Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Experiences implementing a Radiation therapist-led oncology prehabilitation program during COVID-19.

•Multi-modal prehabilitation prior to radiotherapy is valuable and achievable.•Radiation Therapists can be instrumental in developing prehab programs.•Multi-disciplinary care influences the patient's experience of cancer.•Validated screening tools can be easily incorporated into pre-radiotherapy assessments.•Online delivery of a prehabilitation program is feasible and safe.

Trends in pathology diagnoses during 10 years of a colorectal cancer screening programme.

AIMS: We report pathology findings from the first 10 years of the faecal-occult blood-based Northern Ireland Bowel Cancer Screening Programme, presenting summary data and trends in pathology diagnoses and clinicopathological features of screen-detected cancers. METHODS AND RESULTS: Data were analysed from a comprehensive polyp-level pathology database representing all endoscopy specimens from programme inception in 2010 until 2021. A total of 9800 individuals underwent 13 472 endoscopy procedures, yielding 25 967 pathology specimens and 32 119 diagnoses. Index specimen diagnoses (4.1%) and index colonoscopies (10.4%) yielded a diagnosis of colorectal cancer, representing 1045 cancers from 1020 individuals (25 with synchronous cancers). A further 13 index cancers were identified via computed tomography colonography; 65.3% of cancer diagnoses were in males; 41.7% were stage I, 23.1% stage II, 25.8% stage III and 1.8% stage IV (7.6% unstaged). Of 233 pT1 cancers diagnosed within local excision specimens, 79 (33.9%) had completion surgery. Ten-year trends showed a steady decline in the proportion of index colonoscopies that yielded a diagnosis of cancer (14.7% in year 1; 4.8% in year 11) or advanced colorectal polyp. There was a strong upward trend in diagnoses of sessile serrated lesions, which overtook hyperplastic polyps in proportions of total index diagnoses by the end of the study time-frame (8.7% compared to 8.5%). CONCLUSIONS: Over the first 10 years of a population colorectal cancer screening programme, 'real world' pathology data demonstrate success in the form of reduced diagnoses of cancer and advanced colorectal polyp with passage of successive screening rounds. Interesting trends with respect to serrated polyp diagnoses are also evident, probably related to pathologist and endoscopist behaviour.

A Rare Case of Septic Ovarian Thrombophlebitis Caused by Tissierella praeacuta.

We report a case of Tissierella praeacuta bacteremia and septic thrombophlebitis of the ovarian vein as a rare puerperal complication in a young patient. She was successfully managed with subcutaneous low molecular weight heparin (LMWH) and intravenous (IV) antibiotics before transitioning to a prolonged course of oral antibiotics at discharge.

Validation of the bladder neck as an important organ at risk in prostate seed brachytherapy based on D2cc: A single-institution, retrospective review.

Purpose: International guidelines recommend urethral dose volume constraints to minimize the risk of urinary toxicity after prostate brachytherapy. An association between dose to the bladder neck (BN) and toxicity has previously been reported, and we sought to evaluate the impact of this organ at risk on urinary toxicity, based on intra-operative contouring. Material and methods: Rates of acute and late urinary toxicity (AUT and LUT, respectively) were graded according to CTCAE version 5.0 for 209 consecutive patients who underwent low-dose-rate (LDR) brachytherapy monotherapy, with approximately equal numbers treated before and after we began routinely contouring the BN. AUT and LUT were compared in patients treated before and after we began contouring the OAR, and also for those treated after we began contouring who had a D2cc of greater than or less than 50% prescription dose. Results: AUT and LUT fell after intra-operative BN contouring was instituted. Rates of grade ≥ 2 AUT fell from 15/101 (15%) to 9/104 (8.6%), p = 0.245. Grade ≥ 2 LUT decreased from 32/100 (32%) to 18/100 (18%), p = 0.034. Grade ≥ 2 AUT was observed in 4/63 (6.3%) and 5/34 (15%) of those with a BN D2cc >/≤ 50%, respectively, of prescription dose. Corresponding rates for LUT were 11/62 (18%) and 5/32 (16%). Conclusions: There were lower urinary toxicity rates for patients treated after we commenced routine intra-operative contouring of the BN. No clear relationship was observed between dosimetry and toxicity in our population.

Impact of the COVID-19 pandemic on cancer care in Ireland - Perspectives from a COVID-19 and Cancer Working Group.

Upon the COVID-19 pandemic onset in Ireland, cancer service disruptions occurred due to prioritisation of COVID-19 related care, redeployment of staff, initial pausing of screening, diagnostic, medical and surgical oncology procedures, staff shortages due to COVID-19 infection and impacts on the physical and mental health of cancer healthcare workers. This was coupled with reluctance among people with symptoms suspicious for cancer to attend for clinical evaluation, due to concerns of contracting the virus. This was further compounded by a cyber-attack on national health service IT systems on May 14th 2021. The Irish Cancer Society, a national cancer charity with a role in advocacy, research and patient supports, convened a multi-disciplinary stakeholder group (COVID-19 and Cancer Working Group) to reflect on and understand the impact of the pandemic on cancer patients and services in Ireland, and discuss potential mitigation strategies. Perspectives on experiences were gathered across domains including timeliness of data acquisition and its conversion into intelligence, and the resourcing of cancer care to address cancer service impacts. The group highlighted aspects for future research to understand the long-term pandemic impact on cancer outcomes, while also highlighting potential strategies to support cancer services, build resilience and address delayed diagnosis. Additional measures include the need for cancer workforce recruitment and retention, increased mental health supports for both patients and oncology professionals, improvements to public health messaging, a near real-time multimodal national cancer database, and robust digital and physical infrastructure to mitigate impacts of the current pandemic and future challenges to cancer care systems.

The use of Vaccinia Immune Globulin in the Treatment of Severe Mpox. Virus Infection in Human Immunodeficiency Virus/AIDS.

We report a case of progressive, severe mpox virus (MPXV) infection in a patient with AIDS despite a standard course of tecovirimat. He significantly improved after administration of vaccinia immune globulin intravenous (VIGIV) highlighting its use as an adjunct for severe disease in immunocompromised hosts.

Radium-223 in combination with enzalutamide in metastatic castration-resistant prostate cancer: a multi-centre, phase II open-label study.

BACKGROUND: Radium-223 and enzalutamide are approved agents for patients with metastatic castration-resistant prostate cancer (mCRPC). Combining radium-223 and enzalutamide to improve outcomes is of clinical interest due to their differing modes of action and non-overlapping toxicity profiles. METHODS: This phase II study enrolled patients with mCRPC and bone metastases. Patients received six cycles of radium-223 in combination with enzalutamide, followed by enzalutamide alone. The primary endpoint was safety for the combination; secondary endpoints included radiographic/clinical progression-free survival (PFS), PSA PFS, overall survival (OS), change in alkaline phosphatase, patient-reported pain outcomes and skeletal related events. RESULTS: Forty-five patients received the combination treatment: 42 patients (93.3%) received all six cycles. Fourteen patients (31.1%) developed grade 3 or 4 toxicities, most commonly fatigue and neutropaenia. Fractures during the combination period occurred in four patients (8.9%). A further 13 patients (28.9%) developed fractures after completing combination treatment, giving a total of 17 patients (37.8%) who developed a fracture at any time on study. The median time to fracture was greater than 17.2 months [95% confidence interval (CI), 17.2-not estimable]. The median time to PSA progression was 18.1 months (95% CI, 12.68-22.60) and the median time to radiological/clinical progression was 28.0 months (95% CI, 22.54-not reached). At the primary analysis, 19 (42.2%) out of 45 patients had died with a median OS not reached (mean 34.8 months, standard error 1.4). CONCLUSION: In men with progressive mCRPC and bone metastases, the combination of radium-223 and enzalutamide was tolerable with the majority of patients completing the combination treatment. Bone fractures during the combination period were uncommon; however, we did identify a higher incidence of fractures occurring in patients after completing combination treatment. Bone health agents should be administered and bone health should be closely monitored following treatment with radium-223 and enzalutamide.

Spin-Flip Diffusion Length in 5d Transition Metal Elements: A First-Principles Benchmark.

Little is known about the spin-flip diffusion length l_{sf}, one of the most important material parameters in the field of spintronics. We use a density-functional-theory based scattering approach to determine values of l_{sf} that result from electron-phonon scattering as a function of temperature for all 5d transition metal elements. l_{sf} does not decrease monotonically with the atomic number Z but is found to be inversely proportional to the density of states at the Fermi level. By using the same local current methodology to calculate the spin Hall angle Θ_{sH} that characterizes the efficiency of the spin Hall effect, we show that the products ρ(T)l_{sf}(T) and Θ_{sH}(T)l_{sf}(T) are constant.

Immune cell infiltrates as prognostic biomarkers in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis.

Immune cell infiltration has been identified as a prognostic biomarker in several cancers. However, no immune based biomarker has yet been validated for use in pancreatic ductal adenocarcinoma (PDAC). We undertook a systematic review and meta-analysis of immune cell infiltration, measured by immunohistochemistry (IHC), as a prognostic biomarker in PDAC. All other IHC prognostic biomarkers in PDAC were also summarised. MEDLINE, EMBASE and Web of Science were searched between 1998 and 2018. Studies investigating IHC biomarkers and prognosis in PDAC were included. REMARK score and Newcastle-Ottawa scale were used for qualitative analysis. Random-effects meta-analyses were used to pool results, where possible. Twenty-six articles studied immune cell infiltration IHC biomarkers and PDAC prognosis. Meta-analysis found high infiltration with CD4 (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.51-0.83.) and CD8 (HR = 0.68, 95% CI = 0.55-0.84.) T-lymphocytes associated with better disease-free survival. Reduced overall survival was associated with high CD163 (HR = 1.62, 95% CI = 1.03-2.56). Infiltration of CD3, CD20, FoxP3 and CD68 cells, and PD-L1 expression was not prognostic. In total, 708 prognostic biomarkers were identified in 1101 studies. In summary, high CD4 and CD8 infiltration are associated with better disease-free survival in PDAC. Increased CD163 is adversely prognostic. Despite the publication of 708 IHC prognostic biomarkers in PDAC, none has been validated for clinical use. Further research should focus on reproducibility of prognostic biomarkers in PDAC in order to achieve this.

Late Development of Metastatic Ovarian Mucinous Adenocarcinoma From Primary Gallblader Adenocarcinoma and High-grade Dysplasia.

The ovary is a common site of metastatic mucinous adenocarcinoma. In most, but not all, cases the presence of a primary neoplasm elsewhere is already known and the metastasis is picked up at diagnosis or is discovered a relatively short time following the diagnosis of the primary neoplasm. We report 2 cases of metastatic gallbladder adenocarcinoma involving the ovaries of women aged 65 and 59 after long time periods of 8 and 5 yr following diagnosis of high-grade dysplasia or early adenocarcinoma of the gallbladder, respectively. In both cases, a review of the original operative notes suggested the possibility of intraoperative gallbladder rupture or bile leakage suggesting that the metastatic disease may have developed secondary to "seeding." In both cases, p53 immunohistochemistry revealed identical null mutation-type immunoreactivity within the gallbladder and ovarian neoplasms, assisting in confirming the ovarian disease as a metastasis from the gallbladder. The possibility of late ovarian metastasis of gallbladder dysplasia or adenocarcinoma secondary to rupture/bile leakage should be borne in mind.

Non-inferiority randomised phase 3 trial comparing two radiation schedules (single vs. five fractions) in malignant spinal cord compression.

BACKGROUND: The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. METHODS: Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = 'Walk unaided', 2 = 'With walking aid' and 3 = 'Bed-bound'. The margin used to establish non-inferiority was a detrimental change of -0.4 in the mean difference between arms. RESULTS: One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30-87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was -0.12 to 0.6. Since -0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2-3 AE compared with six (11%) patients in the SF arm (p = 0.093). CONCLUSION: For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. CLINICAL TRIAL REGISTRATION: Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.

Disorder Dependence of Interface Spin Memory Loss.

The discontinuity of a spin-current through an interface caused by spin-orbit coupling is characterized by the spin memory loss (SML) parameter δ. We use first-principles scattering theory and a recently developed local current scheme to study the SML for Au|Pt, Au|Pd, Py|Pt, and Co|Pt interfaces. We find a minimal temperature dependence for nonmagnetic interfaces and a strong dependence for interfaces involving ferromagnets that we attribute to the spin disorder. The SML is larger for Co|Pt than for Py|Pt because the interface is more abrupt. Lattice mismatch and interface alloying strongly enhance the SML that is larger for a Au|Pt than for a Au|Pd interface. The effect of the proximity-induced magnetization of Pt is negligible.

Primary Ovarian High-grade Neuroendocrine Carcinoma With Merkel Cell-like Immunophenotype Arising in a Teratoma.

Ovarian high-grade neuroendocrine carcinomas (NECs) (small cell and large cell NEC) are rare neoplasms. They may arise in association with other ovarian tumors, most commonly epithelial neoplasms and rarely teratomas. We report a case of an 19-yr-old female with bilateral ovarian teratomas with a high-grade NEC (immunohistochemically positive with chromogranin, synaptophysin, and CD56 and MIB1 proliferation index in excess of 90%) arising within one of these. Although CK20 was negative, the NEC exhibited an immunophenotype suggestive of a Merkel cell carcinoma with diffuse positive staining with FLI-1, SATB2 and neurofilament, markers which are preferentially expressed in Merkel cell carcinoma compared with other NECs. There was also diffuse staining for SALL4. Immunohistochemistry and molecular studies for Merkel cell polyomavirus were negative. Immunohistochemical staining for CK20, FLI-1, SATB2, neurofilament, and SALL4 was performed in 6 additional primary ovarian high-grade NECs; One, 5, 5, 1, and 0 cases were positive for CK20, FLI-1, SATB2, neurofilament, and SALL4, respectively, usually with very focal immunoreactivity. Pathologists should be aware of these potential unexpected staining patterns in ovarian NECs as positivity may result in consideration of other neoplasms.

Adult Granulosa Cell Tumor With High-grade Transformation: Report of a Series With FOXL2 Mutation Analysis.

Adult granulosa cell tumor (AGCT) is a low-grade malignant neoplasm with a significant propensity for late recurrence and metastasis. Almost all AGCTs are composed of cells with bland nuclear features and even when these tumors recur or metastasize, the nuclear features are almost always low-grade. We report 5 cases of AGCT in patients aged 37 to 88 years composed of areas of typical AGCT with low-grade morphology admixed with areas of high-grade morphology, with marked nuclear atypia, often with bizarre multinucleate cells and high mitotic activity; this is the first reported series of high-grade transformation in AGCTs. The high-grade areas often morphologically closely resembled juvenile granulosa cell tumor with abundant eosinophilic cytoplasm, significant mitotic activity, and intermediate sized follicles. Four cases were FIGO stage IA at diagnosis and 1 was stage IIIC with omental involvement. FOXL2 mutation analysis of both the morphologically low-grade and high-grade areas in 4 of 5 cases confirmed the presence of missense point mutation, c.402C>G, p.(Cys134Trp), providing conclusive evidence that the high-grade component represents transformation of typical AGCT rather than the coexistence of another sex cord-stromal tumor, such as juvenile granulosa cell tumor, which has been suggested for such neoplasms. In 3 of 4 cases where immunohistochemistry was undertaken, there was a striking difference between the p53 staining in the low-grade and high-grade components with wild-type staining in the former and diffuse mutation-type immunoreactivity in the latter, suggesting that TP53 mutation is likely to play a role in high-grade transformation. TP53 mutation analysis covering exons 4 to 10 was undertaken in 4 cases and TP53 mutations were identified in the high-grade component of 2 of the cases. In 1 case, there was diffuse block-type p16 staining in the high-grade component. Follow-up in the 4 stage IA neoplasms revealed no evidence of tumor recurrence in 3 (6 to 9 mo follow-up) while the other patient developed mediastinal, peritoneal, and pulmonary metastasis 17 months after diagnosis. High-grade transformation is uncommon in AGCTs and given that one of our cases was advanced stage at diagnosis, another exhibited widespread metastasis within a short period and there have been occasional case reports of aggressive behavior in AGCTs with high-grade transformation, this event may herald an aggressive clinical course.

Human Papillomavirus (HPV)-associated Lymphoepithelioma-like Carcinoma of the Vagina and Anal Canal: A Rare Variant of Squamous Cell Carcinoma.

Lymphoepithelioma-like carcinoma (LELC) is an uncommon variant of squamous cell carcinoma, which is histologically identical to lymphoepithelial carcinoma of the nasopharynx. LELCs have been reported at a variety of sites, including the stomach, salivary gland, thymus, cervix, endometrium, breast, skin, bladder, and lung. We report 2 LELCs of the vagina and 1 of the anal canal, the first report of LELC at the latter site. All 3 neoplasms were diffusely positive with p16 (block-type immunoreactivity) and the anal canal lesion contained high-risk human papillomavirus type 16; the 2 vaginal neoplasms underwent human papillomavirus testing but were unsuitable for analysis. All cases were Epstein-Barr virus negative. In reporting these cases, we highlight the potential for misdiagnosis and suggest an association with human papillomavirus infection similar to LELCs in the uterine cervix.

An Unusual Case of Ototoxicity with Use of Oral Vancomycin.

INTRODUCTION: Systemic absorption of oral vancomycin is poor due to the size of the molecule and its pharmacokinetics. It has an elimination half life of 5-11 hours in patients with normal renal function. We present a rare case of ototoxicity after oral vancomycin administration and detectable serum vancomycin levels 24 hours after cessation of vancomycin. CASE PRESENTATION: A 42-year-old woman with a history of hypertension, diabetes mellitus, and previously treated Clostridium difficile colitis presented with abdominal pain and diarrhea for two weeks. Clostridium difficile infection was confirmed by PCR, and at the time of diagnosis and initiation of therapy, the patient had normal renal function. Vancomycin was initiated at a dose of 125 mg po q6h. After the third dose of oral vancomycin, the patient reported new symptoms of lightheadedness, sensations of "buzzing" and whistling of bilateral ears, and decreased perception of hearing described as "clogged ears." The patient reported to the emergency department the next day due to worsening of these symptoms, and vancomycin dosing was reduced to every 8 hours; however, the patient reported the auditory symptoms persisted. On day three, vancomycin was discontinued with gradual resolution of symptoms over the next 12 hours. On day four, a serum random vancomycin level obtained 24 hours after the last dose was detectable at 2 mcg/dl. Temporal association of the patient's symptoms and improvement with cessation of therapy along with a detectable vancomycin level indicates systemic absorption of oral vancomycin with subsequent ototoxicity. DISCUSSION: The potential for absorption of oral vancomycin is not well described and is attributed to compromised intestinal epithelium allowing for increased drug absorption. Few studies suggested that oral vancomycin may result in therapeutic or even potentially toxic levels of serum vancomycin in patients with impaired renal function. Ototoxicity may be a transient or permanent side effect of vancomycin therapy and is related to high serum levels. Symptoms usually resolve after decreasing the dose or cessation of vancomycin. No detectable serum vancomycin levels were found in 98% of the patients treated with oral vancomycin in a prospective study. The described case is unusual because despite normal renal function, the patient still developed ototoxicity, and systemic absorption of the drug was confirmed with a measurable vancomycin level approximately 24 hours after the drug was stopped. Additionally, the only other medication prescribed to the patient at the time of vancomycin administration was metformin at a dose of 500 mg po bid which has no known idiosyncratic interactions potentiating adverse side effects to vancomycin. This case reflects that some patients may be more susceptible to increased systemic absorption via the oral route, and the possibility for ototoxicity should be considered and discussed with patients while prescribing oral vancomycin.

Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study.

AIMS: Both morphological and molecular approaches have highlighted the biological and prognostic importance of the tumour microenvironment in colorectal cancer (CRC). Despite this, microscopic assessment of the tumour microenvironment has not been adopted into routine practice. The study aim was to identify those tumour microenvironmental features that are most likely to provide prognostic information and be feasible to use in routine pathology reporting practice. METHODS AND RESULTS: On the basis of existing evidence, we selected specific morphological features relating to peritumoral inflammatory and stromal responses, agreed criteria for scoring, and assessed these in representative haematoxylin and eosin (H&E)-stained whole tumour sections from a population-based cohort of 445 stage II/III colon cancer cases. Moderate/severe peritumoral diffuse lymphoid inflammation and Crohn's disease-like reaction were associated with significantly reduced risks of CRC-specific death [adjusted hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.31-0.76, and HR 0.60, 95% CI 0.42-0.84, respectively]. The presence of >50% tumour stromal percentage, as assessed by global evaluation of tumour area, was associated with a significantly increased risk of CRC-specific death (HR 1.60 95% CI 1.06-2.41). A composite 'fibroinflammatory score' (0-3), combining dichotomized scores of these three features, showed a highly significant association with survival outcomes. Those with a score of ≥2 had an almost 2.5-fold increased risk of CRC-specific death (HR 2.44, 95% CI 1.56-3.81) as compared with those scoring zero. These associations were stronger in microsatellite instability (MSI)-high tumours, potentially identifying a subset of MSI-high colon cancers that lack characteristic morphological features and have an associated worse prognosis. CONCLUSIONS: In summary, reporting on H&E staining of selected microscopic features of the tumour microenvironment, independently or in combination, offers valuable prognostic information in stage II/III colon cancer, and may allow morphological correlation with developing molecular classifications of prognostic and predictive relevance.

Z_{2} Invariance of Germanene on MoS_{2} from First Principles.

We present a low energy Hamiltonian generalized to describe how the energy bands of germanene (Ge[over ¯]) are modified by interaction with a substrate or a capping layer. The parameters that enter the Hamiltonian are determined from first-principles relativistic calculations for Ge[over ¯]|MoS_{2} bilayers and MoS_{2}|Ge[over ¯]|MoS_{2} trilayers and are used to determine the topological nature of the system. For the lowest energy, buckled germanene structure, the gap depends strongly on how germanene is oriented with respect to the MoS_{2} layer(s). Topologically nontrivial gaps for bilayers and trilayers can be almost as large as for a freestanding germanene layer.