relationship a mesenteric inter-arterial stair. The middle colic artery origin could be found cranial (median 3.38 cm) or caudal (median 0.58 cm) to the inferior mesenteric artery. The lateral distance between the two origins was 2.63 cm (median), and the straight distance 4.23 cm (median). The second finding was the different trajectories and confluence pattern of the inferior mesenteric vein. This vein ended in the superior mesenteric/jejunal vein (21 patients) or in the splenic vein (11 patients). The inferior mesenteric vein confluence could be infrapancreatic (17 patients), infrapancreatic with retropancreatic arch (7 patients) or retropancreatic (8 patients). Lastly, the accessory middle colic artery was present in ten patients presenting another pathway for lymphatic dissemination. CONCLUSION: The IMV trajectory when accessible, is the solution to the mesenteric inter-arterial stair. The surgeon could safely follow the IMV to its confluence. When the IMV trajectory is not accessible, the surgeon could follow the caudal border of the pancreas.

Reconstructing topography and extent of injury to the superior mesenteric artery plexus in right colectomy with extended D3 mesenterectomy: a composite multimodal 3-dimensional analysis.

BACKGROUND: Superior mesenteric artery plexus (SMAP) injury is reported to cause postoperative intractable diarrhea after pancreatic/colonic surgery with extended lymphadenectomy. This study aims to describe the SMAP microanatomy and extent of injury after right colectomy with extended D3 mesenterectomy for cancer. METHODS: Three groups (I) anatomical dissection, (II) postmortem histology, and (III) surgical specimen histology were included. Nerve count and area were compared between groups II and III and paravascular sheath thickness between groups I and II. 3D models were generated through 3D histology, nanoCT scanning, and finally through 3D printing. RESULTS: A total of 21 specimens were included as follows: Group (I): 5 (3 females, 80-93 years), the SMAP is a complex mesh surrounding the superior mesenteric artery (SMA), branching out, following peripheral arteries and intertwining between them, (II): 7 (5 females, 71-86 years), nerve count: 53 ± 12.42 (38-68), and area: 1.84 ± 0.50 mm2 (1.16-2.29), and (III): 9 (5 females, 55-69 years), nerve count: 31.6 ± 6.74 (range 23-43), and area: 0.889 ± 0.45 mm2 (range 0.479-1.668). SMAP transection injury is 59% of nerve count and 48% of nerve area at middle colic artery origin level. The median values of paravascular sheath thickness decreased caudally from 2.05 to 1.04 mm (anatomical dissection) and from 2.65 to 1.17 mm (postmortem histology). 3D histology models present nerve fibers exclusively within the paravascular sheath, and lymph nodes were observed only outside. NanoCT-derived models reveal oblique nerve fiber trajectories with inclinations between 35° and 55°. Two 3D-printed models of the SMAP were also achieved in a 1:2 scale. CONCLUSION: SMAP surrounds the SMA and branches within the paravascular sheath, while bowel lymph nodes and vessels lie outside. Extent of SMAP injury on histological slides (transection only) was 48% nerve area and 59% nerve count. The 35°-55° inclination range of SMAP nerves possibly imply an even larger injury when plexus excision is performed (lymphadenectomy). Reasons for later improvement of bowel function in these patients can lie in the interarterial nerve fibers between SMA branches.

Re-interpreting mesenteric vascular anatomy on 3D virtual and/or physical models: positioning the middle colic artery bifurcation and its relevance to surgeons operating colon cancer.

BACKGROUND: The impact of the position of the middle colic artery (MCA) bifurcation and the trajectory of the accessory MCA (aMCA) on adequate lymphadenectomy when operating colon cancer have as of yet not been described and/or analysed in the literature. The aim of this study was to determine the MCA bifurcation position to anatomical landmarks and to assess the trajectory of aMCA. METHODS: The colonic vascular anatomy was manually reconstructed in 3D from high-resolution CT datasets using Osirix MD and 3-matic Medical and analysed. CT datasets were exported as STL files and supplemented with 3D printed models when required. RESULTS: Thirty-two datasets were analysed. The MCA bifurcation was left to the superior mesenteric vein (SMV) in 4 (12.1%), in front of SMV in 17 (53.1%) and right to SMV in 11 (34.4%) models. Median distances from the MCA origin to bifurcation were 3.21 (1.18-15.60) cm. A longer MCA bifurcated over or right to SMV, while a shorter bifurcated left to SMV (r = 0.457, p = 0.009). The main MCA direction was towards right in 19 (59.4%) models. When initial directions included left, the bifurcation occurred left to or anterior to SMV in all models. When the initial directions included right, the bifurcation occurred anterior or right to SMV in all models. The aMCA was found in 10 (31.3%) models, following the inferior mesenteric vein (IMV) in 5 near the lower pancreatic border. The IMV confluence was into SMV in 18 (56.3%), splenic vein in 11 (34.4%) and jejunal vein in 3 (9.4%) models. CONCLUSION: Awareness of the wide range of MCA bifurcation positions reported is crucial for the quality of lymphadenectomy performed. The aMCA occurs in 31.3% models and its trajectory is in proximity to the lower pancreatic border in one half of models, indicating that it needs to be considered when operating splenic flexure cancer.

Stool dynamics after extrinsic nerve injury during right colectomy with extended D3-mesenterectomy.

INTRODUCTION: To improve oncological outcome in right colon cancer surgery, an extended mesenterectomy (D3) is under evaluation. In this procedure, all tissue anterior and posterior to the superior mesenteric vessels from the middle colic to ileocolic artery origin is removed, causing injury to the superior mesenteric nerve plexus. The aim was to study the effects of this injury on bowel dynamics and quality of life (QoL). METHODS: Patients undergoing right colectomy with conventional D2- and extended D3-mesenterectomy were asked to record stool number and consistency for 60 d after surgery and complete questionnaires regarding QoL and bowel function (BF) before and after recovery from surgery. We compared early postoperative stool dynamics and long-term QoL in the groups and presented graphs depicting the temporal profile of stool numbers and consistency. RESULTS: Thirty-three patients operated with a D3-resection and 12 patients with a D2-resection participated. The results revealed significantly higher stool numbers in the D3-group until day 26, with significantly more loose-watery stools until day 40. The most pronounced difference was found on day 9 (Mean difference in the total number of stools: 2.25 stools/day, p=.004. Mean difference in loose-watery stools/day: 2.81 p<.001). About 25% in the D2- and 69.7% in the D3-group reported having more than three stools/day in the early postoperative phase. There were no differences in long-term QoL and BF between the groups except in stool consistency (p=.039). DISCUSSION/CONCLUSIONS: Denervation following extended D3-mesenterectomy leads to transitory reduced consistency and increased frequency. It does not affect long-term QoL or BF.

Value of the surgeon's sightline on hologram registration and targeting in mixed reality.

PURPOSE: Mixed reality (MR) is being evaluated as a visual tool for surgical navigation. Current literature presents unclear results on intraoperative accuracy using the Microsoft HoloLens 1®. This study aims to assess the impact of the surgeon's sightline in an inside-out marker-based MR navigation system for open surgery. METHODS: Surgeons at Akershus University Hospital tested this system. A custom-made phantom was used, containing 18 wire target crosses within its inner walls. A CT scan was obtained in order to segment all wire targets into a single 3D-model (hologram). An in-house software application (CTrue), developed for the Microsoft HoloLens 1, uploaded 3D-models and automatically registered the 3D-model with the phantom. Based on the surgeon's sightline while registering and targeting (free sightline /F/or a strictly perpendicular sightline /P/), 4 scenarios were developed (FF-PF-FP-PP). Target error distance (TED) was obtained in three different working axes-(XYZ). RESULTS: Six surgeons (5 males, age 29-62) were enrolled. A total of 864 measurements were collected in 4 scenarios, twice. Scenario PP showed the smallest TED in XYZ-axes mean = 2.98 mm ± SD 1.33; 2.28 mm ± SD 1.45; 2.78 mm ± SD 1.91, respectively. Scenario FF showed the largest TED in XYZ-axes with mean = 10.03 mm ± SD 3.19; 6.36 mm ± SD 3.36; 16.11 mm ± SD 8.91, respectively. Multiple comparison tests, grouped in scenarios and axes, showed that the majority of scenario comparisons had significantly different TED values (p < 0.05). Y-axis always presented the smallest TED regardless of scenario tested. CONCLUSION: A strictly perpendicular working sightline in relation to the 3D-model achieves the best accuracy results. Shortcomings in this technology, as an intraoperative visual cue, can be overcome by sightline correction. Incidentally, this is the preferred working angle for open surgery.

Preventing chylous ascites after right hemicolectomy with D3 extended mesenterectomy.

BACKGROUND: We aim to find the incidence of chylous ascites in patients undergoing D3 extended mesenterectomy and evaluate if a routine fat-reduced diet (FRD) has a prophylactic effect. METHODS: Data from 138 patients included in a D3 extended mesenterectomy trial were collected prospectively. Surgical drains and biochemical testing of drain fluid were used to find the incidence of chylous ascites among the first 39 patients, and a prophylactic fat-reduced diet was then implemented in the next 99 patients as a prophylactic measure. RESULTS: In the first 39 patients, we found that 16 (41.0%) developed chylous ascites. After the fat-reduced diet was implemented, 1 (1.0%) of 99 patients developed chylous ascites. Drain discharge was 150 vs. 80 mL daily, respectively, and a regression analysis shows the average leakage in the group with fat-reduced diet was 105 mL/day less than in the patients with no dietary restrictions (p < 0.001). There were no significant differences in the rate of other complications (Fisher exact test, one-tailed p = 0.8845), and although there was a tendency to a shorter hospital stay when given a fat-reduced diet (7.3 ± 5.4 vs. 8.9 ± 4.9 days), the difference was not significant (p = 0.19). CONCLUSIONS: Chylous ascites is a very common postoperative occurrence after right colectomy with extended D3 mesenterectomy and may be prevented using a routine fat-reduced diet.

Lithium - Pharmacological and Toxicological Aspects: The Current State of the Art.

Lithium is the smallest monovalent cation with many different biological effects. Although lithium is present in the pharmacotherapy of psychiatric illnesses for decades, its precise mechanism of action is still not clarified. Today lithium represents first-line therapy for bipolar disorders (because it possesses both antimanic and antidepressant properties) and the adjunctive treatment for major depression (due to its antisuicidal effects). Beside, lithium showed some protective effects in neurological diseases including acute neural injury, chronic degenerative conditions, Alzheimer's disease as well as in treating leucopenia, hepatitis and some renal diseases. Recent evidence suggested that lithium also possesses some anticancer properties due to its inhibition of Glycogen Synthase Kinase 3 beta (GSK3ß) which is included in the regulation of a lot of important cellular processes such as: glycogen metabolism, inflammation, immunomodulation, apoptosis, tissue injury, regeneration etc. Although recent evidence suggested a potential utility of lithium in different conditions, its broader use in clinical practice still trails. The reason for this is a narrow therapeutic index of lithium, numerous toxic effects in various organ systems and some clinically relevant interactions with other drugs. Additionally, it is necessary to perform more preclinical as well as clinical studies in order to a precise therapeutic range of lithium, as well as its detailed mechanism of action. The aim of this review is to summarize the current knowledge concerning the pharmacological and toxicological effects of lithium.

Semi-automated vs. manual 3D reconstruction of central mesenteric vascular models: the surgeon's verdict.

BACKGROUND: 3D vascular anatomy roadmaps are currently being implemented for surgical planning and navigation. Quality of the reconstruction is critical. The aim of this article is to compare anatomical completeness of models produced by manual and semi-automatic segmentation. METHODS: CT-datasets from patients included in an ongoing trial, underwent 3D vascular reconstruction applying two different segmentation methods. This produced manually-segmented models (MSMs) and semi-automatically segmented models (SAMs) which underwent a paired comparison. Datasets were delivered for reconstruction in 4 batches of 6, of which only batch 4 contained patients with abnormal anatomy. Model completeness was assessed quantitatively using alignment and distance error indexes and qualitatively with systematic inspection. MSMs were the gold standard. Assessed vessels were those of interest to the surgeon performing D3-right colectomy. RESULTS: 24 CT-datasets (13 females, age 44-77) were used in a paired comparative analysis of 48 3D-models. Quantitatively, SAMs showed structural improvement from Batch 1 to 3. Batch 4, with abnormal vessels, showed the highest error-index values. Qualitatively, 91.7% of SAMs did not contain all mesenteric branches relevant to the surgeon. In SAMs, 1 (12.5%) right colic artery-RCA scored as a complete vessel. 3 (37.5%) RCAs scored as incomplete and 4 (50%) RCAs were absent. 6 (25%) of 24 middle colic arteries-MCA scored as complete vessels. 11 (45.8%) scored as incomplete while 7 (29.2%) MCAs were absent. 13 (54.2%) of 24 ileocolic arteries-ICA were complete vessels. 11 (45.8%) scored as incomplete. None (0%) were absent. Additionally, it was observed that 10 (41.7%) of SAMs contained all their jejunal arteries, when compared to MSMs. Calibers of "complete" vessels were significantly higher than in "missing" vessels (MCA p < 0.001, RCA p = 0.016, ICA p < 0.001, JAs p < 0.001). CONCLUSION: Despite acceptable results from quantitative analysis, qualitative comparison indicates that semi-automatically generated 3D-models of the central mesenteric vasculature could cause considerable confusion at surgery.