Microbiome modulates immunotherapy response in cutaneous squamous cell carcinoma.

The gut microbiome is increasingly recognized to alter cancer risk, progression and response to treatments such as immunotherapy, especially in cutaneous melanoma. However, whether the microbiome influences immune checkpoint inhibitor (ICI) immunotherapy response to non-melanoma skin cancer has not yet been defined. As squamous cell carcinomas (SCC) are in closest proximity to the skin microbiome, we hypothesized that the skin microbiome, which regulates cutaneous immunity, might affect SCC-associated anti-PD1 immunotherapy treatment response. We used ultraviolet radiation to induce SCC in SKH1 hairless mice. We then treated the mice with broad-band antibiotics to deplete the microbiome, followed by colonisation by candidate skin and gut bacteria or persistent antibiotic treatment, all in parallel with ICI treatment. We longitudinally monitored skin and gut microbiome dynamics by 16S rRNA gene sequencing and tumour burden by periodic tumour measurements and histologic assessment. Our study revealed that antibiotics-induced abrogation of the microbiome reduced the tumour burden, suggesting a functional role of the microbiome in non-melanoma skin cancer therapy response.

Structure Matters: Asymmetric CO Oxidation at Rh Steps with Different Atomic Packing.

Curved crystals are a simple but powerful approach to bridge the gap between single crystal surfaces and nanoparticle catalysts, by allowing a rational assessment of the role of active step sites in gas-surface reactions. Using a curved Rh(111) crystal, here, we investigate the effect of A-type (square geometry) and B-type (triangular geometry) atomic packing of steps on the catalytic CO oxidation on Rh at millibar pressures. Imaging the crystal during reaction ignition with laser-induced CO2 fluorescence demonstrates a two-step process, where B-steps ignite at lower temperature than A-steps. Such fundamental dissimilarity is explained in ambient pressure X-ray photoemission (AP-XPS) experiments, which reveal partial CO desorption and oxygen buildup only at B-steps. AP-XPS also proves that A-B step asymmetries extend to the active stage: at A-steps, low-active O-Rh-O trilayers buildup immediately after ignition, while highly active chemisorbed O is the dominant species on B-type steps. We conclude that B-steps are more efficient than A-steps for the CO oxidation.

Gynecologic surgical skill acquisition through simulation with outcomes at the time of surgery: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of simulation training vs traditional hands-on surgical instruction on learner operative skills and patient outcomes in gynecologic surgeries. DATA SOURCES: PubMed, Embase, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials from inception to January 12, 2021. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, prospective comparative studies, and prospective single-group studies with pre- and posttraining assessments that reported surgical simulation-based training before gynecologic surgery were included. METHODS: Reviewers independently identified the studies, obtained data, and assessed the study quality. The results were analyzed according to the type of gynecologic surgery, simulation, comparator, and outcome data, including clinical and patient-related outcomes. The maximum likelihood random effects model meta-analyses of the odds ratios and standardized mean differences were calculated with estimated 95% confidence intervals. RESULTS: Twenty studies, including 13 randomized controlled trials, 1 randomized crossover trial, 5 nonrandomized comparative studies, and 1 prepost study were identified. Most of the included studies (14/21, 67%) were on laparoscopic simulators and had a moderate quality of evidence. Meta-analysis showed that compared with traditional surgical teaching, high- and low-fidelity simulators improved surgical technical skills in the operating room as measured by global rating scales, and high-fidelity simulators decreased the operative time. Moderate quality evidence was found favoring warm-up exercises before laparoscopic surgery. There was insufficient evidence to conduct a meta-analysis for other gynecologic procedures. CONCLUSION: Current evidence supports incorporating simulation-based training for a variety of gynecologic surgeries to increase technical skills in the operating room, but data on patient-related outcomes are lacking.

Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.

Pleuropulmonary blastoma-like peritoneal sarcoma: a newly described malignancy associated with biallelic DICER1 pathogenic variation.

Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye, and brain among other sites. This report documents our experience with another manifestation: a primitive sarcoma that resembles PPB and DICER1-associated sarcoma of the kidney. These tumors are distinguished by their unusual location in the peritoneal cavity, associated with visceral and/or parietal mesothelium. A total of seven cases were identified through pathology review in children presenting at a median age of 13 years (range 3-14 years). Primary sites of origin included the fallopian tube (four cases), serosal surface of the colon (one case), and pelvic sidewall (two cases). One case had pathologic features of type I PPB, another type Ir (regressed) PPB, and the remaining five had features of type II or III PPB with a mixed primitive sarcomatous pattern with or without cystic elements. All had a pathogenic DICER1 variation identified in germline and/or tumor DNA. PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements. Tumors arising from the fallopian tube or elsewhere in the abdomen/pelvis, especially those with heterogeneous rhabdomyosarcomatous and/or cartilaginous differentiation, should prompt consideration of germline and tumor DICER1 testing.

Catalytic Oxidation of CO on a Curved Pt(111) Surface: Simultaneous Ignition at All Facets through a Transient CO-O Complex*.

The catalytic oxidation of CO on transition metals, such as Pt, is commonly viewed as a sharp transition from the CO-inhibited surface to the active metal, covered with O. However, we find that minor amounts of O are present in the CO-poisoned layer that explain why, surprisingly, CO desorbs at stepped and flat Pt crystal planes at once, regardless of the reaction conditions. Using near-ambient pressure X-ray photoemission and a curved Pt(111) crystal we probe the chemical composition at surfaces with variable step density during the CO oxidation reaction. Analysis of C and O core levels across the curved crystal reveals that, right before light-off, subsurface O builds up within (111) terraces. This is key to trigger the simultaneous ignition of the catalytic reaction at different Pt surfaces: a CO-Pt-O complex is formed that equals the CO chemisorption energy at terraces and steps, leading to the abrupt desorption of poisoning CO from all crystal facets at the same temperature.

Bone marrow transplant and pediatric multiple myeloma.

Multiple myeloma is a malignant plasma cell disorder that is rare in the pediatric population, with only approximately 0.3% of cases diagnosed before the age of 30. In this report, we present two patients diagnosed with multiple myeloma between the ages of 12 and 16. Their respective treatment regimens are discussed, including the use of both autologous and allogeneic stem cell transplant.

Measuring Quality in Minimally Invasive Gynecologic Surgery: What, How, and Why?

In healthcare, the goal of maximizing value by improving the quality of care and lowering costs has been notoriously challenging to achieve. The fee-for-service model in gynecology and other fields has historically promoted the reduction of nonsurgical or minimally invasive approaches in favor of complex, often morbid procedures. In this review, we seek to define quality and value in the healthcare field and describe strategies that promote quality over production. We then discuss national, non-specialty-based efforts in the context of Surgical Care Improvement Project measures to improve quality of care. Finally, we present a case study through the Kaiser Permanente Minimally Invasive Hysterectomy Initiative, one such model that successfully built on the quality metrics of the foregoing strategies to improve patient care.

Every woman deserves a high-volume gynecologic surgeon.

Most women undergoing hysterectomy in the United States have their surgery performed by a low-volume gynecologic surgeon. Evidence supports that, when compared to patients operated on by high-volume surgeons, these women have worse outcomes including fewer minimally invasive procedures and increased rates of complications. The factors that promote low-volume surgeons and suggestions for how to change this are reviewed in this Viewpoint.

Posterior Reversible Encephalopathy Syndrome and Cerebral Sinus Thrombosis in a Case of Pediatric B-Cell ALL.

Posterior reversible encephalopathy syndrome (PRES) and cerebral sinus thrombosis are 2 known complications of acute lymphoblastic leukemia and its treatment. We describe a patient with acute lymphoblastic leukemia whose course was complicated by both of these conditions. This case is novel both for the fact that PRES developed before the initiation of therapy and that PRES was followed shortly by the development of cerebral sinus thrombosis. Our patient's story raises questions about our current understanding of the pathophysiology of PRES, and it suggests that PRES may actually be a predisposing risk factor for cerebral sinus thrombosis.

Hypothalamic Glioma in a Patient With Sturge-Weber Syndrome.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations involving brain, skin, and occasionally eyes. There is no recognized tumor predisposition in patients with SWS as there is with some other phakomatoses. We present a patient with SWS who developed a low-grade glioma (LGG). We hypothesize that there could be an association between SWS and LGG formation, noting that GNAQ mutations have been implicated in the underlying biology of both SWS and a subset of pediatric LGG. It is suggested that SWS may be a cancer predisposition syndrome.

Coexisting massive and massless Dirac fermions in symmetry-broken bilayer graphene.

Charge carriers in bilayer graphene are widely believed to be massive Dirac fermions that have a bandgap tunable by a transverse electric field. However, a full transport gap, despite its importance for device applications, has not been clearly observed in gated bilayer graphene, a long-standing puzzle. Moreover, the low-energy electronic structure of bilayer graphene is widely held to be unstable towards symmetry breaking either by structural distortions, such as twist, strain, or electronic interactions that can lead to various ground states. Which effect dominates the physics at low energies is hotly debated. Here we show both by direct band-structure measurements and by calculations that a native imperfection of bilayer graphene, a distribution of twists whose size is as small as ~0.1°, is sufficient to generate a completely new electronic spectrum consisting of massive and massless Dirac fermions. The massless spectrum is robust against strong electric fields, and has a unusual topology in momentum space consisting of closed arcs having an exotic chiral pseudospin texture, which can be tuned by varying the charge density. The discovery of this unusual Dirac spectrum not only complements the framework of massive Dirac fermions, widely relevant to charge transport in bilayer graphene, but also supports the possibility of valley Hall transport.

Topical amphotericin B in combination with standard therapy for severe necrotizing skin and soft-tissue mucormycosis in an infant with bilineal leukemia: case report and review.

During chemotherapy for bilineal leukemia, a 6-month-old infant presented with a necrotizing skin and soft-tissue infection of the chest wall due to Rhizopus sp. Successful outcome was achieved by systemically administered liposomal amphotericin B and local wound control with the novel administration of topical deoxycholate amphotericin B and surgical resection.

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis.

BACKGROUND: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). INTERPRETATION: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

Hysterectomy Techniques and Outcomes for Benign Large Uteri: A Systematic Review.

OBJECTIVE: To identify the optimal hysterectomy approach for large uteri in gynecologic surgery for benign indications from a perioperative morbidity standpoint. DATA SOURCES: PubMed and Embase databases were searched from inception through September 19, 2022. Meta-analyses were conducted as feasible. METHODS OF STUDY SELECTION: This review included studies that compared routes of hysterectomy with or without bilateral salpingo-oophorectomy for large uteri (12 weeks or more or 250 g or more) and excluded studies with any concurrent surgery for pelvic organ prolapse, incontinence, gynecologic malignancy, or any obstetric indication for hysterectomy. TABULATION, INTEGRATION, AND RESULTS: The review included 25 studies comprising nine randomized trials, two prospective, and 14 retrospective nonrandomized comparative studies. Studies were at high risk of bias. There was lower operative time for total vaginal hysterectomy compared with laparoscopically assisted vaginal hysterectomy (LAVH) (mean difference 39 minutes, 95% CI, 18-60) and total vaginal hysterectomy compared with total laparoscopic hysterectomy (mean difference 50 minutes, 95% CI, 29-70). Total laparoscopic hysterectomy was associated with much greater risk of ureteral injury compared with total vaginal hysterectomy (odds ratio 7.54, 95% CI, 2.52-22.58). There were no significant differences in bowel injury rates between groups. There were no differences in length of stay among the laparoscopic approaches. For LAVH compared with total vaginal hysterectomy, randomized controlled trials favored total vaginal hysterectomy for length of stay. When rates of blood transfusion were compared between these abdominal hysterectomy and robotic-assisted total hysterectomy routes, abdominal hysterectomy was associated with a sixfold greater risk of transfusion than robotic-assisted total hysterectomy (6.31, 95% CI, 1.07-37.32). Similarly, single studies comparing robotic-assisted total hysterectomy with LAVH, total laparoscopic hysterectomy, or total vaginal hysterectomy all favored robotic-assisted total hysterectomy for reduced blood loss. CONCLUSION: Minimally invasive routes are safe and effective and have few complications. Minimally invasive approach (vaginal, laparoscopic, or robotic) results in lower blood loss and shorter length of stay, whereas the abdominal route has a shorter operative time. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021233300.

Mapping the genetic landscape establishing a tumor immune microenvironment favorable for anti-PD-1 response in mice and humans.

Identifying host genetic factors modulating immune checkpoint inhibitor (ICI) efficacy has been experimentally challenging because of variations in both host and tumor genomes, differences in the microbiome, and patient life exposures. Utilizing the Collaborative Cross (CC) multi-parent mouse genetic resource population, we developed an approach that fixes the tumor genomic configuration while varying host genetics. With this approach, we discovered that response to anti-PD-1 (aPD1) immunotherapy was significantly heritable in four distinct murine tumor models (H2 between 0.18-0.40). For the MC38 colorectal carcinoma system (H2 = 0.40), we mapped four significant ICI response quantitative trait loci (QTL) localized to mouse chromosomes (mChr) 5, 9, 15 and 17, and identified significant epistatic interactions between specific QTL pairs. Differentially expressed genes within these QTL were highly enriched for immune genes and pathways mediating allograft rejection and graft vs host disease. Using a cross species analytical approach, we found a core network of 48 genes within the four QTLs that showed significant prognostic value for overall survival in aPD1 treated human cohorts that outperformed all other existing validated immunotherapy biomarkers, especially in human tumors of the previously defined immune subtype 4. Functional blockade of two top candidate immune targets within the 48 gene network, GM-CSF and high affinity IL-2/IL-15 signaling, completely abrogated the MC38 tumor transcriptional response to aPD1 therapy in vivo. Thus, we have established a powerful cross species in vivo platform capable of uncovering host genetic factors that establish the tumor immune microenvironment configuration propitious for ICI response.