Genomics correlates of brain metastasis and progression in colorectal cancer.

Background: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event that undermines longevity and neurocognitive function. However, the molecular basis of BM in CRC is poorly understood. We analyzed next-generation sequencing (NGS) from patients with CRC to identify genomic features associated with BM and intracranial progression (IP).

Therapeutic targeting of mismatch repair-deficient cancers.

DNA mismatch repair (MMR) is one of many evolutionarily conserved processes that act as guardians of genomic integrity. MMR proteins recognize errors that occur during DNA replication and initiate countermeasures to rectify those mistakes. MMR deficiency (MMRd) therefore leads to a dramatic accumulation of mutations.

Consensus Guideline for the Management of Patients with Appendiceal Tumors, Part 2: Appendiceal Tumors with Peritoneal Involvement.

Background: Appendiceal tumors comprise a heterogeneous group of tumors that frequently disseminate to the peritoneum. Management of appendiceal tumors is lacking high quality data given their rarity and heterogeneity. In general, appendiceal tumor treatment is extrapolated in part from colorectal cancer or pooled studies, without definitive evidence of disease-specific benefit.

Consensus Guideline for the Management of Patients with Appendiceal Tumors, Part 1: Appendiceal Tumors Without Peritoneal Involvement.

Background: Appendiceal tumors comprise a heterogeneous group of tumors that may be localized or disseminate throughout the peritoneum. Limited high quality clinical data exist and many practices have been extrapolated from colorectal cancer without validation in appendiceal cohorts. There are many controversies regarding the treatment of appendiceal tumors, and practices vary widely between centers and care settings.

Consensus Guideline for the Management of Colorectal Cancer with Peritoneal Metastases.

Background: The peritoneum is a common site of metastases from colorectal cancer (CRC), yet controversy exists regarding optimal treatment strategies. These guidelines describe the results of a national consensus addressing the management of CRC with peritoneal metastases (CRC-PM).

Methods: An update of the 2018 Chicago Consensus Guidelines was conducted using a modified Delphi technique.

Consensus guideline for the management of patients with appendiceal tumors, part 2: Appendiceal tumors with peritoneal involvement.

Background: Appendiceal tumors comprise a heterogeneous group of tumors that frequently disseminate to the peritoneum. Management of appendiceal tumors is lacking high-quality data given their rarity and heterogeneity. In general, appendiceal tumor treatment is extrapolated in part from colorectal cancer or pooled studies, without definitive evidence of disease-specific benefit.

Consensus guideline for the management of colorectal cancer with peritoneal metastases.

The peritoneum is a common site of metastases from colorectal cancer (CRC), yet controversy exists regarding optimal treatment strategies. These guidelines describe the results of a national consensus addressing the management of CRC with peritoneal metastases (CRC-PM). An update of the 2018 Chicago consensus guidelines was conducted with a modified Delphi technique.

Consensus guideline for the management of patients with appendiceal tumors, part 1: Appendiceal tumors without peritoneal involvement.

Background: Appendiceal tumors comprise a heterogeneous group of tumors that may be localized or disseminated throughout the peritoneum. Limited high-quality clinical data exist, and many practices have been extrapolated from colorectal cancer without validation in appendiceal cohorts. There are many controversies regarding the treatment of appendiceal tumors, and practices vary widely between centers and care settings.

Induction of a mismatch repair deficient genotype by tailored chemical mutagenesis in experimental models of cancer.

Mismatch repair deficient (MMRd) tumors harbor thousands of somatic mutations enriched for insertion-deletion (indels) conferring high sensitivity to immunotherapy. We sought to reproduce this phenotype using mutagenic agents to engineer an MMRd genotype in immunoresistant cells. The combination of temozolomide (TMZ) and cisplatin led to a rapid accumulation of a high mutational load enriched for indels in murine cell lines resulting from the epigenetic loss of Msh2.

Nonoperative Management of Mismatch Repair-Deficient Tumors.

Background: Among patients with mismatch repair-deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown.

Methods: We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months.

The role of recurrent somatic mutations that alter conserved mA motifs in human cancer.

N-methyladenosine (mA) is the most abundant internal RNA modification in eukaryotes and plays a key role in cellular growth and development. Global changes in cellular methylated RNA and mA-mediated transcript regulation significantly impact oncogenesis. Here, we investigate how recurrent synonymous and non-synonymous somatic mutations abolishing individual canonical methylated mA motifs affect transcript levels and survival of patients with cancer.

Patient outcomes in advanced ovarian cancer treated with an anti-FOLR1 antibody-drug conjugate.

Background: Mirvetuximab soravtansine-gynx (MIRV) is a FOLR1-binding antibody-drug conjugate (ADC) with a microtubule inhibitor payload. We investigated MIRV's efficacy, toxicity profile, and determinants of resistance in a cohort of patients with recurrent/persistent high FOLR1-expressing high-grade serous ovarian cancer (HGSOC).

Methods: This retrospective study included 170 patients with recurrent/persistent FOLR1-high (≥75 % of tumor cells with ≥2+ membranous staining intensity) HGSOC who received standard-of-care MIRV monotherapy.

Enhancing immunotherapy with tumour-responsive nanomaterials.

The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies.

Paired primary-metastasis patient-derived organoids and mouse models identify phenotypic evolution and druggable dependencies of peritoneal metastasis from appendiceal cancer.

Peritoneal carcinomatosis is a common yet deadly manifestation of gastrointestinal cancers, with few effective treatments. To identify targetable determinants of peritoneal metastasis, we focused on appendiceal adenocarcinoma (AC), a gastrointestinal cancer that metastasizes almost exclusively to the peritoneum. Current treatments are extrapolated from colorectal cancer (CRC), yet AC has distinct genomic alterations, mucinous morphology and peritoneum restricted metastatic pattern.

Predictors of Recurrence in Nonmetastatic Appendiceal Epithelial Cancers: An Updated Single-Center Experience Over 25 Years.

Background: Appendiceal epithelial tumors are rare and encompass a broad set of adenocarcinoma histologies, including mucinous (mAC), colonic-type (cAC), and goblet cell (GCA) adenocarcinomas. It has previously been reported that nodal disease predicted recurrence in patients with nonmetastatic appendiceal adenocarcinomas, supporting diagnostic laparoscopy with right hemicolectomy for staging and assessment for risk of recurrence. In this update, we sought to identify predictors of nodal disease on initial diagnostic pathology in nonmetastatic adenocarcinomas.

Analysis of Shared Variants between Cancer Biospecimens.

Purpose: Mutational data from multiple solid and liquid biospecimens of a single patient are often integrated to track cancer evolution. However, there is no accepted framework to resolve if individual samples from the same individual share variants due to common identity versus coincidence.

Experimental Design: Utilizing 8,000 patient tumors from The Cancer Genome Atlas across 33 cancer types, we estimated the background rates of co-occurrence of mutations between discrete pairs of samples across cancers and by cancer type.

Molecular and Clinicopathologic Impact of GNAS Variants Across Solid Tumors.

Purpose: The molecular drivers underlying mucinous tumor pathogenicity are poorly understood. mutations predict metastatic burden and treatment resistance in mucinous appendiceal adenocarcinoma. We investigated the pan-cancer clinicopathologic relevance of variants.

Predicting response to immune checkpoint blockade therapy among mismatch repair-deficient patients using mutational signatures.

Despite the overall efficacy of immune checkpoint blockade (ICB) for mismatch repair deficiency (MMRD) across tumor types, a sizable fraction of patients with MMRD still do not respond to ICB. We performed mutational signature analysis of panel sequencing data (n = 95) from MMRD cases treated with ICB. We discover that T>C-rich single base substitution (SBS) signatures-SBS26 and SBS54 from the COSMIC Mutational Signatures catalog-identify MMRD patients with significantly shorter overall survival.

Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade.

Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). The ability of ICB to prevent dMMR malignant or pre-malignant neoplasia development in patients with Lynch syndrome (LS) is unknown. Of 172 cancer-affected patients with LS who had received ≥1 ICB cycles, 21 (12%) developed subsequent malignancies after ICB exposure, 91% (29/32) of which were dMMR, with median time to development of 21 months (interquartile range, 6-38).

Killing tumor-associated bacteria with a liposomal antibiotic generates neoantigens that induce anti-tumor immune responses.

Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%.

Metastatic well differentiated serotonin-producing pancreatic neuroendocrine tumor with carcinoid heart disease: a case report.

Background: Less than two percent of pancreatic neuroendocrine tumors (NETs) produce serotonin. Serotonin can cause carcinoid syndrome and less commonly carcinoid heart disease (CHD). CHD is associated with increased mortality and requires a more aggressive approach.

Facts and Hopes in Colorectal Cancer Immunotherapy.

Although a minority of colorectal cancers exhibit mismatch repair deficiency and associated sensitivity to immune checkpoint inhibitors (ICI), the vast majority of colorectal cancers arise in a tolerogenic microenvironment with mismatch repair proficiency, low tumor-intrinsic immunogenicity, and negligible immunotherapy responsiveness. Treatment strategies to augment tumor immunity with combination ICIs and chemotherapy have broadly failed in mismatch repair-proficient tumors. Similarly, although several small single-arm studies have shown that checkpoint blockade plus radiation or select tyrosine kinase inhibition may show improved outcomes compared with historical controls, this finding has not been clearly validated in randomized trials.