To assess the association of systemic inflammation and outcome after major abdominal surgery.
Major abdominal surgery carries a high postoperative morbidity and mortality rate. Studies suggest that ...inflammation is associated with unfavorable outcome.
Levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α and the systemic inflammatory response syndrome (SIRS) were assessed in 137 patients undergoing major abdominal surgery. Blood samples were drawn on days 0, 1, 3, and 7, and SIRS was scored during 48 hours after surgery. Primary outcome was a composite of mortality, pneumonia, sepsis, anastomotic dehiscence, wound infection, noncardiac respiratory failure, atrial fibrillation, congestive heart failure, myocardial infarction, and reoperation within 30 days of surgery.
An IL-6 level more than 432 pg/mL on day 1 was associated with an increased risk of complications (adjusted odds ratio: 3.3; 95% confidence interval CI: 1.3-8.5) and a longer median length of hospital stay (7 vs 12 days, P < 0.001). As a single test, an IL-6 cut-off level of 432 pg/mL on day 1 yielded a specificity of 70% and a sensitivity of 64% for the prediction of complications (area under the curve: 0.67; 95% CI: 0.56-0.77). Levels of CRP started to discriminate from day 3 onward with a specificity of 87% and a sensitivity of 58% for a cut-off level of 203 mg/L (AUC: 0.73; 95% CI: 0.63-0.83).
A high IL-6 level on day 1 is associated with postoperative complications. Levels of IL-6 help distinguish between patients at low and high risk for complications before changes in levels of CRP.
Background
Despite its increasing use, pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) has never been prospectively investigated as a palliative monotherapy for ...colorectal peritoneal metastases in clinical trials. This trial aimed to assess the safety (primary aim) and antitumor activity (key secondary aim) of PIPAC-OX monotherapy in patients with unresectable colorectal peritoneal metastases.
Methods
In this two-center, single-arm, phase II trial, patients with isolated unresectable colorectal peritoneal metastases in any line of palliative treatment underwent 6-weekly PIPAC-OX (92 mg/m
2
). Key outcomes were major treatment-related adverse events (primary outcome), minor treatment-related adverse events, hospital stay, tumor response (radiological, biochemical, pathological, ascites), progression-free survival, and overall survival.
Results
Twenty enrolled patients underwent 59 (median 3, range 1–6) PIPAC-OX procedures. Major treatment-related adverse events occurred in 3 of 20 (15%) patients after 5 of 59 (8%) procedures (abdominal pain, intraperitoneal hemorrhage, iatrogenic pneumothorax, transient liver toxicity), including one possibly treatment-related death (sepsis of unknown origin). Minor treatment-related adverse events occurred in all patients after 57 of 59 (97%) procedures, the most common being abdominal pain (all patients after 88% of procedures) and nausea (65% of patients after 39% of procedures). Median hospital stay was 1 day (range 0–3). Response rates were 0% (radiological), 50% (biochemical), 56% (pathological), and 56% (ascites). Median progression-free and overall survival were 3.5 months (interquartile range IQR 2.5–5.7) and 8.0 months (IQR 6.3–12.6), respectively.
Conclusions
In patients with unresectable colorectal peritoneal metastases undergoing PIPAC-OX monotherapy, some major adverse events occurred and minor adverse events were common. The clinical relevance of observed biochemical, pathological, and ascites responses remains to be determined, especially since radiological response was absent.
Postoperative pancreatic fistula is a potentially life-threatening complication after pancreatoduodenectomy. Evidence for best management is lacking.
To evaluate the clinical outcome of patients ...undergoing catheter drainage compared with relaparotomy as primary treatment for pancreatic fistula after pancreatoduodenectomy.
A multicenter, retrospective, propensity-matched cohort study was conducted in 9 centers of the Dutch Pancreatic Cancer Group from January 1, 2005, to September 30, 2013. From a cohort of 2196 consecutive patients who underwent pancreatoduodenectomy, 309 patients with severe pancreatic fistula were included. Propensity score matching (based on sex, age, comorbidity, disease severity, and previous reinterventions) was used to minimize selection bias. Data analysis was performed from January to July 2016.
First intervention for pancreatic fistula: catheter drainage or relaparotomy.
Primary end point was in-hospital mortality; secondary end points included new-onset organ failure.
Of the 309 patients included in the analysis, 209 (67.6%) were men, and mean (SD) age was 64.6 (10.1) years. Overall in-hospital mortality was 17.8% (55 patients): 227 patients (73.5%) underwent primary catheter drainage and 82 patients (26.5%) underwent primary relaparotomy. Primary catheter drainage was successful (ie, survival without relaparotomy) in 175 patients (77.1%). With propensity score matching, 64 patients undergoing primary relaparotomy were matched to 64 patients undergoing primary catheter drainage. Mortality was lower after catheter drainage (14.1% vs 35.9%; P = .007; risk ratio, 0.39; 95% CI, 0.20-0.76). The rate of new-onset single-organ failure (4.7% vs 20.3%; P = .007; risk ratio, 0.15; 95% CI, 0.03-0.60) and new-onset multiple-organ failure (15.6% vs 39.1%; P = .008; risk ratio, 0.40; 95% CI, 0.20-0.77) were also lower after primary catheter drainage.
In this propensity-matched cohort, catheter drainage as first intervention for severe pancreatic fistula after pancreatoduodenectomy was associated with a better clinical outcome, including lower mortality, compared with primary relaparotomy.
In the era of advanced surgical techniques and improved perioperative care, the willingness to perform emergency operations in elderly patients continues to increase. This systematic review aimed at ...assessing the clinical outcomes of early cholecystectomy in elderly patients with acute cholecystitis.
Medline, Embase, and Cochrane Library databases were systematically searched for studies reporting on early cholecystectomy for acute cholecystitis in patients aged ≥70 years. The conversion rate, perioperative morbidity, and mortality were calculated using a random-effects model.
Eight articles fell within the scope of this study. In total, 592 patients were identified. The mean age was 81 years. Early cholecystectomy was performed laparoscopically in 316 patients (53%) and open in 276 patients (47%). The procedure was associated with a conversion rate of 23% (95% CI 18.6-28.3), a perioperative morbidity of 24% (95% CI 20.5-27.5), and a mortality of 3.5% (95% CI 2.3-5.4).
Early cholecystectomy seems to be a feasible treatment in elderly patients with acute cholecystitis. To reduce morbidity, patients who may benefit from surgery ought to be selected carefully. Future prospective studies should compare early cholecystectomy with alternative treatments to select the treatment that is most appropriate for elderly patients.
Introduction
Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In ...obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients.
Methods
Twenty morbidly obese patients (with a median total body weight TBW of 140.1 kg range 106–193.1 kg and body mass index BMI of 45.1 kg/m
2
40–55.2 kg/m
2
) and eight non-obese patients (with a TBW of 69.4 kg 53.4–91.7 and BMI of 21.8 kg/m
2
19.4–27.4) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM.
Results
In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC
0–8h
) of acetaminophen was significantly smaller (
P
= 0.009), while the AUC
0–8h
ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (
P
= 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight LBW (population mean relative standard error 0.0185 L/min 15 %,
P
< 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (
P
< 0.001). Glucuronidation clearance (0.219 L/min 5 %) and sulphation clearance (0.0646 L/min 6 %) also increased with LBW (
P
< 0.001).
Conclusion
Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment.
Background
Electrostatic pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a palliative treatment for unresectable peritoneal metastases from various primary cancers. However, little is ...known about the systemic pharmacokinetics of oxaliplatin after ePIPAC.
Methods
Twenty patients with unresectable colorectal peritoneal metastases were treated with repetitive ePIPAC monotherapy with oxaliplatin (92 mg/m
2
) and a simultaneous intravenous bolus of leucovorin (20 mg/m
2
) and 5-fluorouracil (400 mg/m
2
). Samples were collected during each ePIPAC: whole blood at
t
= 0,
t
= 5,
t
= 10,
t
= 20,
t
= 30,
t
= 60,
t
= 120,
t
= 240,
t
= 360 and
t
= 1080 min for plasma and plasma ultrafiltrate concentrations; urine at
t
= 0,
t
= 1,
t
= 3,
t
= 5 and
t
= 7 days. Samples were analyzed using atomic absorption spectrometry. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling.
Results
Four patients received one ePIPAC, three patients received two ePIPAC, and thirteen patients received ≥ 3 ePIPAC. The population pharmacokinetic models adequately described the pharmacokinetics of oxaliplatin after ePIPAC. The plasma ultrafiltrate
C
max
of oxaliplatin reached 1.36–1.90 µg/mL after 30 min with an AUC
0–24 h
of 9.6–11.7 µg/mL * h. The plasma
C
max
reached 2.67–3.28 µg/mL after 90 min with an AUC
0–24 h
of 49.0–59.5 µg/mL * h. The absorption rate constant (Ka) was 1.13/h. Urine concentrations of oxaliplatin rapidly decreased to less than 3.60 µg/mL in 90% of the samples at day 7.
Discussion
Systemic exposure to oxaliplatin after ePIPAC seemed comparable to that after systemic chemotherapy, as described in other literature. Since this is an indirect comparison, future research should focus on the direct comparison between the systemic exposure to oxaliplatin after ePIPAC and after systemic chemotherapy.
Trial registration:
NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.
Background
CRC-PIPAC prospectively assessed repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) as a palliative monotherapy (i.e., without concomitant systemic ...therapy in between subsequent procedures) for unresectable colorectal peritoneal metastases (CPM). The present study explored patient-reported outcomes (PROs) during trial treatment.
Methods
In this single-arm phase 2 trial in two tertiary centers, patients with isolated unresectable CPM received 6-weekly PIPAC-OX (92 mg/m
2
). PROs (calculated from EQ-5D-5L, and EORTC QLQ-C30 and QLQ-CR29) were compared between baseline and 1 and 4 weeks after the first three procedures using linear mixed modeling with determination of clinical relevance (Cohen’s
D
≥ 0.50) of statistically significant differences.
Results
Twenty patients underwent 59 procedures (median 3 range 1–6). Several PROs solely worsened 1 week after the first procedure (index value − 0.10,
p
< 0.001; physical functioning − 20,
p
< 0.001; role functioning − 27,
p
< 0.001; social functioning − 18,
p
< 0.001; C30 summary score − 16,
p
< 0.001; appetite loss + 15,
p
= 0.007; diarrhea + 15,
p
= 0.002; urinary frequency + 13,
p
= 0.004; flatulence + 13,
p
= 0.001). These PROs returned to baseline at subsequent time points. Other PROs worsened 1 week after the first procedure (fatigue + 23,
p
< 0.001; pain + 29,
p
< 0.001; abdominal pain + 32,
p
< 0.001), second procedure (fatigue + 20,
p
< 0.001; pain + 21,
p
< 0.001; abdominal pain + 20,
p
= 0.002), and third procedure (pain + 22,
p
< 0.001; abdominal pain + 22,
p
= 0.002). Except for appetite loss, all changes were clinically relevant. All analyzed PROs returned to baseline 4 weeks after the third procedure.
Conclusions
Patients receiving repetitive PIPAC-OX monotherapy for unresectable CPM had clinically relevant but reversible worsening of several PROs, mainly 1 week after the first procedure.
Trial registration
Clinicaltrials.gov: NCT03246321; Netherlands trial register: NL6426.
Oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) is an emerging palliative treatment for patients with unresectable colorectal peritoneal metastases. Previously, our ...study group reported that patients experienced abdominal pain for several weeks after PIPAC-OX. However, it is unknown how this compares to abdominal pain after regular colorectal cancer surgery. To provide some perspective, this study compared the presence of abdominal pain after PIPAC-OX to the presence of abdominal pain after primary tumor surgery. Patient reported abdominal pain scores (EORTC QLQ-CR-29), from two prospective, Dutch cohorts were used in this study. Scores ranged from 0 to 100, a higher score represents more abdominal pain. Abdominal pain at baseline and at four weeks after treatment were compared between the two groups. Twenty patients who underwent PIPAC-OX and 322 patients who underwent primary tumor surgery were included in the analysis. At baseline, there were no differences in abdominal pain between both groups (mean 20 vs. 18, respectively; p = 0.688). Four weeks after treatment, abdominal pain was significantly worse in the PIPAC group (39 vs 15, respectively; p < 0.001; Cohen's d = 0.99). The differential effect over time for abdominal pain differed significantly between both groups (mean difference: 19 vs - 3, respectively; p = 0.004; Cohen's d = 0.88). PIPAC-OX resulted in significantly worse postoperative abdominal pain than primary tumor surgery. These results can be used for patient counseling and stress the need for adequate analgesia during and after PIPAC-OX. Further research is required to prevent or reduce abdominal pain after PIPAC-OX.Trial registration CRC-PIPAC: Clinicaltrails.gov NCT03246321 (01-10-2017).
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