Abstract Background Family and other unpaid caregivers play an active role in the recovery of individuals with pancreatic and periampullary cancer after pancreatectomy. However, little is known about caregivers’ experiences and how to better support them. Methods Caregivers accompanying patients to 1-month postpancreatectomy visits at 3 hospitals completed an electronic survey between November 2018 and February 2020. We examine measures of absenteeism and work productivity loss among the subset of caregivers who reported working for pay and comparatively assess caregiver experiences by employment status. All analyses were performed as 2-sided tests. Results Of 265 caregivers approached for study participation, 240 (90.6%) enrolled. Caregivers were primarily female (70.8% female, 29.2% male) and spouses (58.3%) or adult children (25.8%) of patients, with a median age of 60 years. Of the 240 caregivers included in the study, 107 (44.6%) worked for pay. Nearly half (44.4%) of working caregivers reported being absent from work because of caregiving amounting to a 14% loss in work hours. While at work, 58.9% of working caregivers reported increased work difficulty as a result of caregiving. Taken together, an estimated 59.7% loss in work productivity was experienced because of caregiving in the month following pancreatectomy. After adjustment for sociodemographic factors, working (vs nonworking) caregivers reported increased financial (odds ratio [OR] = 2.32; P = .04) and emotional (OR = 1.93; P = .04) difficulties and daily activity restrictions (OR = 1.85; P = .048). Conclusions Working caregivers of patients with pancreatic and periampullary cancer experience negative impacts on work and productivity, and caregiving-related financial and emotional difficulties may be amplified. This study highlights the need for workplace policies to support unpaid cancer caregiving.
Patients with pancreatic and periampullary cancers may experience significant reduction in their quality of life and often rely on family and unpaid caregivers for assistance after surgery. However, as caregivers are not systematically identified, little is known about the nature, difficulty, and personal demands of assistance they provide. We aim to assess the frequency and difficulty of specific assistance caregivers provide and identify potential interventions that could alleviate the caregiving demands.
Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with improved survival for patients with colorectal peritoneal metastases (CR-PM). However, the role of neoadjuvant chemotherapy (NAC) prior to CRS-HIPEC is poorly understood. A retrospective review of adult patients with CR-PM who underwent CRS+/-HIPEC from 2000–2017 was performed. Among 298 patients who underwent CRS+/-HIPEC, 196 (65.8%) received NAC while 102 (34.2%) underwent surgery first (SF). Patients who received NAC had lower peritoneal cancer index score (12.1 + 7.9 vs. 14.3 + 8.5, p = 0.034). There was no significant difference in grade III/IV complications (22.4% vs. 16.7%, p = 0.650), readmission (32.3% vs. 23.5%, p = 0.114), or 30-day mortality (1.5% vs. 2.9%, p = 0.411) between groups. NAC patients experienced longer overall survival (OS) (median 32.7 vs. 22.0 months, p = 0.044) but similar recurrence-free survival (RFS) (median 13.8 vs. 13.0 months, p = 0.456). After controlling for confounding factors, NAC was not independently associated with improved OS (OR 0.80) or RFS (OR 1.04). Among patients who underwent CRS+/-HIPEC for CR-PM, the use of NAC was associated with improved OS that did not persist on multivariable analysis. However, NAC prior to CRS+/-HIPEC was a safe and feasible strategy for CR-PM, which may aid in the appropriate selection of patients for aggressive cytoreductive surgery.
Mucinous appendiceal carcinoma is a rare malignancy that commonly spreads to the peritoneum leading to peritoneal metastases. Complete cytoreduction with perioperative intraperitoneal chemotherapy (PIC) is the mainstay of treatment, administered as either hyperthermic intra peritoneal chemotherapy (HIPEC) or early post-operative intraperitoneal chemotherapy (EPIC). Our goal was to assess the perioperative and long term survival outcomes associated with these two PIC methods. Patients with mucinous appendiceal carcinoma were identified in the US HIPEC Collaborative database from 12 academic institutions. Patient demographics, clinical characteristics, and survival outcomes were compared among patients who underwent HIPEC vs. EPIC with inverse probability weighting (IPW) used for adjustment. Among 921 patients with mucinous appendiceal carcinoma, 9% underwent EPIC while 91% underwent HIPEC. There was no difference in Grade III–V complications between the two groups (18.5% for HIPEC vs. 15.0% for EPIC, p=.43) though patients who underwent HIPEC had higher rates of readmissions (21.2% vs. 8.8%, p Among patients with mucinous appendiceal carcinoma, both EPIC and HIPEC appear to be associated with similar perioperative and long-term outcomes.
Immunotherapy holds great potential to treat cancers such as sarcomas. A major impediment for immune mediated tumor killing in sarcomas is a strong presence of suppressive cell types such as Myeloid Derived Suppressor Cells (MDSC) dominating the Tumor Immune Micro-Environment (TIME) and a dearth of effector cell types such as T Cells.1 Cellular metabolism has emerged as a novel checkpoint to modulate immune responses by targeting various metabolic pathways. Glutamine is a key metabolite participating in the TCA cycle and is implicated in sarcoma-genesis2 and its blockade has shown to skew immune cell function and phenotype.3 We used JHU083, a novel prodrug of a glutamine antagonist (6-Diazo-5-oxo-L-norleucine) to rid the TME of glutamine and interrogate its downstream effects on the TIME.
Methods
Cells derived from primary tumors from LSL-KrasG12D/+ p53flox/flox mice (KP Cells)4 were subcutaneously injected in C57BL/6J mice. The mice were treated with JHU083 (1mg/kg on days 7–11 and 0.3mg/kg daily till end) and anti-PD1 monoclonal antibody (100ug on days 7, 9, 11 and 13) or saline and euthanized at Day 20. We studied the 3 major tumor infiltrating myeloid cells, namely, Monocytic MDSC, Granulocytic MDSC (GMDSC) and Macrophages by flow cytometry and FACS sorted them to profile their transcriptome using NanoString Mouse Myeloid Innate Immunity Panel.
Results
The combination treated group had significantly less tumor burden at the end of Day 20 than the control group. We saw a significant reduction in the percentage of GMDSC in the combination treated group. We observed a consistent reduction in expression of Csf3 and Csf3r and an upregulation of complement related genes specifically C1qa, C1qb and C1qc across the three subsets in the treated group. Transcriptionally, the most affected cell type was the GMDSC subset which saw an upregulation of Apoe and other genes such as Acly, Calr, Pf4, Grn, Trem2 upon glutamine blockade. These genes are known to be expressed in a subset of myeloid cells in multiple human cancers.5
Conclusions
Combination of glutamine blockade and anti-PD1 therapy can be an effective strategy to modulate myeloid cell frequency and phenotype in this model of soft tissue sarcomas. Transcriptional changes upon glutamine blockade, especially upregulation of Apoe, a key apolipoprotein implicated in cholesterol transport points towards rewiring of metabolism of the myeloid cells. This hints that the heterogenous metabolome/lipidome might hold clues to the differential responses to glutamine blockade in the myeloid subsets.
References
L Chen. The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures, Clinical Cancer Research, 26:4018–4030 Lee P, Malik D, Perkons N, et al. Targeting glutamine metabolism slows soft tissue sarcoma growth. Nat Commun 2020;11:498. Min-Hee Oh. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest. 2020;130(7):3865–3884 D Kirsch. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat Med. 2007 Aug;13(8):992–7 RY Ma. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends in Immunology. July 2022;43(7):546–563.
Ethics Approval
All animal procedures performed were approved by the Johns Hopkins University Animal Care Committee.
