Navigation-Assisted Surgery for Locally Advanced Primary and Recurrent Rectal Cancer.

BACKGROUND: In some surgical disciplines, navigation-assisted surgery has become standard of care, but in rectal cancer, indications for navigation and the utility of different technologies remain undetermined. METHODS: The NAVI-LARRC prospective study (NCT04512937; IDEAL Stage 2a) evaluated feasibility of navigation in patients with locally advanced primary (LARC) and recurrent rectal cancer (LRRC). Included patients had advanced tumours with high risk of incomplete (R1/R2) resection, and navigation was considered likely to improve the probability of complete resection (R0). Tumours were classified according to pelvic compartmental involvement, as suggested by the Royal Marsden group. The BrainlabTM navigation platform was used for preoperative segmentation of tumour and pelvic anatomy, and for intraoperative navigation with optical tracking. R0 resection rates, surgeons' experiences, and adherence to the preoperative resection plan were assessed. RESULTS: Seventeen patients with tumours involving the posterior/lateral compartments underwent navigation-assisted procedures. Fifteen patients required abdominosacral resection, and 3 had resection of the sciatic nerve. R0 resection was obtained in 6/8 (75%) LARC and 6/9 (69%) LRRC cases. Preoperative segmentation was time-consuming (median 3.5 h), but intraoperative navigation was accurate. Surgeons reported navigation to be feasible, and adherence to the resection plan was satisfactory. CONCLUSIONS: Navigation-assisted surgery using optical tracking was feasible. The preoperative planning was time-consuming, but intraoperative navigation was accurate and resulted in acceptable R0 resection rates. Selected patients are likely to benefit from navigation-assisted surgery.

Survival after lymphadenectomy of nodal metastases from melanoma of unknown primary site.

Although the vast majority of melanomas have a primary site, 3%-4% of all melanomas in distant sites display no known primary site (MUP). This phenomenon is not fully understood and various hypotheses have been introduced. The prognostic significance of MUP has been unclear, with some studies showing no survival benefit while others find improved survival compared to stage-matched patients with melanoma of known primary site (MKP). Between 1997 and 2014, 864 patients underwent an en bloc resection of clinical nodal metastases at a referral centre for metastatic melanoma in Norway. The MUP (n = 113) and MKP (n = 751) patients were graded with stage III or IV. The overall survival (OS) was calculated with the Kaplan-Meier method, and multivariate analysis identified factors of significance for the two groups. A significant five-year OS emerged for stage III, MUP = 58% and 42% for MKP, but not for stage IV. The five-year relapse-free survival (RFS) was 41% and 31% for MUP and MKP respectively (p = 0.049). The statistically significant inter-group differences (MUP/MKP) were observed in the univariate and multivariate analyses of age, gender, number of affected nodes, tumour size and perinodal growth within stage III and tumour size within stage IV. After regional lymphadenectomy, MUP patients with clinical nodal metastases had a better outcome than MKP patients. This finding supports the theory that an endogenously mediated immune response may promote the regression of a cutaneous melanoma.

Melanoma - investigation and primary treatment. / Melanom ­ utredning og primærbehandling.

Melanoma is a relatively common diagnosis, both in the primary and specialist health service. Ongoing research and new evidence base means that the recommendations for investigation and treatment are continually changing. This can lead to uncertainty among doctors who do not treat this patient group regularly. In this clinical review we give a summary of the latest recommendations, primarily aimed at general practitioners, dermatologists and doctors in local hospitals.

Merkel cell carcinoma. / Merkelcellekarsinom.

Merkel cell carcinoma is an uncommon but aggressive tumour with a high metastatic potential. A rapidly growing, non-tender cutaneous tumour on sun-exposed areas of the body in older patients should raise suspicion of the condition. It may be necessary to combine the patient history with clinical, radiological and pathological findings in order to make the correct diagnosis. Excision with a 1-2 cm margin, direct closure and simultaneous sentinel-node biopsy should be performed without delay. Adjuvant radiation therapy of the tumour site may be relevant. After the diagnosis is made, assessment and treatment should take place in hospitals with special experience of the condition.

Randomized Study of Wound Drainage on Early Complications After Lymph Node Dissection for Melanoma.

INTRODUCTION: The complication rate after axillary lymph node dissection (ALND) and inguinal lymph node dissection (ILND) in melanoma patients is high. The aim of this randomized non-inferiority study was to evaluate the effect of postoperative wound drainage on early complications after ALND and ILND. MATERIALS AND METHODS: Between 2018 and 2020, 104 stage III melanoma patients operated on with ALND or ILND were randomized to a study group with complete wound drain removal 3 wk after surgery or a control group with progressive drain removal. The primary end point was overall early complications graded according to the modified Clavien-Dindo classification. Secondary endpoints were length of hospital stay and prognostic factors for early complications. RESULTS: Of the 99 patients analyzed, ALND was performed in 58 patients and ILND in 41 patients. Overall, 62 patients (62.6%) developed early complications: 30 in the study group and 32 in the control group (P = 0.53). The confidence interval for the difference in proportions of patients without early complications in the two groups was -0.27 to 0.11 (P = 0.42), hence non-inferiority could be claimed. Length of hospital stay was 5 d in the study group compared to 6 in the control group (P < 0.01). ILND was associated with increased risk of early complications compared to ALND (75.6% versus 53.4%, P = 0.04). CONCLUSIONS: Complete drain removal 3 wk after ALN and ILND in stage III melanoma patients did not increase the risk of early complications compared to progressive drain removal.

Targeting AXL and the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Melanoma.

Receptor tyrosine kinase AXL is found upregulated in various types of cancer, including melanoma, and correlates with an aggressive cancer phenotype, inducing cell proliferation and epithelial-to-mesenchymal transition. In addition, AXL has recently been linked to chemotherapy resistance, and inhibition of AXL is found to increase DNA damage and reduce expression of DNA repair proteins. In light of this, we aimed to investigate whether targeting AXL together with DNA damage response proteins would be therapeutically beneficial. Using melanoma cell lines, we observed that combined reduction of AXL and CHK1/CHK2 signaling decreased proliferation, deregulated cell-cycle progression, increased apoptosis, and reduced expression of DNA damage response proteins. Enhanced therapeutic effect of combined treatment, as compared with mono-treatment, was further observed in a patient-derived xenograft model and, of particular interest, when applying a three-dimensional ex vivo spheroid drug sensitivity assay on tumor cells harvested directly from 27 patients with melanoma lymph node metastases. Together, these results indicate that targeting AXL together with the DNA damage response pathway could be a promising treatment strategy in melanoma, and that further investigations in patient groups lacking treatment alternatives should be pursued.

A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases.

Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) ex vivo drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lymph node metastases and 21 patient derived xenografts (PDXs) to clinical relevant drugs for 7 days, and examined its potential to evaluate therapy response. A strong association between Vemurafenib response and BRAF mutation status was achieved (P < .0001), while enhanced viability was seen in some NRAS mutated tumors. BRAF and NRAS mutated tumors responded comparably to the MEK inhibitor Cobimetinib. Based on the ex vivo results, two tumors diagnosed as BRAF wild-type by routine pathology examinations had to be re-evaluated; one was subsequently found to have a complex V600E mutation, the other a double BRAF mutation (V600E/K601 N). No BRAF inhibitor resistance mechanisms were identified, but PIK3CA and NF1 mutations were identified in two highly responsive tumors. Concordance between ex vivo drug responses using tissue from PDXs and corresponding patient tumors demonstrate that PDX models represent an indefinite source of tumor material that may allow ex vivo evaluation of numerous drugs and combinations, as well as studies of underlying molecular mechanisms. In conclusion, we have established a rapid and low cost ex vivo drug efficacy assay applicable on tumor tissue from patient biopsies. The 3D/spheroid format, limiting the influence from normal adjacent cells and allowing assessment of drug sensitivity to numerous drugs in one week, confirms its potential as a supplement to guide clinical decision, in particular in identifying non-responding patients.

Vertical Rectus Abdominis Musculocutaneous Flap Repair Improves Perineal Wound Healing after Abdominoperineal Resection for Irradiated Locally Advanced Rectal Cancer.

BACKGROUND: Radiotherapy (RT) and subsequent abdominoperineal resection (APR) for locally advanced rectal cancer (LARC) is associated with significant perineal wound morbidity. The aim of the present study was to investigate if vertical rectus abdominis musculocutaneous (VRAM) flap repair after APR in LARC patients improves perineal wound healing compared with direct perineal wound closure (non-VRAM). METHODS: LARC patients (n = 329) operated with APR between January 2006 and December 2015 after neoadjuvant RT of ≥ 25 Gy were identified, including 260 and 69 patients in the non-VRAM and VRAM groups, respectively. Perineal wound healing was assessed 3 months postoperatively, and risk factors for perineal wound complications and associations with short- and long-term outcome were analyzed. RESULTS: Delayed perineal wound healing after 3 months was more frequent in the non-VRAM group (31.5%) compared with the VRAM group (10.4%) (p < 0.01). In the non-VRAM group, 26.9% of patients developed pelvic abscess, compared with 10.1% in the VRAM group (p < 0.01). Significant risk factors for perineal wound morbidity were non-VRAM (odds ratio [OR] 3.94, 95% confidence interval [CI] 1.72-9.00; p = 0.02), positive circumferential resection margin (R1; OR 3.64, 95% CI 1.91-6.93; p < 0.01), pelvic abscess (OR 3.27, 95% CI 1.90-5.63; p < 0.01), and short-course RT (OR 3.81, 95% CI 1.75-8.30; p < 0.01). Perineal wound morbidity was not associated with impaired long-term oncologic outcome. CONCLUSIONS: VRAM flap reconstruction of the perineum is associated with an increased wound healing rate and may protect against pelvic abscess development. However, procedure-related long-term morbidity is incompletely studied and the procedure should be reserved for selected patients.

Fibromatosis in vertical rectus abdominis myocutaneous flap imitating tumor recurrence after surgery for locally advanced rectal cancer: case report.

BACKGROUND: Abdominoperineal excision is performed in patients with locally advanced, low rectal carcinoma. Reconstruction of the dorsal vagina and perineum using the vertical rectus abdominis myocutaneous flap following extensive surgery results in favorable surgical outcome and quality of life. However, the rectus abdominis muscle, as part of the anterior abdominal wall, may develop fibrous lesions also as a transplant. CASE PRESENTATION: A 39-year-old female patient with low rectal cancer and extensive colorectal polyposis was treated with neoadjuvant chemoradiotherapy followed by colectomy and abdominoperineal excision with resection of the dorsal vaginal wall and subsequent reconstruction of the perineum using the vertical rectus abdominis myocutaneous flap. At the 6-month follow-up, a suspected 2 × 2 cm tumor recurrence was detected in the transposed tissue and was subsequently surgically removed. Histologic examination concluded with fibromatosis. Genetic testing revealed a known disease-causing mutation in the adenomatous polyposis coli gene, confirming the diagnosis of familial adenomatous polyposis. CONCLUSIONS: Fibromatosis may affect the anterior abdominal wall, that is the rectus abdominis muscle, at the primary site or may develop in the muscle after its transposition into the perineum at pelvic reconstruction. Fibromatosis in the muscle flap after pelvic reconstruction may present a difficult diagnostic challenge for the multidisciplinary team.