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"Weiss, Matthew"
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Surgery for Oligometastatic Pancreatic Cancer: Defining Biologic Resectability
Pancreatic ductal adenocarcinoma (PDAC) is most often metastatic at diagnosis. As systemic therapy continues to improve alongside advanced surgical techniques, the focus has shifted toward defining biologic, rather than technical, resectability. Several centers have reported metastasectomy for oligometastatic PDAC, yet the indications and potential benefits remain unclear. In this review, we attempt to define oligometastatic disease in PDAC and to explore the rationale for metastasectomy. We evaluate the existing evidence for metastasectomy in liver, peritoneum, and lung individually, assessing the safety and oncologic outcomes for each. Furthermore, we explore contemporary biomarkers of biological resectability in oligometastatic PDAC, including radiographic findings, biochemical markers (such as CA 19-9 and CEA), inflammatory markers (including neutrophil-to-lymphocyte ratio, C-reactive protein, and scoring indices), and liquid biopsy techniques. With careful consideration of existing data, we explore the concept of biologic resectability in guiding patient selection for metastasectomy in PDAC.
Journal Article
Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers
The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient’s primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.
Journal Article
Deemed consent for deceased organ donation
The basic definition of deemed consent is that all competent members of a jurisdiction are assumed to have given their consent for deceased organ donation unless they have explicitly registered otherwise. Canada joined this international debate on Jan 18, 2021, when Nova Scotia implemented North America's first deemed consent model. Policy-makers across Canada are now asking if they should pursue similar policies, but lessons learned from experts around the world suggest that consent models should be changed only with clear objectives in mind and within a transparent system that has other foundational elements already in place. Here, Weiss and Dirk discuss what is known globally about the impact of deemed consent models, what other jurisdictions have learned about implementation and how the policy should be evaluated in Nova Scotia.
Journal Article
Analyzing online public commentary responding to the announcement of deemed consent organ donation legislation in the Canadian province of Nova Scotia
The Canadian province of Nova Scotia recently became the first jurisdiction in North America to pass deemed consent organ donation legislation. The announcement of this legislation generated substantial online discussion, which we analyzed to provide insights on public perception.
We performed directed content analysis on 2663 user-generated comments appearing on two widely-shared Canadian Broadcasting Company (CBC) articles published online in April 2019. We determined levels of support and opposition in comments and described the specific rhetoric used for doing so. We also performed one-way ANOVA and Pearson chi-square tests to determine how the comments were being received and engaged by other users.
A range of commentary was present in both support and opposition to the changes in legislation. There were more negative than positive comments, and negative commentary generated more replies. Positive comments were received more positively by other users while negative comments were received more negatively. The total sum of negative comments was greatly influenced by a small number of very active participants. Negative commentary focused more on broad concepts and principles related to government, power, and individual rights rather than specific issues in the Nova Scotian context. Substantial issues of trust in the government and healthcare system were evident.
There were strong positive and negative sentiments expressed in the comments, but the total sum of negativity in the comments was significantly influenced by a small number of commentators. Analysis on the presumed consent concerns can be helpful to inform public outreach efforts.
Journal Article
Impact Total Psoas Volume on Short- and Long-Term Outcomes in Patients Undergoing Curative Resection for Pancreatic Adenocarcinoma: a New Tool to Assess Sarcopenia
Background
While sarcopenia is typically defined using total psoas area (TPA), characterizing sarcopenia using only a single axial cross-sectional image may be inadequate. We sought to evaluate total psoas volume (TPV) as a new tool to define sarcopenia and compare patient outcomes relative to TPA and TPV.
Method
Sarcopenia was assessed in 763 patients who underwent pancreatectomy for pancreatic adenocarcinoma between 1996 and 2014. It was defined as the TPA and TPV in the lowest sex-specific quartile. The impact of sarcopenia defined by TPA and TPV on overall morbidity and mortality was assessed using multivariable analysis.
Result
Median TPA and TPV were both lower in women versus men (both
P
< 0.001). TPA identified 192 (25.1 %) patients as sarcopenic, while TPV identified 152 patients (19.9 %). Three hundred sixty-nine (48.4 %) patients experienced a postoperative complication. While TPA-sarcopenia was not associated with higher risk of postoperative complications (OR 1.06;
P
= 0.72), sarcopenia defined by TPV was associated with morbidity (OR 1.79;
P
= 0.002). On multivariable analysis, TPV-sarcopenia remained independently associated with an increased risk of postoperative complications (OR 1.69;
P
= 0.006), as well as long-term survival (HR 1.46;
P
= 0.006).
Conclusion
The use of TPV to define sarcopenia was associated with both short- and long-term outcomes following resection of pancreatic cancer. Assessment of the entire volume of the psoas muscle (TPV) may be a better means to define sarcopenia rather than a single axial image.
Journal Article
The Impact of Postoperative Complications on the Administration of Adjuvant Therapy Following Pancreaticoduodenectomy for Adenocarcinoma
Background
The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy (PD) for adenocarcinoma is still unclear.
Methods
A retrospective review of all patients undergoing PD at our institution between 1995 and 2011 was performed. Clinicopathological data, including Clavien–Dindo complication grade, time to adjuvant therapy (TTA), and survival, were analyzed.
Results
A total of 1,144 patients underwent PD for adenocarcinoma between 1995 and 2011. The overall complication rate was 49.1 % and clinically severe complications (≥IIIb) occurred in 4.2 %. Overall, 621 patients (54.3 %) were known to have received adjuvant therapy. The median TTA was 60 days. Although the presence of a complication was associated with a delay in TTA (
p
=
0.002), the grade of complication was not (
p
=
0.112). On multivariate analysis, only age > 68 years (
p
<
0.001) and length of stay >9 days (
p
=
0.002) correlated with no adjuvant therapy. Patients with postoperative complications were more likely to receive single adjuvant chemotherapy or radiation therapy (31.4 %) than were patients without complications (17.1 %;
p
<
0.001). Patients without a complication had a longer median survival compared with patients who experienced complications (19.5 vs. 16.1 months;
p
=
0.001). Patients without complications who received adjuvant therapy had longer median survival than patients with complications who received no adjuvant therapy (22.5 vs. 10.7 months;
p
<
0.001). Multivariate analysis demonstrated that complications [hazard ratio (HR) 1.16;
p
=
0.023] and adjuvant therapy (HR 0.67;
p
<
0.001) were related to survival.
Conclusion
Complications and no adjuvant therapy are common following PD for adenocarcinoma. Postoperative complications delay TTA and reduce the likelihood of multimodality adjuvant therapy. Identifying patients at increased risk for complications and those unlikely to receive adjuvant therapy warrants further investigation as they may benefit from a neoadjuvant approach.
Journal Article
Organ donation after medical assistance in dying: a descriptive study from 2018 to 2022 in Quebec
ABSTRACTBackgroundSince the implementation of medical assistance in dying (MAiD), deceased organ donation after MAiD has been possible in Quebec. We sought to describe organ donations after MAiD in the first 5 years after this practice was implemented in Quebec. MethodsWe reviewed all cases referred for donation after MAiD from January 2018 to December 2022. We presented all data descriptively with no comparison statistics. ResultsTransplant Québec received 245 referrals for donation after MAiD, of which 82 were retained (33.5%). Of the 163 nonretained referrals, 152 (93.2%) had a recorded reason, including 91 (55.8%) for medical unsuitability on initial screen (e.g., organ dysfunction, medical history), 34 (20.8%) for patient refusal and 21 (12.9%) instances where patients withdrew from the MAiD process entirely. Six patients died before MAiD. Eighteen of the 82 retained cases were cancelled later in the process, almost all ( n = 17, 94.4%) because of medical contraindication discovered during detailed donor evaluation. Sixty-four patients became actual donors after MAiD, increasing from 8 in 2018 to 24 in 2022. The total conversion rate from referral to an actual donor was 26.1% (64/245). A total of 182 organs (116 kidneys, 20 livers and 46 lungs) were transplanted after MAiD. During the study period, MAiD donors represented 8.0% (64/803) of total deceased donors, increasing from 4.9% (8/164) in 2018 to 14.0% (24/171) in 2022. InterpretationThese data describe a substantial increase in deceased donation after MAiD in the first 5 years of implementation in Quebec. Future studies should focus on how to optimize systems to ensure these requests are treated in the most ethical and medically effective way.
Journal Article
Carcinomas assemble a filamentous CXCL12–keratin-19 coating that suppresses T cell–mediated immune attack
Cancer immunotherapy frequently fails because most carcinomas have few T cells, suggesting that cancers can suppress T cell infiltration. Here, we show that cancer cells of human pancreatic ductal adenocarcinoma (PDA), colorectal cancer, and breast cancer are coated with transglutaminase-2 (TGM2)–dependent covalent CXCL12–keratin-19 (KRT19) heterodimers that are organized as filamentous networks. Since a dimeric form of CXCL12 suppresses the motility of human T cells, we determined whether this polymeric CXCL12–KRT19 coating mediated T cell exclusion. Mouse tumors containing control PDA cells exhibited the CXCL12–KRT19 coating, excluded T cells, and did not respond to treatment with anti–PD-1 antibody. Tumors containing PDA cells not expressing either KRT19 or TGM2 lacked the CXCL12–KRT19 coating, were infiltrated with activated CD8⁺ T cells, and growth was suppressed with anti–PD-1 antibody treatment. Thus, carcinomas assemble a CXCL12–KRT19 coating to evade cancer immune attack.
Journal Article