Transforming Growth Factor-ß Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy.

BACKGROUND & AIMS: Transforming growth factor-b (TGFb) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating CD8 T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFb inhibition has shown limited efficacy against pancreatic cancer in mice or humans. METHODS: We evaluated the TGFß-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment. RESULTS: Blockade of TGFß with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFß blockade was preserved in CD8-depleted or recombination activating gene 2 (RAG2-/-) mice. TGFß blockade decreased total α-smooth muscle actin-positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex vivo revealed that tumor cells treated with TGFß blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFß blockade increased chemotherapy-induced cell death in vivo. CONCLUSIONS: TGFß regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFß blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.

Robotic Function-Preserving Resection of Gastric Gastrointestinal Stromal Tumor.

INTRODUCTION: Gastric gastrointestinal stromal tumors (GISTs) located at the gastroesophageal junction (GEJ), lesser curvature, posterior gastric wall, or antrum present challenges for gastric function preservation. The aim of this study was to evaluate safety and effectiveness of robot-assisted resection of gastric GIST in challenging anatomic locations. METHODS: This was a single-center case series of robotic gastric GIST resections in challenging anatomic locations performed from 2019 to 2021. GEJ GISTs are defined as tumors within 5 cm of the GEJ. Location of the tumor and distance from the GEJ were determined from the endoscopy report and/or cross-sectional imaging and operative findings. RESULTS: There were 25 consecutive patients who underwent a robot-assisted partial gastrectomy for a gastric GIST in challenging anatomic locations. Tumors were located at the GEJ (n = 12), lesser curvature (n = 7), posterior gastric wall (n = 4), fundus (n = 3), greater curvature (n = 3), and antrum (n = 2). Median distance of tumor from GEJ was 2.5 cm. Both GEJ and pylorus were successfully preserved in all patients regardless of tumor location. Median operative time was 190 min with a median estimated blood loss of 20 mL and no conversion to open approach. Median hospital stay was 3 d with solid diet intake starting 2 d after surgery. Two (8 %) patients had Grade III or higher postoperative complications. Median tumor size upon resection was 3.9 cm. Negative margins were obtained in 96.3%. There was no evidence of recurrent disease with a median follow-up of 11.3 mo. CONCLUSIONS: We demonstrate the safety and feasibility of using the robotic approach to facilitate function preservation gastrectomy in challenging anatomic locations without compromising oncologic resection.

Blockade of IL-1ß and PD-1 with combination chemotherapy reduces systemic myeloid suppression in metastatic pancreatic cancer with heterogeneous effects in the tumor.

Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Here we report clinical and translational results from a phase Ib trial testing whether IL-1ß blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD-1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n=10) were treated with canakinumab, a high-affinity monoclonal human anti-interleukin-1ß (IL-1ß), the PD-1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSCs) by flow cytometry for patients in the trial, but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD-1 and IL-1ß blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.

Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders.

BACKGROUND: Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed. METHODS: This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18). RESULTS: In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder's TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response. CONCLUSIONS: Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.

Robotic-Assisted Transabdominal Inferior Retroperitoneal Approach: an Alternative to Cattell-Braash Maneuver.

INTRODUCTION: The Cattell-Braasch maneuver has been widely used to provide adequate exposure for aorto-caval space (ACS) since the 1960s. Given its requirement of complex visceral mobilization and significant physiological disturbance, we proposed a new alternative surgical technique to access ACS: the transabdominal inferior retroperitoneal approach (TIRA) with robotic assistance. METHODS: Patients were placed in the Trendelenburg position, and the retroperitoneum was accessed from the iliac artery level and dissected toward the 3rd and 4th portion of the duodenum along the anterior surface of IVC and aorta. RESULTS: TIRA has been used in 5 consecutive patients at our institution whose tumors were located in the ACS below the level of SMA origin. The tumor sizes ranged from 1.7 to 5.6 cm. The median OR time was 192 min with a median EBL of 5 ml. Four out of the five patients passed flatus before or on post operative day (POD) 1, and the other patient passed flatus at POD2. The shortest length of stay was < 24 h, and the longest was 8 days due to pre-existing pain (the median length of stay was 4). CONCLUSION: The proposed robotic-assisted TIRA procedure is designed for tumors in the inferior portion of ACS, specifically for the tumor involving D3, D4, para-aortic, para-caval, and kidney regions. Since this approach does not involve organ mobilization and all the dissections are following an avascular plane, it can be easily adapted to laparoscopic and/or open surgery setting.

Immune mechanisms of toxicity from checkpoint inhibitors.

Immunotherapy has changed the treatment landscape for cancer over the past decade. Inhibitors of the immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset of patients with metastatic disease. However, these treatments can be limited by inflammatory toxicities that can affect any organ system in the body and in some cases can be life threatening. Considerable progress has been made in understanding the drivers of these toxicities as well as effective management strategies. Further research into understanding the molecular and cellular mechanisms that drive toxicity will enable better prediction of toxicity and development of optimized therapies for these toxicities that avoid interfering with antitumor immunity. In this review, we discuss our current understanding of the inflammatory toxicities from immune checkpoint inhibitors (ICIs) and propose optimal treatment strategies for these toxicities.

Trends in the size of treated unruptured intracranial aneurysms over 35 years.

OBJECTIVE: In the absence of clear guidelines and consistent natural history data, the decision to treat unruptured intracranial aneurysms (UIAs) is a matter of some controversy. Currently, decisions are often guided by a consensus of cerebrovascular specialist teams and patient preferences. It is unclear how paradigm-shifting developments in the detection and treatment of UIAs have affected the size of the UIAs that are selected for treatment. Herein, the authors aimed to study potential changes in the average size of the UIAs that were treated over time. They hypothesized that the average size of UIAs that are treated is decreasing over time. METHODS: A systematic search of the literature was performed to identify all studies describing the size of UIAs that were treated using any modality. Scatter diagrams with trend lines were used to plot the size of the aneurysms treated over time and assess for the presence of a potentially significant trend via statistical correlation tests. Subgroup analyses based on type of treatment, country of study, and specialty of the authors were performed. RESULTS: A total of 240 studies including 35,150 UIAs treated between 1987 and 2021 met all eligibility criteria and were entered in the analysis. The mean age of patients was 55.5 years, and 70.7% of the patients were females. There was a significant decrease in the size of treated UIAs over time (Spearman's r = -0.186, p < 0.001), with a 0.71-mm decrease in the average size of treated UIAs every 5 years since 1987 and an annual mean dropping below 7 mm in 2012. This decreasing trend was present in surgically and endovascularly treated UIAs (p < 0.001 for both), in more developed and developing countries (p < 0.001 for both), within neurosurgical and non-neurosurgical specialties (p < 0.001 for both), most prominently in the US (Spearman's r = -0.482, p < 0.001), and less prominently in Europe (Spearman's r = -0.221, p < 0.001) and was not detected in East Asia. CONCLUSIONS: The present study indicates that based on the treated UIA size data published in the literature over the past 35 years, smaller UIAs are being treated over time. This trend is likely driven by safer treatments. However, future studies should elucidate the cost-effectiveness of treating smaller UIAs as well as the possible real-world contribution of this trend in preventing aneurysmal subarachnoid hemorrhage.

Gestational Pseudoangiomatous Stromal Hyperplasia Presenting as Gigantomastia: A Case Report of a Rare Breast Entity with Clinical Recommendations by a Multidisciplinary Team.

Introduction: Pseudoangiomatous stromal hyperplasia (PASH) presenting as gigantomastia is rare in pregnancy but can result in severe clinical consequences for both mother and fetus. Case Presentation. A 43-year-old female with a history of biopsy-proven bilateral PASH presented at 22 3/7 weeks gestation with massive bilateral breast enlargement that was symptomatic. After multidisciplinary care, she underwent bilateral mastectomies and delivered at term with no additional complications. Conclusion: Pregnant women who undergo mastectomies for PASH-induced gigantomastia during their second trimesters will likely recover quickly, and fetal risks are low. Given the rarity of this breast entity, management guidelines are sparse. Our case report is an effort to comprehensively review this condition and share the clinical recommendations made by our institution's multidisciplinary team.

Trends in the Age of Patients Treated for Unruptured Intracranial Aneurysms from 1990 to 2020.

BACKGROUND: The decision for treatment for unruptured intracranial aneurysms (UIAs) is often difficult. Innovation in endovascular devices have improved the benefit-to-risk profile especially for elderly patients; however, the treatment guidelines from the past decade often recommend conservative management. It is unknown how these changes have affected the overall age of the patients selected for treatment. Herein, we aimed to study potential changes in the average age of the patients that are being treated over time. METHODS: A systematic search of the literature was performed to identify all studies describing the age of the UIAs that were treated by any modality. Scatter diagrams with trend lines were used to plot the age of the patients treated over time and assess the presence of a potential significant trend via statistical correlation tests. RESULTS: A total of 280 studies including 83,437 UIAs treated between 1987 and 2021 met all eligibility criteria and were entered in the analysis. Mean age of the patients was 55.5 years, and 70.7% were female. There was a significant increasing trend in the age of the treated patients over time (Spearman r: 0.250; P < 0.001), with a 1-year increase in the average age of the treated patients every 5 years since 1987. CONCLUSIONS: The present study indicates that based on the treated UIA patient data published in the literature, older UIAs are being treated over time. This trend is likely driven by safer treatments while suggesting that re-evaluation of certain UIA treatment decision scores may be of great interest.

G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans.

BACKGROUND: Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens. METHODS: Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils. RESULTS: Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation. CONCLUSIONS: Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.