Multicentre phase II trial of cabozantinib in patients with hepatocellular carcinoma after immune checkpoint inhibitor treatment.

BACKGROUND & AIMS: Prospective data on treatment after immune checkpoint inhibitor (ICI) therapy in hepatocellular carcinoma (HCC) are lacking. We conducted a phase II multicentre study on cabozantinib after ICI treatment in HCC. METHODS: This is an investigator-initiated, single-arm, clinical trial involving academic centres in Hong Kong and Korea. Key eligibility criteria included diagnosis of HCC, refractoriness to prior ICI-based treatment, and Child-Pugh A liver function. A maximum of two prior lines of therapy were allowed. All patients were commenced on cabozantinib at 60 mg/day. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were recruited from Oct 2020 to May 2022; 27 and 20 patients had received one and two prior therapies, respectively. Median follow-up was 11.2 months. The median PFS was 4.1 months (95% CI 3.3-5.3). The median overall survival (OS) was 9.9 months (95% CI 7.3-14.4), and the 1-year OS rate was 45.3%. Partial response and stable disease occurred in 3 (6.4%) and 36 (76.6%) patients, respectively. When used as a second-line treatment (n = 27), cabozantinib was associated with a median PFS and OS of 4.3 (95% CI 3.3-6.7) and 14.3 (95% CI 8.9-NR) months, respectively. The corresponding median PFS and OS were 4.3 (95% CI 3.3-11.0) and 14.3 (95% CI 9.0-NR) months, respectively, for those receiving ICI-based regimens with proven benefits (n = 17). The most common grade 3-4 treatment-related adverse event was thrombocytopenia (6.4%). The median dose of cabozantinib was 40 mg/day. The number of prior therapies was an independent prognosticator (one vs. two; hazard ratio = 0.37; p = 0.03). CONCLUSIONS: Cabozantinib demonstrated efficacy in patients who had received prior ICI regimens; survival data for second-line cabozantinib following first-line ICI regimens provide a reference for future clinical trial design. The number of prior lines of treatment may be considered a stratification factor in randomised studies. IMPACT AND IMPLICATIONS: Prospective data on systemic treatment following prior immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) are lacking. This phase II clinical trial provides efficacy and safety data on cabozantinib in patients who had received prior ICI-based treatment. Exploratory analyses showed that the performance of cabozantinib differed significantly when used as a second- or third-line treatment. The above data could be used as a reference for clinical practice and the design of future clinical trials on subsequent treatment lines following ICIs. GOV IDENTIFIER: NCT04588051.

Organ-specific responses to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma: A multicentre, retrospective study.

BACKGROUND AND AIMS: Anti-programmed death 1 (PD-1) monotherapy triggers various responses by each organ. In advanced hepatocellular carcinoma (HCC), while extrahepatic lesions demonstrate objective response rates (ORR) of 20%-40%, only 10% of intrahepatic lesions respond. Although first-line atezolizumab/bevacizumab has shown survival benefits in advanced HCC, organ-specific responses remain unexplored. Therefore, we aimed to assess organ-specific responses in patients with advanced HCC receiving atezolizumab/bevacizumab. METHODS: This retrospective, multicenter, observational study included patients who received first-line atezolizumab/bevacizumab for advanced HCC. Patients with Child-Pugh class A, measurable tumour lesions and serial imaging available for response evaluation were eligible. RESULTS: Between May 2020 and June 2021, 131 patients (median age: 62) from three cancer referral institutions were included. Ninety-one had hepatitis B (69.5%), 108 were at Barcelona clinic liver cancer stage C (82.4%), and 78 had extrahepatic metastasis (59.5%). After a median follow-up of 10.1 months, median progression-free survival was 6.8 months (95% confidence interval [CI], 4.6-9.2), median overall survival remained unreached (95% CI, range unavailable) and the ORR was 29.0%. Among 270 individual tumour lesions, the liver was the most commonly involved organ (n = 158). Atezolizumab/bevacizumab induced ORR of 27.8%, 42.2%, 29.1% and 21.0% for liver, lymph nodes, lungs and other sites, respectively. The organ-specific response rate for intrahepatic tumours decreased with increasing size (35.6%: <5 cm, 15.0%: ≥ 5 cm). CONCLUSIONS: Unlike anti-PD-1 monotherapy, atezolizumab/bevacizumab demonstrated favourable responses in intrahepatic lesions, comparable to those in extrahepatic lesions, and may potentially overcome the immune-tolerant hepatic microenvironment in patients with advanced HCC.

From Inflammation to Oncogenesis: Tracing Serum DCLK1 and miRNA Signatures in Chronic Liver Diseases.

Chronic liver diseases, fibrosis, cirrhosis, and HCC are often a consequence of persistent inflammation. However, the transition mechanisms from a normal liver to fibrosis, then cirrhosis, and further to HCC are not well understood. This study focused on the role of the tumor stem cell protein doublecortin-like kinase 1 (DCLK1) in the modulation of molecular factors in fibrosis, cirrhosis, or HCC. Serum samples from patients with hepatic fibrosis, cirrhosis, and HCC were analyzed via ELISA or NextGen sequencing and were compared with control samples. Differentially expressed (DE) microRNAs (miRNA) identified from these patient sera were correlated with DCLK1 expression. We observed elevated serum DCLK1 levels in fibrosis, cirrhosis, and HCC patients; however, TGF-ß levels were only elevated in fibrosis and cirrhosis. While DE miRNAs were identified for all three disease states, miR-12136 was elevated in fibrosis but was significantly increased further in cirrhosis. Additionally, miR-1246 and miR-184 were upregulated when DCLK1 was high, while miR-206 was downregulated. This work distinguishes DCLK1 and miRNAs' potential role in different axes promoting inflammation to tumor progression and may serve to identify biomarkers for tracking the progression from pre-neoplastic states to HCC in chronic liver disease patients as well as provide targets for treatment.

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells.

While significant strides have been made in understanding cancer biology, the enhancement in patient survival is limited, underscoring the urgency for innovative strategies. Epigenetic modifications characterized by hereditary shifts in gene expression without changes to the DNA sequence play a critical role in producing alternative gene isoforms. When these processes go awry, they influence cancer onset, growth, spread, and cancer stemness. In this review, we delve into the epigenetic and isoform nuances of the protein kinase, doublecortin-like kinase 1 (DCLK1). Recognized as a hallmark of tumor stemness, DCLK1 plays a pivotal role in tumorigenesis, and DCLK1 isoforms, shaped by alternative promoter usage and splicing, can reveal potential therapeutic touchpoints. Our discussion centers on recent findings pertaining to the specific functions of DCLK1 isoforms and the prevailing understanding of its epigenetic regulation via its two distinct promoters. It is noteworthy that all DCLK1 isoforms retain their kinase domain, suggesting that their unique functionalities arise from non-kinase mechanisms. Consequently, our research has pivoted to drugs that specifically influence the epigenetic generation of these DCLK1 isoforms. We posit that a combined therapeutic approach, harnessing both the epigenetic regulators of specific DCLK1 isoforms and DCLK1-targeted drugs, may prove more effective than therapies that solely target DCLK1.

ParD Antitoxin Hotspot Alters a Disorder-to-Order Transition upon Binding to Its Cognate ParE Toxin, Lessening Its Interaction Affinity and Increasing Its Protease Degradation Kinetics.

Type-II toxin-antitoxin (TA) systems are comprised of two tightly interacting proteins, and operons encoding these systems have been identified throughout the genomes of bacteria. In contrast to secretion system effector-immunity pairs, TA systems must remain paired to protect the host cell from toxicity. Continual depletion of the antitoxin results in a shorter half-life than that of the toxin, though it is unclear if antitoxins can be effectively degraded when complexed with toxins. The current work probed the protein-protein interface of the PaParDE1 TA system, guided by an X-ray crystal structure, to determine contributions of antitoxin amino acids to interaction kinetics and affinity. These studies identified a "hotspot" position that alters the binding mode and resulting affinity (KD) from 152 pM for a 1:1 model for wild type to 25.5 and 626 nM for a 2:1 model with mutated antitoxin. This correlates with an altered induced secondary structure upon complexation with PaParE1 and increased kinetics of Lon protease digestion of the antitoxin despite the toxin presence. However, the decreased affinity at this hotspot was essentially reversed when the antitoxin dimerization region was deleted, yielding insights into complex interactions involved in the tight association. Removal of the antitoxin C-terminal seven amino acids, corresponding to the site of a disorder-to-order transition, completely prevents association. These studies combine to provide a model for the initiation of the TA interaction and highlight how manipulation of the sequence can impact the antitoxin disorder-to-order transition, weakening the affinity and resulting in increased antitoxin susceptibility to degradation.

A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma.

BACKGROUND: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC). METHODS: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC. RESULTS: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9-6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3-78.0 weeks) vs. 15.14 weeks (95% CI: 13.4-15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes. CONCLUSIONS: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. TRIAL REGISTRATION NUMBER: NCT01092091. Date of registration: March 23, 2010.

Emerging immune checkpoint inhibitors for the treatment of hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a major challenge in oncology. It ranks fourth in most common causes of cancer death worldwide. Despite advancements in cancer treatment, limited effective treatment options exist for advanced HCC. Immune checkpoint inhibitors have become an irreplaceable tool in the treatment of many metastatic cancers. Early phase trials have demonstrated superior efficacy and good safety profile of immune checkpoint inhibitors and its combination with other drugs in the treatment of advanced HCC. AREAS COVERED: The scientific rationale and the current state-of-the-art of treatment in HCC involving immune checkpoint inhibitors, either as monotherapy or in combination with other drugs are reviewed and discussed. EXPERT OPINION: Immune checkpoint inhibitors have shown clinically relevant benefits as monotherapy in advanced HCC. These agents have shown superior survival benefits, durable response and manageable safety profiles in advanced HCC. Recent triumph of combination strategy with immune checkpoint inhibitor and anti-VEGF agent will likely bring a paradigm shift in systemic treatment of advanced HCC. Further research are needed to identify predictive biomarkers for response and best treatment sequence prioritization. Financial cost remains a major impediment for the widespread use of these novel treatments.

Characterization and Evolution of Germ1, an Element that Undergoes Diminution in Lampreys (Cyclostomata: Petromyzontidae).

The sea lamprey (Petromyzon marinus) undergoes substantial genomic alterations during embryogenesis in which specific sequences are deleted from the genome of somatic cells yet retained in cells of the germ line. One element that undergoes diminution in P. marinus is Germ1, which consists of a somatically rare (SR) region and a fragment of 28S rDNA. Although the SR-region has been used as a marker for genomic alterations in lampreys, the evolutionary significance of its diminution is unknown. We examined the Germ1 element in five additional species of lamprey to better understand its evolutionary significance. Each representative species contained sequences similar enough to the Germ1 element of P. marinus to be detected via PCR and Southern hybridizations, although the SR-regions of Lampetra aepyptera and Lethenteron appendix are quite divergent from the homologous sequences of Petromyzon and three species of Ichthyomyzon. Lamprey Germ1 sequences have a number of features characteristic of the R2 retrotransposon, a mobile element that specifically targets 28S rDNA. Phylogenetic analyses of the SR-regions revealed patterns generally consistent with relationships among the species included in our study, although the 28S-fragments of each species/genus were most closely related to its own functional rDNA, suggesting that the two components of Germ1 were assembled independently in each lineage. Southern hybridizations showed evidence of genomic alterations involving Germ1 in each species. Our results suggest that Germ1 is a R2 retroelement that occurs in the genome of P. marinus and other petromyzontid lampreys, and that its diminution is incidental to the reduction in rDNA copies during embryogenesis.

A network approach to exploring the functional basis of gene-gene epistatic interactions in disease susceptibility.

Motivation: Individual genetic variants explain only a small fraction of heritability in some diseases. Some variants have weak marginal effects on disease risk, but their joint effects are significantly stronger when occurring together. Most studies on such epistatic interactions have focused on methods for identifying the interactions and interpreting individual cases, but few have explored their general functional basis. This was due to the lack of a comprehensive list of epistatic interactions and uncertainties in associating variants to genes. Results: We conducted a large-scale survey of published research articles to compile the first comprehensive list of epistatic interactions in human diseases with detailed annotations. We used various methods to associate these variants to genes to ensure robustness. We found that these genes are significantly more connected in protein interaction networks, are more co-expressed and participate more often in the same pathways. We demonstrate using the list to discover novel disease pathways. Contact: kevinyip@cse.cuhk.edu.hk. Supplementary information: Supplementary data are available at Bioinformatics online.

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

OBJECTIVES: First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure. MATERIALS AND METHODS: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS). RESULTS: A total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0-652) after progression on osimertinib. Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65). TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis. CONCLUSIONS: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.

Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment.

Emergence of multi-targeted kinase inhibitors (MTIs) and immune checkpoint inhibitors (ICI) have changed the landscape of management in hepatocellular carcinoma (HCC). Combination therapy involving ICI has superseded sorafenib as the first-line treatment option for advanced HCC due to their superior response rates and survival benefits based on recently published phase III trials. However, the role of first-line lenvatinib remains uncertain as no prospective trials have compared its efficacy with ICI in advanced HCC. Several retrospective studies have shown that first-line lenvatinib may not be inferior to ICI combination. Indeed, a growing body of evidence suggests that ICI treatment is associated with inferior treatment outcome in non-viral HCC patients, questioning the supremacy of ICI treatment in all patients and rendering first-line lenvatinib as a potential preferred treatment option. Furthermore, in high-burden intermediate-stage HCC, accumulating evidence supports first-line lenvatinib, or in combination with transarterial chemoembolization (TACE), as a preferred treatment option over TACE alone. In this Review, we describe the latest evidence surrounding the evolving role of first-line lenvatinib in HCC.

Why Psychiatrists Should Read (and Watch) the Lord of the Rings.

Stories have, throughout all of time, given human beings an opportunity to contrast our own experiences and thoughts with a character's. To imagine another's situation, empathize with it, and then learn of their struggles or achievements, is an excellent opportunity for us to grow. It is transformative. These meaningful messages should be examined, rather than simply dismissed. Medicine has learned much from examining animals, nature, and history. Is it outlandish to consider the possibility that examination of Middle Earth, Hobbits and Elves, could be equally useful? When we consider psychiatric illness or distress, we are examining many very complicated processes happening within an individual's mind. Similarly, when we read or watch a well-done novel or film, the impact can be very far from fictitious. We experience the story with the characters, often reciprocating their emotions and deliberating on their decisions. To chalk this experience up as "fake" would be a disservice. After all, the effects of the physical world and a person's imagination can have comparable reverberations throughout the psyche. Stories have considerable impact on our psychological health, and the insight that we extract from them can improve overall emotional wellbeing. The Lord of the Rings is a classic and brilliantly depicted narrative. Despite many characters being of different species, they teach very tangible human lessons. This article will explore some of these lessons, all the while considering their influence and importance in life, whether psychiatrically beneficial or destructive. Specifically, six lessons will be discussed.

Mapping of quantitative trait loci for canopy-wilting trait in soybean (Glycine max L. Merr).

Drought stress adversely affects [Glycine max (L.) Merr] soybean at most developmental stages, which collectively results in yield reduction. Little information is available on relative contribution and chromosomal locations of quantitative trait loci (QTL) conditioning drought tolerance in soybean. A Japanese germplasm accession, PI 416937, was found to possess drought resistance. Under moisture-deficit conditions, PI 416937 wilted more slowly in the field than elite cultivars and has been used as a parent in breeding programs to improve soybean productivity. A recombinant inbred line (RIL) population was derived from a cross between PI 416937 and Benning, and the population was phenotyped for canopy wilting under rain-fed field conditions in five distinct environments to identify the QTL associated with the canopy-wilting trait. In a combined analysis over environments, seven QTL that explained 75 % of the variation in canopy-wilting trait were identified on different chromosomes, implying the complexity of this trait. Five QTL inherited their positive alleles from PI 416937. Surprisingly, the other two QTL inherited their positive alleles from Benning. These putative QTL were co-localized with other QTL previously identified as related to plant abiotic stresses in soybean, suggesting that canopy-wilting QTL may be associated with additional morpho-physiological traits in soybean. A locus on chromosome 12 (Gm12) from PI 416937 was detected in the combined analysis as well as in each individual environment, and explained 27 % of the variation in canopy-wilting. QTL identified in PI 416937 could provide an efficient means to augment field-oriented development of drought-tolerant soybean cultivars.

Spermatogenesis-specific features of the meiotic program in Caenorhabditis elegans.

In most sexually reproducing organisms, the fundamental process of meiosis is implemented concurrently with two differentiation programs that occur at different rates and generate distinct cell types, sperm and oocytes. However, little is known about how the meiotic program is influenced by such contrasting developmental programs. Here we present a detailed timeline of late meiotic prophase during spermatogenesis in Caenorhabditis elegans using cytological and molecular landmarks to interrelate changes in chromosome dynamics with germ cell cellularization, spindle formation, and cell cycle transitions. This analysis expands our understanding C. elegans spermatogenesis, as it identifies multiple spermatogenesis-specific features of the meiotic program and provides a framework for comparative studies. Post-pachytene chromatin of spermatocytes is distinct from that of oocytes in both composition and morphology. Strikingly, C. elegans spermatogenesis includes a previously undescribed karyosome stage, a common but poorly understood feature of meiosis in many organisms. We find that karyosome formation, in which chromosomes form a constricted mass within an intact nuclear envelope, follows desynapsis, involves a global down-regulation of transcription, and may support the sequential activation of multiple kinases that prepare spermatocytes for meiotic divisions. In spermatocytes, the presence of centrioles alters both the relative timing of meiotic spindle assembly and its ultimate structure. These microtubule differences are accompanied by differences in kinetochores, which connect microtubules to chromosomes. The sperm-specific features of meiosis revealed here illuminate how the underlying molecular machinery required for meiosis is differentially regulated in each sex.