Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer.

BACKGROUND: Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. METHODS: Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors. RESULTS: BRAF mutations were detected in 27% of the patients, and the BRAF-mutated subgroup had inferior overall survival compared to wild-type cases (median 16 vs 36 months, respectively, p < 0.001). BRAF mutations were associated with RNF43/RSPO aberrations and low expression of negative Wnt regulators (ligand-dependent Wnt activation). Furthermore, BRAF mutations were associated with gene expression changes in transport solute carrier proteins (specifically SLC7A6) and drug metabolism enzymes (CES1 and CYP3A4) that could influence the efficacy of MMC and irinotecan, respectively. BRAF-mutated tumors additionally exhibited increased expression of members of the novel butyrophilin subfamily of immune checkpoint molecules (BTN1A1 and BTNL9). CONCLUSIONS: BRAF mutations were frequently detected and were associated with particularly poor survival in this cohort, possibly related to ligand-dependent Wnt activation and altered drug transport and metabolism that could confer resistance to MMC and irinotecan. Drugs that target ligand-dependent Wnt activation or the BTN immune checkpoints could represent two novel therapy approaches.

Hyperthermic intraperitoneal chemotherapy in colorectal cancer.

BACKGROUND: This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. PATIENTS AND METHODS: Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. RESULTS: Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. CONCLUSIONS: Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.

Short-term results after robot-assisted surgery for primary rectal cancers requiring beyond total mesorectal excision in multiple compartments.

AIM: Rectal cancers requiring beyond total mesorectal excision (bTME) are traditionally operated using an open approach, but the use of minimally invasive robot-assisted procedures is increasing. Introduction of minimal invasive surgery for complex cancer cases could be associated with compromised surgical margins or increased complication rates. Therefore, reporting results both clinical and oncological in large series is important. Since bTME procedure reports are heterogeneous, comparing results is often difficult. In this study, a magnetic resonance imaging (MRI) classification system was used to describe the bTME surgery according to pelvic compartments. METHODS: Consecutive patients with primary rectal cancer operated with laparoscopic robot-assisted bTME were prospectively included for 2 years. All patients had tumors that threatened the mesorectal fascia, invaded adjacent organs, and/or involved metastatic pelvic lateral lymph nodes. Short-term clinical outcomes and oncological specimen quality were registered. Surgery was classified according to pelvic compartments resected. RESULTS: Clear resection margins (R0 resection) were achieved in 95 out of 105 patients (90.5%). About 26% had Accordion Severity Grading System of Surgical Complications grade 3-4 complications and 15% required re-operations. About 7% were converted to open surgery. The number of compartments resected ranged from one to the maximum seven, with 83% having two or three compartments resected. All 10 R1 resections occurred in the lateral and posterior compartments. CONCLUSIONS: The short-term clinical outcomes and oncological specimen quality after robot-assisted bTME surgery were comparable to previously published open bTME surgery. The description of surgical procedures using the Royal Marsden MRI compartment classification was feasible.

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.

Drafting in long-track speed skating team pursuit on the ice rink.

Drafting is distinctive for team pursuit races in long-track speed skating. This study aims to compare the impact of drafting on physical intensity (heart rate [HR]) and perceived intensity (ratings of perceived exertion [RPE]) per drafting position. Eighteen skilled male (n = 9) and female (n = 9) skaters (20.0 ± 4.8 years) skated three trials, in first, second or third position, with consistent average velocity (F2,10 = 2.30, p = 0.15, ηp2 = 0.32). Differences in HR and RPE (Borg CR-10 scale) were compared within-subjects (three positions) using a repeated-measures ANOVA (p < 0.05). Compared to the first position, HR was lower in the second (benefit 3.2%) and third (benefit 4.7%) position and lower in third compared to second position (benefit 1.5%), observed in 10 skaters (F2,28 = 28.9, p < 0.001, ηp2= 0.67). RPE was lower when comparing second (benefit 18.5%) and third (benefit 16.8%) position to first (F1.3,22.1 = 7.02, p < 0.05, ηp2= 0.29) and similar for third and second positions., observed in 8 skaters. Even though the physical intensity was lower when drafting in third versus second position, the perceived intensity was equal. There were large interindividual differences between skaters. Coaches are advised to adopt a multidimensional, tailored approach when selecting and training skaters for a team pursuit.

Perioperative chemotherapy in colorectal cancer with peritoneal metastases: A global propensity score matched study.

Background: There is a paucity of studies evaluating perioperative systemic chemotherapy in conjunction with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colorectal cancer peritoneal metastases (CRCPM). The aim was to evaluate neoadjuvant and/or adjuvant systemic therapy in CRCPM. Methods: Patients with CRCPM from 39 treatment centres globally from January 1, 1991, to December 31, 2018, who underwent CRS+HIPEC were identified and stratified according to neoadjuvant/adjuvant use. Crude data analysis, propensity score matching (PSM) and Cox-proportional hazard modelling was performed. Findings: Of 2093 patients, 1613 were included in neoadjuvant crude evaluation with 708 in the PSM cohort (354 patients/arm). In the adjuvant evaluation, 1176 patients were included in the crude cohort with 778 in the PSM cohort (389 patients/arm). The median overall survival (OS) in the PSM cohort receiving no neoadjuvant vs neoadjuvant therapy was 37.0 months (95% CI: 32.6-42.7) vs 34.7 months (95% CI: 31.2-38.8, HR 1.08 95% CI: 0.88-1.32, p = 0.46). The median OS in the PSM cohort receiving no adjuvant therapy vs adjuvant therapy was 37.0 months (95% CI: 32.9-41.8) vs 45.7 months (95% CI: 38.8-56.2, HR 0.79 95% CI: 0.64-0.97, p = 0.022). Recurrence-free survival did not differ in the neoadjuvant evaluation but differed in the adjuvant evaluation - HR 1.04 (95% CI: 0.87-1.25, p = 0.66) and 0.83 (95% CI: 0.70-0.98, p = 0.03), respectively. Multivariable Cox-proportional hazard modelling in the crude cohorts showed hazard ratio 1.08 (95% CI: 0.92-1.26, p = 0.37) for administering neoadjuvant therapy and 0.86 (95% CI: 0.72-1.03, p = 0.095) for administering adjuvant therapy. Interpretation: Neoadjuvant therapy did not confer a benefit to patients undergoing CRS+HIPEC for CRCPM, whereas adjuvant therapy was associated with a benefit in this retrospective setting. Funding: None.

Cancer therapy with isolated limb perfusion. / Kreftbehandling med isolert ekstremitetsperfusjon.

For locally advanced soft tissue sarcomas and metastases from melanoma located in the extremities, mutilating surgery or amputation may be necessary to achieve local control. Isolated limb perfusion with high-dose chemotherapy may represent an alternative to amputation for this patient group.

Metastases in locally advanced rectal cancer undergoing curatively intended treatment.

BACKGROUND: The main cause of mortality in locally advanced rectal cancer (LARC) is metastatic progression. The aim of the present study was to describe frequency, pattern and outcome of metastatic disease in a cohort of LARC patients after curative resection. METHODS: This was a single-centre cohort study of 628 LARC cases after neoadjuvant chemoradiotherapy/radiotherapy (CRT/RT) and surgery. Data, including the first site of metastasis, was registered in an institutional database linked to the National Cancer Registry. RESULTS: Metastases were diagnosed in 270 patients (43.0%) with liver and lungs as the first site in 113 and 96 cases, respectively. Involved resection margins, high tumour stage and poor response to CRT/RT were associated with metastasis development and inferior overall survival (OS). Metastasectomy was performed in 76 (67.3%) patients with liver metastases and 28 (29.2%) patients with lung metastases. Five-year OS was 89% in patients without metastases and 32% in metastatic cases. In patients selected for metastasectomy, 5-year OS was 69% and 53% for lung and liver metastases, respectively. Corresponding numbers without metastasectomy were 12% and 0%. CONCLUSION: In this large LARC cohort undergoing curatively intended treatment, liver and lung metastases occurred at similar frequencies. Liver as the first metastatic site was associated with inferior long-term outcome, while selection for metastasectomy was associated with better OS, with more than half of the resected patients being alive five years after LARC surgery. Our results show that the presence of resectable metastatic disease at diagnosis should not exclude a curative therapeutic approach in LARC.

ImmunoPeCa trial: Long-term outcome following intraperitoneal MOC31PE immunotoxin treatment in colorectal peritoneal metastasis.

BACKGROUND: The ImmunoPeCa trial investigated the use of intraperitoneal MOC31PE immunotoxin as a novel therapeutic principle for the treatment of peritoneal metastasis from colorectal cancer (PM-CRC). We here report long-term outcome from the trial. METHODS: This was a dose-finding trial aiming to evaluate safety and toxicity (primary endpoint) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with mitomycin C. Overall survival (OS) and disease-free survival (DFS) were secondary endpoints. Twenty-one patients received the study drug at four dose levels on the first postoperative day, including six patients constituting an expansion cohort. RESULTS: With a 34-month follow-up, the median OS was not reached and the estimated 3-year OS was 78%. Median DFS for all patients was 21 months and the 3-year DFS was 33%, with a median follow-up of 31 months. When excluding patients with potential favorable characteristics from the analysis (n = 4), the median DFS was 13 months and the 3-year OS 72%. CONCLUSIONS: The promising long-term outcome combined with low systemic absorbance, high drug concentration and cytotoxic activity in peritoneal fluid support further investigations of clinical efficacy.

Incidence, predictors and prognostic implications of dyspnea at admission among acute coronary syndrome patients without heart failure.

BACKGROUND: Among patients with stable coronary artery disease, effort-related dyspnea is associated with a larger ischemic territory and worse outcome. Whether dyspnea, not related to heart failure, is also associated with adverse outcome among patients with acute coronary syndromes (ACS) has not been fully elucidated. METHODS: We studied ACS patients enrolled in the biennial Acute Coronary Syndrome Israeli Surveys (ACSIS) during 2010-2013 who were classified as Killip 1. A retrospective comparative analysis was performed between patients with chest pain alone (n = 2017) and those with chest pain with dyspnea (n = 417). RESULTS: Patients with dyspnea were older (64.4 ±â€¯13 vs.61.8 ±â€¯12, p < 0.001), more frequently women (81% vs. 75% p < 0.001) and had higher rates of multiple comorbidities. Statistically significant predictors for dyspnea as a presenting symptom were female sex [HR 1.47 (1.11, 1.89)], chronic kidney disease [HR 1.81 (1.30, 2.52)], chronic obstructive pulmonary disease [HR 1.59 (1.045, 2.429)] and angina ≥24 h [HR 1.46 (1.147, 1.86)]. Patients presenting with dyspnea were less likely to undergo primary reperfusion (31% vs. 42%, p < 0.001) and overall coronary intervention (71% vs. 78%, p < 0.001) during their hospitalization. Mortality rates were significantly higher among patients presenting with dyspnea both at 30-day (3% vs. 2%, p = 0.017) and at 1-year follow-up (9% vs. 4%, p < 0.001). Dyspnea was as an independent predictor of 1-year mortality. CONCLUSION: The presence of dyspnea is frequent and associated with adverse outcome among patients with ACS without signs of heart failure. Early identification of this higher-risk cohort of patients may allow intensifying treatment and careful follow-up may be warranted.

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer.

Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial-to-mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer-compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.

Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response.

Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. LATS1/2 were identified as the main mutational drivers together with homozygous loss of BAP1 and PBRM1, which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to BAP1 loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine.

Pacing Behavior of Elite Youth Athletes: Analyzing 1500-m Short-Track Speed Skating.

PURPOSE: To gain insight into the development of pacing behavior of youth athletes in 1500-m short-track speed-skating competition. METHODS: Lap times and positioning of elite short-track skaters during the seasons 2011/2012-2015/2016 were analyzed (N = 9715). The participants were grouped into age groups: under 17 (U17), under 19 (U19), under 21 (U21), and senior. The difference between age groups, sexes, and stages of competition within each age group were analyzed through a multivariate analysis of variance (P < .05) of the relative section times (lap time as a percentage of total race time) per lap and by analyzing Kendall tau-b correlations between intermediate positioning and final ranking. RESULTS: The velocity distribution over the race differed between all age groups, explicitly during the first 4 laps (U17: 7.68% [0.80%], U19: 7.77% [0.81%], U21: 7.82% [0.81%], and senior: 7.80% [0.82%]) and laps 12, 13, and 14 (U17: 6.92% [0.14%], U19: 6.83% [0.13%], U21: 6.79% [0.14%], and senior: 6.69% [0.12%]). In all age groups, a difference in velocity distribution was found between the sexes and between finalists and nonfinalists. Positioning data demonstrated that youth skaters showed a higher correlation between intermediate position and final ranking in laps 10, 11, and 12 than seniors. CONCLUSIONS: Youth skaters displayed less conservative pacing behavior than seniors. The pacing behavior of youths, expressed in relative section times and positioning, changed throughout adolescence and came to resemble that of seniors. Pacing behavior and adequately responding to environmental cues in competition could therefore be seen as a self-regulatory skill that is under development throughout adolescence.

Optimal Development of Youth Athletes Toward Elite Athletic Performance: How to Coach Their Motivation, Plan Exercise Training, and Pace the Race.

Elite athletes have invested many years in training and competition to reach the elite level. One very important factor on the road to elite performance is the decision-making process regarding the regulation of effort over time, termed as pacing behavior. The regulation of effort is vital for optimal athletic performance during a single race and over a longer period of time (e.g., a competitive season) as an inadequate regulation could result in a higher risk of injuries, overtraining, and drop-out. Despite this, there is limited knowledge on how young athletes learn and develop the abilities related to pacing. Pacing behavior of athletes develops from childhood throughout adolescence and is thought to be closely connected to physical maturation, the development of pre-frontal cortical related (meta-) cognitive functions, as well as the gathering of experience with exercise tasks. The motivation of an athlete can critically influence how an athlete paces a single race, but also how they distribute their effort over a longer period of time. Coaches are advised to closely monitor the development of pacing behavior during adolescence (e.g., by gathering split times, and related physiological measurement, during training and competition), as well as the underlying factors including physical maturation (meta-) cognitive development and the motivation of young athletes. Furthermore, pacing behavior development could be aided by providing training in which the task, individual, and environment are manipulated. Hereby, presenting athletes with the opportunity to gain experience in situations which closely resemble the perceptual-motor conditions of upcoming competitions.

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.

Sodium phosphate enemas do not worsen renal function among hospitalized patients with mild to moderate renal failure: a matched, case-control study.

BACKGROUND: Sodium phosphate enemas (SPEs) are widely used among hospitalized patients despite their potential to worsen renal failure. AIM: We decided to assess the extent to which this side effect is clinically relevant. DESIGN: We conducted a matched case-control, retrospective study in a cohort of hospitalized patients. METHODS: Patients treated and untreated with SPEs were matched for age, gender, baseline creatinine, usage of certain medications and several background diagnoses. Three groups of matched patients (whole study cohort, patients with baseline creatinine > 1.5 mg/dl and those with baseline creatinine > 2 mg/dl) were compared with regards to their creatinine and blood electrolyte concentrations during 3 consecutive hospitalization days after SPE application. RESULTS: Four hundred and twelve patients were included in this study of which 206 were treated by single SPEs. Exact matching was done for the whole study cohort, for 108 patients with baseline creatinine > 1.5 mg/dl and for 58 patients with baseline creatinine > 2 mg/dl. During 3 consecutive days after SPEs, the maximal blood concentrations of creatinine, phosphor and potassium did not differ significantly between treated patients and matched controls, in all three patients' groups. CONCLUSION: Application of SPEs neither seem to worsen mild to moderate renal failure, nor are associated with hyperphosphatemia or hyperkalemia in patients hospitalized in internal medicine departments.

Accuracy of 3D fluoro-navigated anterior transpedicular screws in the subaxial cervical spine: an experimental study on human specimens.

INTRODUCTION: Pedicle screw stabilization, the standard technique in the thoracic and lumbar spine, is increasingly used in the cervical spine. Initial studies on the use of anterior pedicle screws (ATPS) in the cervical spine have been recently published. ATPS use has theoretical advantages over posterior stabilization. We have already established a 3D-fluoroscopy navigation setup in a study of artificial bones. The aim of the current study was to evaluate the positioning quality/accuracy of ATPS introduced to human specimens. METHODS: 36 cannulated screws (3.5 mm) were implanted anteriorly into the C3-C7 segments of four spines (unfixed, frozen, cadaveric specimens) using a 3D-fluoroscopy navigation system. Placement accuracy was evaluated using a recently published classification on postoperative CT scans. Grade 1 is perfect position with pedicle wall perforation <1 mm, grade 2 is perforation <2 mm, etc., and finally grade 5 is cortical perforation of >4 mm and/or transverse foramen entry. RESULTS: 36 anterior pedicle screws were inserted into four human cervical spine specimens. Of these, seven screws were introduced to C3, five to C4 and eight each to C5, C6, and C7. Classified with the modified G&R, 21 of 36 (58.3%) were grade 1. Ten screws (27.8%) were grade 2. Grade 4 was assessed for two screws and grade 5 for three. Customary "good" positioning, combining grades 1 and 2, was thus found in 86.1%. Five screws (13.9%) did not meet this criterion (grade ≥3). CONCLUSIONS: With 86.1% of good positioning (grade 2 or better), a 3D-fluoroscopy navigation of ATPS screws into human c-spine specimens achieved a satisfying results. These are at least comparable to results presented in the literature for posteriorly introduced subaxial pedicle screws.

Novel Treatment with Intraperitoneal MOC31PE Immunotoxin in Colorectal Peritoneal Metastasis: Results From the ImmunoPeCa Phase 1 Trial.

BACKGROUND: MOC31PE immunotoxin was developed to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule, which is highly expressed in colorectal cancer. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer long-term survival to patients with peritoneal metastasis from colorectal cancer (PM-CRC), most patients experience disease relapse and novel therapeutic options are needed. On this basis, MOC31PE is being developed as a novel therapeutic principle to target PM-CRC. METHODS: This was a dose-escalating phase I trial to evaluate the safety and toxicity (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon intraperitoneal administration of MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with Mitomycin C. Fifteen patients received the study drug at four dose levels (3+3+3+6), administered intraperitoneally as a single dose the day after CRS-HIPEC. RESULTS: No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. There was negligible systemic absorption of the study drug. Drug concentrations in peritoneal fluid samples were in the cytotoxic range and increased in a dose-dependent manner. MOC31PE recovered from peritoneal cavity retained its cytotoxic activity in cell-based assays. All patients developed neutralizing antibodies. CONCLUSIONS: Intraperitoneal administration of MOC31PE was safe and well tolerated, and combined with low systemic uptake, MOC31PE seems ideal for local intraperitoneal treatment. The drug will be further evaluated in an ongoing phase II expansion cohort.