Impact of laparoscopic ultrasound during PIPAC directed treatment of unresectable peritoneal metastasis

Objectives: Laparoscopic ultrasound (LUS) combines both laparoscopy and ultrasound imaging of the peritoneum liver and retroperitoneum. LUS has not been described in treatments with pressurized intraperitoneal aerosol chemotherapy (PIPAC). We present our experience with LUS in patients undergoing PIPAC. Methods: Retrospective study of LUS findings from the prospective PIPAC-OPC2 trial. Main outcome was changes in overall treatment strategy due to LUS findings. Results: PIPAC-OPC2 included 143 patients of which 33 patients were treated with electrostatic precipitation PIPAC. Nine patients were excluded due to primary non-access. During PIPAC 1, LUS was performed in 112 of 134 (84 %) PIPAC procedures and changed overall treatment strategy in one patient due to detection of multiple liver metastases unseen by baseline CT. During PIPAC 2 and 3 LUS was performed in 59 of 104 (57 %) and 42 of 78 (54 %) PIPAC procedures, respectively. Throughout PIPAC 1–3, LUS also detected pathological lymph nodes in 16 patients, and focal liver lesions in another four patients of uncertain origin. No further examinations were performed in these patients, and the overall treatment strategy was not changed according to the PIPAC-OPC2 protocol. One patient had a splenic capsule rupture related to the LUS itself. This was managed conservatively. Conclusions: LUS may be safely performed during PIPAC. However, LUS has limited clinical impact in patients scheduled for PIPAC, and cannot be recommended as a routine procedure when performing PIPAC.</p

Pressurized IntraPeritoneal Aerosol Chemotherapy with one minute of electrostatic precipitation (ePIPAC) is feasible, but the histological tumor response in peritoneal metastasis is insufficient

Introduction: Electrostatic precipitation Pressurized IntraPeritoneal Aerosol Chemotherapy (ePIPAC) has shown superior penetration depth and tissue uptake compared to standard PIPAC. We investigated the feasibility and objective tumor response to ePIPAC with 1 min of precipitation in patients with peritoneal metastasis (PM). Materials and methods: Patients with PM from various abdominal cancers were included in an amendment to the ongoing prospective PIPAC-OPC2 trial. Colorectal and appendiceal PM were treated with oxaliplatin, patients with PM from other primaries were treated with a combination of cisplatin and doxorubicin. Three ePIPAC procedures were planned in each patient including repeated peritoneal biopsies for response evaluation. After emission to the peritoneal cavity, the aerosolized chemotherapeutics were precipitated for 1 min followed by immediate exsufflation and abdominal closure. Histological regression from the first to the third ePIPAC was evaluated according to the Peritoneal Regression Grading Score (PRGS) and compared to data from the PIPAC-OPC1 trial. Complications and toxicities were recorded according to Dindo-Clavien and CTCAE. Results: Sixty-five ePIPAC procedures were performed in 33 patients (median 2, range 1–6). Ten patients were eligible for response evaluation based on biopsies from the first and third ePIPAC procedure. Four patients had disease progression, four patients had regressive disease, and two patients had stable disease according to PRGS. No life threatening adverse reactions and no mortality was observed following ePIPAC. Conclusion: One minute ePIPAC was feasible and safe, but the histological tumor response was insufficient compared to standard PIPAC directed therapy with 30 min passive diffusion time.</p

Association of patient-reported psychosocial healthcare and risk of readmissions and mortality in patients with ischemic heart disease:A population-based cohort study

ObjectivePsychosocial risk factors are common in patients with ischemic heart disease (IHD) and linked to poor prognosis. Psychosocial healthcare is recommended in international guidelines and has demonstrated positive effects, primarily on psychosocial symptoms. We examined the association between patient-reported psychosocial healthcare and hospital readmissions and mortality in patients with IHD.MethodsA population-based cohort study with register-based follow-up. Patient-reported psychosocial healthcare was measured by seven items in a survey sent to a random sample of patients with incident IHD in Denmark in 2014. We used multivariable Cox proportional hazards models and Poisson regression to examine the association between psychosocial healthcare and readmissions and all-cause mortality.ResultsIn total, 1083 (57%) patients were followed up to 4½ years. Low psychosocial support was reported by 53.4%, medium by 26.2% and high by 20.4% patients. The hazard of acute cardiac readmission for patients reporting low psychosocial healthcare was 2.08 higher than for patients reporting high psychosocial healthcare (95%CI:1.01–4.30). No association was found with time to first all-cause readmission. The acute cardiac readmission rate was 3.24 (95%CI:1.66–6.29) and 4.23 (95%CI:2.15–8.33) times higher among patients reporting low and medium psychosocial healthcare compared to high, and the all-cause readmission rate was 1.30 (95%CI:1.16–1.46) and 1.32 (95%CI:1.17–1.49) times higher. The hazard of death was 2.86 (95%CI:1.23–6.69) and 2.88 (95%CI:1.18–7.04) times higher among patients reporting low and medium psychosocial healthcare compared to high.ConclusionIn patients with IHD, a high level of patient-reported psychosocial healthcare was significantly associated with reduced hospital readmissions and all-cause mortality

Facile generation of monoclonal antibodies suitable for conjugation

Monoclonal antibodies (mAb) are unique tools in therapeutics and immunodiagnostics applications but many of these applications rely on conjugated mAbs. Whether conjugating drugs or tracers, the conjugation process, frequently taking advantage of primary amines on lysine residues, may affect the binding activity of the antibodies. Furthermore, due to the sticky nature of many mAbs, unfavorable interactions may become eminent, with the result of high background signals. The workload associated with producing mAbs, able to withstand conjugation, preserving stability and affinity and avoiding off-target interactions, is comprehensive and related with only incidental success. We designed a method, where uncloned hybridomas were pre-selected for secretion of mAbs with the above characteristics. Using human collectin K1 (CL-K1, alias CL-11, Colec11) as a model antigen, mAbs present in culture supernatant from uncloned hybridomas were immobilized on Protein A beads, followed by solid phase biotinylation and subsequent elution. ELISA was employed to compare the binding activity of conjugated vs. unconjugated mAbs, and furthermore for their application in combination with other antibodies. From a group of 96 uncloned hybridomas we accomplished in obtaining five suitable mAbs, among which, two mAbs were superior. The successful conjugation of the selected mAbs with fluorophores and subsequent applications in microscopy and flow cytometry were further demonstrated. In conclusion, pre-selection of uncloned hybridomas, by testing of their mAbs' ability to withstand conjugation with tracers or drugs, is a successful strategy to avoid a huge workload of cloning numerous hybridomas, in order to obtain conjugatable mAbs.</p

Advancements in decadal climate predictability: the role of nonoceanic drivers

We review recent progress in understanding the role of sea ice, land surface, stratosphere, and aerosols in decadal-scale predictability and discuss the perspectives for improving the predictive capabilities of current Earth system models (ESMs). These constituents have received relatively little attention because their contribution to the slow climatic manifold is controversial in comparison to that of the large heat capacity of the oceans. Furthermore, their initialization as well as their representation in state-of-the-art climate models remains a challenge. Numerous extraoceanic processes that could be active over the decadal range are proposed. Potential predictability associated with the aforementioned, poorly represented, and scarcely observed constituents of the climate system has been primarily inspected through numerical simulations performed under idealized experimental settings. The impact, however, on practical decadal predictions, conducted with realistically initialized full-fledged climate models, is still largely unexploited. Enhancing initial-value predictability through an improved model initialization appears to be a viable option for land surface, sea ice, and, marginally, the stratosphere. Similarly, capturing future aerosol emission storylines might lead to an improved representation of both global and regional short-term climatic changes. In addition to these factors, a key role on the overall predictive ability of ESMs is expected to be played by an accurate representation of processes associated with specific components of the climate system. These act as “signal carriers,” transferring across the climatic phase space the information associated with the initial state and boundary forcings, and dynamically bridging different (otherwise unconnected) subsystems. Through this mechanism, Earth system components trigger low-frequency variability modes, thus extending the predictability beyond the seasonal scale

RNA expression profiling of peritoneal metastasis from pancreatic cancer treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

Objectives: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to examine mRNA profile of fibrosis due to response after systemic chemotherapy and PIPAC (Regression) compared to treatment-naïve PM-PC and chronic cholecystitis-related peritoneal fibrosis (Controls). Methods: Peritoneal biopsies (PBs) from PM-PC patients who had undergone systemic chemotherapy and PIPAC were evaluated with Peritoneal Regression Grading Score (PRGS). We extracted RNA from PBs with Regression (PRGS 1, n=11), treatment-naïve PM-PC (n=10), and Controls (n=10). Profiling of 800 mRNAs was performed (NanoString nCounter, PanCancer Immuno-Oncology 360 (IO-360) and 30 additional stroma-related mRNAs). Results: Regression vs. PM-PC identified six up-regulated and 197 down-regulated mRNAs (FDR≤0.05), linked to TNF-α signaling via NF-kB, G2M checkpoint, epithelial-mesenchymal transition, estrogen response, and coagulation. Regression vs. Controls identified 43 significantly up-regulated mRNAs, linked to interferon-α response, and down-regulation of 99 mRNAs, linked to TNF-α signaling via NF-kB, inflammatory response, epithelial-mesenchymal transition, KRAS signaling, and hypoxia (FDR≤0.05). Conclusions: In regressive fibrosis of PM-PC after systemic chemotherapy and PIPAC (Regression), downregulation of mRNAs related to key tumor biological pathways was identified. Regression also showed transcriptional differences from unspecific, benign fibrosis (Controls). Future studies should explore whether mRNA profiling of PBs with PM from PC or other primaries holds prognostic or predictive value.</p

Importance of biopsy site selection for peritoneal regression grading score (PRGS) in peritoneal metastasis treated with repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC)

Objectives: The four-tiered peritoneal regression grading score (PRGS) is used for histological response evaluation in patients with peritoneal metastasis (PM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Four quadrant biopsies (QBs) from the parietal peritoneum should be assessed by PRGS, but consensus on biopsy site strategy for follow-up biopsies during repeated PIPACs is lacking. We aimed to evaluate whether there is a difference between PRGS in QBs from clips marked PM (QB-CM) compared to biopsies from PM with the visually most malignant features (worst biopsy, WB). Methods: Prospective, descriptive study. During the first PIPAC, index QBs sites were marked with metal clips. During the second PIPAC, an independent surgical oncologist selected biopsy site for WB and biopsies were taken from QB-CM and WB. One blinded pathologist evaluated all biopsies according to PRGS. From each biopsy, three step sections were stained H&amp;E, followed by an immunostained section, and another three step sections stained H&amp;E. Results: Thirty-four patients were included from March 2020 to May 2021. Median age 64 years. Maximum mean PRGS in QB-CM at PIPAC 1 was 3.3 (SD 1.2). Maximum mean PRGS in QB-CM at PIPAC 2 was 2.6 (SD 1.2), whereas mean PRGS in WB at PIPAC 2 was 2.4 (SD 1.3). At PIPAC 2, there was agreement between maximum PRGS from QB-CM and PRGS from WB in 21 patients. Maximum PRGS from QB-CM was higher in nine and lower in four patients, compared to PRGS from WB. Conclusions: Biopsies from QB-CM did not overestimate treatment response compared to biopsies from WB.</p

The impact of type 2 diabetes on long-term gastrointestinal sequelae after colorectal cancer surgery:national population-based study

BACKGROUND: Long-term gastrointestinal sequelae are common after colorectal cancer surgery, but the impact of type 2 diabetes (T2D) is unknown. METHODS: In a cross-sectional design, questionnaires regarding bowel function and quality of life (QoL) were sent to all Danish colorectal cancer survivors, who had undergone surgery between 2001 and 2014 and had more than 2 years follow-up without relapse. The prevalence of long-term gastrointestinal sequelae among colorectal cancer survivors with and without T2D were compared while stratifying for type of surgical resection and adjusting for age, sex, and time since surgery. RESULTS: A total of 8747 out of 14 488 colorectal cancer survivors answered the questionnaire (response rate 60 per cent), consisting of 3116 right-sided colonic, 2861 sigmoid, and 2770 rectal resections. Of these, 690 (7.9 per cent) had a diagnosis of T2D before surgery. Survivors with T2D following rectal resection had a 15 per cent (95 per cent c.i. 7.8 to 22) higher absolute risk of major low anterior resection syndrome, whereas survivors with T2D following right-sided and sigmoid resection had an 8 per cent higher risk of constipation (P < 0.001) but otherwise nearly the same long-term risk of bowel symptoms as those without T2D. For all types of colorectal cancer resections, T2D was associated with a 6–10 per cent higher risk of severe pain (P < 0.035) and a 4–8 per cent higher risk of impaired QoL. CONCLUSION: T2D at time of surgery was associated with a higher risk of long-term bowel dysfunction after rectal resection, but not after colon resection excluding a higher risk of constipation. T2D was associated with a slightly higher frequency of severe pain and inferior QoL after both rectal and colonic cancer resection

What is long-term survival in patients with peritoneal metastasis from gastric, pancreatic, or colorectal cancer?:A study of patients treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC)

OBJECTIVES: A definition of long-term survival (LTS) in patients with peritoneal metastasis (PM) from gastric cancer (GC), pancreatic cancer (PC) or colorectal cancer (CRC) treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) is lacking. We aimed to define LTS and investigate characteristics and treatment response in patients who reached LTS in data from two prospective trials.METHODS: Retrospective study of patients with GC-, PC-, or CRC-PM from the prospective PIPAC-OPC1 and PIPAC-OPC2 studies. The definition of LTS was based on published systematic reviews and randomized controlled trials. LTS was defined at the time point where 25 % of the patients were alive in these studies. Histology based response was evaluated by the mean Peritoneal Regression Grading Score (PRGS) using biopsies obtained prior to PIPAC 3, and defined by a mean PRGS of ≤2.0 or a decrease of mean PRGS of ≥1, compared to baseline.RESULTS: LTS was defined at 21 (GC), 15 (PC), and 24 (CRC) months. Fifty-one (47.2 %) patients (nine GC, 17 PC, 25 CRC) reached LTS calculated from the date of PM diagnosis. All but one received palliative chemotherapy before PIPAC, and 37 % received bidirectional treatment. More than 90 % of the LTS patients had response according to PRGS. The mOS from PIPAC 1 was 23.3, 12.4, and 28.5 months for GC, PC, and CRC LTS patients.CONCLUSIONS: Patients with PM from GC, PC, and CRC treated with systemic chemotherapy and PIPAC can reach LTS and most show histological response. Causality must be further investigated.</p

Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin

After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm