October 2024

Synopsis: This is a retrospective cohort study examining time to operation and its effect on morbidity and mortality. Using the NSQIP database including adults who underwent one of six nonelective intra-abdominal operations over a five-year period, the authors found that late operations (defined as >48 hours) were correlated with postoperative morbidity and mortality.

Summary: The understanding of which patients require emergency surgery has evolved significantly over the years. However, there is conflicting evidence regarding the optimal timing of surgery and whether it affects morbidity and mortality. This retrospective cohort study included 269,959 patients aged 18-89 undergoing any of six selected emergency general surgery (EGS) operations, including appendectomy, cholecystectomy, small bowel resection, lysis of adhesions, or colectomy (partial or total), from 2015 to 2020 using the NSQIP database. Patients who underwent nonemergent surgeries, surgery beyond hospital day 11, or were missing key variables were excluded. Patients were classified as undergoing early (<48 hours) or late (>48 hours) operations. The primary outcome was 30-day postoperative mortality; secondary outcomes included serious morbidity and all (any) morbidity. The goal was to characterize time-to-operation patterns among emergent general surgery operations and determine the relationship between delayed operation and morbidity and mortality using a multivariable logistic regression model to generate adjusted risk estimates for variables like age, sex, frailty, smoking status, preoperative sepsis, and other comorbidities.

Over half of the patients underwent surgery within the first 24 hours (64.8%), with 23.9% occurring between 24 and 48 hours. A majority of appendectomies (76.3%) and small bowel resections (55.6%) occurred within the first hospital day. Only 11.31% of patients underwent late operations, with the highest proportions of late operations being cholecystectomies and colectomies. Patients who underwent late operations were more likely to be older, frail, and smokers. Postoperative 30-day mortality was overall uncommon but was significantly increased in patients who underwent late operations in both unadjusted (5.52% vs. 1.61% mortality) and risk-adjusted analyses (OR 1.55; 95% CI 1.45-1.64). This difference persisted when looking at secondary outcomes, where those undergoing late operations had an increased risk of serious morbidity (OR 1.47; 95% CI 1.42-1.52) and any morbidity (OR 1.46; 95% CI 1.42-1.51). Regarding each procedure subgroup, late operations were associated with a higher risk of both serious morbidity and any morbidity, except in the cholecystectomy group.

While this study has the benefit of including a diverse range of procedures and patient populations, there are several limitations. Notably, time-to-operation data is collected in 24-hour intervals, limiting granularity and failing to reflect the reality that many of these decisions about operative timing are made on the scale of hours rather than days. Due to the limitations of the dataset itself, the study cannot account for the reasons for delay, such as delays related to obtaining further diagnostic information, failure of nonoperative management, or resource availability. Lastly, while the authors attempted to account for confounding factors that could impact patient outcomes, several patient- and hospital-related factors were not incorporated in the risk-adjusted model and analysis.

Bottom Line: In this study of patients undergoing common emergent general surgical procedures, operations occurring more than 48 hours after admission were an independent risk factor for postoperative morbidity and mortality.

Synopsis: This recent article, published by Penn Surgery graduate Ian Folkert and colleagues, investigated the role of a novel iron-rich tumor-associated macrophage (iTAM) population within the tumor microenvironment (TME) of various cancers. The authors concluded that iTAMs are a distinct macrophage subset regulated by heme exposure and the Bach1 transcription factor, characterized by Ednrb-mediated immunosuppressive and angiogenic functions.

Summary: Tumor-associated macrophages (TAMs) are one of the most frequent leukocyte populations found within the tumor microenvironment (TME). They exhibit a wide range of roles and can switch between functions, depending on the environment they inhabit, including pro- or anti-inflammatory states. Tumors often exploit the plasticity of TAMs to their advantage, driving resistance to immunotherapy. Therefore, understanding and targeting the pathways that regulate macrophage states hold the potential to impact tumor biology and enhance cancer immunotherapy.

In this study, the investigators explored the myeloid compartment of various mouse sarcoma models, using single-cell RNA sequencing (scRNA-seq) to identify subsets of TAMs. They found two closely related clusters enriched in genes involved in heme and iron metabolism. By leveraging their heme-containing properties, they isolated these cells from tumors using magnetic columns and F4/80 beads (F4/80 enriches for TAMs). After confirming that they had successfully isolated the cells identified in scRNA-seq, they further characterized these TAMs and identified high expression of endothelin receptor type B (Ednrb) as a key marker of what they termed iron-rich TAMs (iTAMs) in both mouse models and human tumors. Finally, using transcriptional and spatial transcriptomic studies, they showed that iTAMs are derived from monocytes and become two separate subsets associated either with endothelial cells (perivascular iTAMs) or within the stroma (stromal iTAMs).

After identifying and characterizing iTAMs, the authors next asked what their role was within the TME. Using an Ednrb mouse knockout model, they demonstrated that selectively knocking out Ednrb in TAMs led to decreased tumor growth, increased MHC-II expression, and decreased vascular density, suggesting that Ednrb+ iTAMs likely have a tumor-promoting role. The authors also showed that pharmacologic inhibition of the Ednrb signaling pathway, using macitentan, in combination with anti-PD-1 therapy, decreased tumor size and prolonged survival in their mouse sarcoma model. They further demonstrated that Ednrb expression is increased in immunosuppressive tumor microenvironments and non-responders to immune checkpoint blockade in various human cancers. This allowed the authors to conclude that Ednrb+ iTAMs play an immunosuppressive pro-tumor role within the TME.

In their final experiments, the authors aimed to identify signals that would drive TAMs toward the iTAM phenotype within the TME. Using transcriptional data, they identified Bach1 as the master transcriptional regulator of iTAMs. Importantly, Bach1 is degraded in the presence of heme, allowing for upregulation of heme and iron metabolism genes seen in iTAMs. To confirm the role of heme in iTAMs, they created a hemorrhagic tumor mouse model by injecting anti-coagulated blood into tumors in mice. They observed an increase in iTAMs within these mice, suggesting that heme exposure in the TME leads to Bach1 degradation within TAMs, pushing them toward an iTAM phenotype.

While this study provides an exploratory analysis, there are limitations. The findings are primarily based on murine models, which may not fully capture the complexity of human tumors. Additionally, while the therapeutic potential of targeting iTAMs through Ednrb and Bach1 is suggested, more research is required to explore their long-term effects and safety in clinical settings.

Bottom Line: The authors identify a novel tumor-associated macrophage population activated by intra-tumor hemorrhage, which plays an overall immunosuppressive, tumor-promoting role within the microenvironment of various mouse and human cancers.

Synopsis: This prospective multicenter study examined the prognostic value of circulating tumor DNA (ctDNA) as a biomarker for molecular residual disease (MRD) in colorectal cancer (CRC) patients after surgery. The study found that detectable ctDNA was associated with a significantly higher risk of recurrence, while undetectable ctDNA indicated a high likelihood of being disease-free across different CRC stages.

Summary: This prospective multicenter study aimed to evaluate the prognostic value of circulating tumor DNA (ctDNA) as a biomarker for molecular residual disease (MRD) in colorectal cancer (CRC) patients following surgery. The study enrolled 330 patients diagnosed with clinical stage I–IV CRC from three hospitals in China, and 309 patients with successful curative-intent surgery were analyzed. Patients' tumor tissue was collected during surgery, and plasma samples were taken at several postoperative intervals to detect ctDNA levels. The primary goal was to determine whether ctDNA detection could predict the likelihood of cancer recurrence and to assess its positive predictive value (PPV) and negative predictive value (NPV) in various stages of CRC.

With a median follow-up time of 19.5 months, the results showed that 14.3% of patients had detectable ctDNA in their postoperative plasma samples. Among ctDNA-positive patients, the recurrence rate was significantly higher (72.1%) compared to those with undetectable ctDNA (6.6%). The study demonstrated that ctDNA is a strong predictor of disease recurrence across all stages, with a particularly high negative predictive value (NPV) of 91.5%, indicating that patients with undetectable ctDNA were highly likely to remain disease-free. There was no correlation between ctDNA and clinicopathologic factors, including microsatellite instability and stage. These results indicate that ctDNA monitoring can help distinguish patients who would benefit most from adjuvant therapy from those who could safely avoid it, minimizing side effects and enhancing recovery.

This study aligns with findings from the GALAXY trial, which also investigated the utility of ctDNA in CRC. In the GALAXY trial, ctDNA was used to track minimal residual disease in patients with stage II–III CRC, aiming to refine the timing and necessity of chemotherapy. It reinforced that ctDNA-positive patients after surgery had a higher risk of recurrence, validating ctDNA as a biomarker for recurrence risk. Similarly, the AGITG DYNAMIC study in rectal cancer explored ctDNA to personalize postoperative treatment decisions. This study focused on stage II and III rectal cancer patients and found that ctDNA testing could effectively determine whether adjuvant therapy was necessary. DYNAMIC’s results showed that ctDNA-guided therapy allowed patients who were ctDNA-negative post-surgery to avoid additional treatment without increasing their risk of recurrence. While the results of this study were only recently presented at ASCO, the study terminated early as more rectal cancer patients have shifted towards a total neoadjuvant approach.

These studies collectively underscore the value of ctDNA as a tool in improving clinical outcomes by customizing treatment strategies for CRC patients. By integrating ctDNA analysis into clinical practice, we can better determine which patients need adjuvant chemotherapy, sparing those with low recurrence risk from its associated toxicity while improving monitoring and intervention for those at higher risk.

There were some limitations to this study. The follow-up period was relatively short, with a median duration of 19.5 months, limiting the ability to observe long-term outcomes and recurrences. Additionally, only 52 cases of recurrence were recorded, which may reduce the statistical power of the study's conclusions. Finally, the small sample size of patients undergoing post-adjuvant chemotherapy (ACT) ctDNA analysis restricted the ability to evaluate whether ctDNA-positive patients would benefit from different adjuvant treatment strategies.

Bottom line: This study confirms the utility of ctDNA-based MRD detection as a prognostic tool in CRC patients post-resection. It underscores the potential of undetectable MRD to define a potentially cured population, though challenges remain in detecting MRD in specific metastatic cases.

Synopsis: This multicenter, prospective, non-inferiority phase 3 randomized clinical trial conducted in Italy, Switzerland, Spain, and Chile showed that omission of axillary surgery was non-inferior to sentinel lymph node biopsy (SLNB) in women of any age with breast cancer up to 2 cm and a negative result on pre-operative axillary ultrasound, with equivalent distant disease-free survival, locoregional relapses, distant metastases, and overall survival.

Summary: This multicenter randomized phase 3 clinical trial aimed to assess the oncologic safety of omitting axillary surgery in women with small breast cancers and a negative pre-operative axillary ultrasound result. A total of 1,463 women of any age with breast cancer up to 2 cm and a negative pre-operative axillary ultrasound who were planned to undergo breast-conserving surgery and radiotherapy were randomized in a 1:1 ratio between February 2012 and June 2017 to receive SLNB or no axillary surgery. The primary endpoint was distant disease-free survival (DDFS) over 5 years, with secondary endpoints including overall survival, disease-free survival, cumulative incidence of axillary and distant recurrences, as well as adjuvant treatment recommendations. Patients with pre-operative presence of multiple suspicious lymph nodes, multifocality, bilateral or prior cancer, synchronous distant metastases, or ongoing pregnancy or lactation were excluded.

A total of 1,405 women were included in the intention-to-treat analysis, with 708 randomized to the SLNB group and 697 randomized to the no axillary surgery group. The median (IQR) age was 60 (52-68) years, the median (IQR) tumor size was 1.1 (0.8-1.5) cm, and 1,234 patients (87.8%) had ER-positive, ERBB2 (formerly HER2 or HER2/neu) negative breast cancer. Baseline characteristics were similar in both groups. After a median follow-up of 5.7 years, the 5-year DDFS was 97.7% for the SLNB group and 98.0% in the no axillary surgery group (log-rank P = .67; HR 0.84; 90% CI, 0.45-1.54; noninferiority P = .02), confirming non-inferiority. The cumulative incidence of axillary recurrences was very low in both groups (0.4% for each), and overall survival rates were comparable (98.4% vs. 98.2%, respectively). Both groups (SLNB and no axillary surgery group) had similar rates of locoregional recurrences (1.7% vs. 1.6%), distant metastases (1.8% vs. 2.0%), and deaths (3.0% vs. 2.6%). Adjuvant treatments were also comparable between the groups, indicating that the decision to treat was not significantly influenced by the presence of pathological nodal information.

Key limitations included selection bias due to enrollment criteria favoring low-risk patients. Additionally, the trial was underpowered to detect minor differences in treatment recommendations. Finally, the follow-up period was a median of 5.7 years, which may not be long enough to capture late recurrences, especially for estrogen receptor (ER)-positive, HER2-negative breast cancer patients, who tend to experience recurrences later. However, the study plans to continue follow-up with a formal analysis after 10 years.

Bottom Line: This study demonstrated that omitting axillary surgery in women with small breast cancer and negative axillary lymph node ultrasound was non-inferior to sentinel lymph node biopsy (SLNB) for distant disease-free survival (DDFS) at 5 years. These results suggest that axillary surgery may be safely omitted in this population without affecting treatment outcomes.