WHO 2022 classification of penile and scrotal cancers: updates and evolution.

Squamous cell carcinoma (SCC) is the most common malignant tumour of the penis. The 2022 WHO classification reinforces the 2016 classification and subclassifies precursor lesions and tumours into human papillomavirus (HPV)-associated and HPV-independent types. HPV-associated penile intraepithelial neoplasia (PeIN) is a precursor lesion of invasive HPV- associated SCC, whereas differentiated PeIN is a precursor lesion of HPV-independent SCC. Block-type positivity of p16 immunohistochemistry is the most practical daily utilised method to separate HPVassociated from HPVindependent penile SCC. If this is not feasible, the term SCC, not otherwise specified (NOS) is appropriate. Certain histologies that were previously classified as "subtypes" are now grouped, and coalesced as "patterns", under the rubric of usual type SCC and verrucous carcinoma (e.g. usual-type SCC includes pseudohyperplastic and acantholytic/pseudoglandular carcinoma, and carcinoma cuniculatum is included as a pattern of verrucous carcinoma). If there is an additional component of the usual type of invasive SCC (formerly termed hybrid histology), the tumour would be a mixed carcinoma (e.g. carcinoma cuniculatum or verrucous carcinoma with usual invasive SCC); in such cases, reporting of the relative percentages in mixed tumours may be useful. The consistent use of uniform nomenclature and reporting of percentages will inform the refinement of future reporting classification schemes and guidelines/recommendations. The classification of scrotal tumours is provided for the first time in the fifth edition of the WHO Blue book, and it follows the schema of penile cancer classification for both precursor lesions and the common SCC of the scrotum. Basal cell carcinoma of the scrotum may have a variable clinical course and finds a separate mention.

Long-term outcomes with multi-targeted immunosuppressive protocol in children with severe proliferative lupus nephritis.

We have previously reported the one-year outcomes of 16 children with severe proliferative lupus nephritis (LN) who were treated using a multi-targeted induction protocol based on intravenous (IV) pulse methylprednisolone (MP), mycophenolate mofetil (MMF) and cyclosporine (CSA). This study examined the long-term renal outcomes of these 16 children, followed up for a median duration of 9.2 years (range 5.8-14.2 years). Primary treatment outcome was complete renal remission. Secondary outcomes included patient and renal survival as well as relapse-free and event-free survival. All patients achieved complete renal remission within 24 months (median 8.7 months, range 4.0-24.0 months). Comparing clinical and laboratory parameters at induction and last follow-up, respectively, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (25.4 ± 8.7 vs. 0.4 ± 0.8), serum complement C3 (47 ± 21 vs. 107 ± 27 mg/dL), estimated glomerular filtration rate (eGFR) (72 ± 57 vs. 109.7 ± 43 ml/min/1.73 m2) and urine protein (6.97 ± 7.09 vs. 0.2 ± 0.02 g/day/1.73 m2) improved significantly (p < 0.05). Kaplan-Meier survival analysis showed a cumulative ten-year renal relapse-free survival of 73.3% when considering relapses with severe proteinuria >1 g/day/1.73 m2. Cumulative probability that hospitalization would not be required was 93.8% at one year, and 71.4% at ten years. Our multi-targeted protocol for induction and maintenance therapy in Asian children with severe proliferative LN resulted in good long-term patient survival and renal preservation, with a good safety profile.

Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience.

Taking cognizance of the purported variation of phyllodes tumours in Asians compared with Western populations, this study looked at phyllodes tumours of the breast diagnosed at the Department of Pathology, University of Malaya Medical Centre over an 8-year period with regards to patient profiles, tumour parameters, treatment offered and outcome. Sixty-four new cases of phyllodes tumour were diagnosed during the period, however only 30 (21 benign, 4 borderline and 5 malignant) finally qualified for entry into the study. These were followed-up for 4-102 months (average = 41.7 months). Thirteen cases (8 benign, 3 borderline, 2 malignant) were Chinese, 9 (all benign) Malay, 7 (4 benign, 1 borderline, 2 malignant) Indian and 1 (malignant) Indonesian. Prevalence of benign versus combined borderline and malignant phyllodes showed a marginally significant difference (p=0.049) between the Malays and Chinese. Patients' ages ranged from 21-70 years with a mean of 44.9 years with no significant difference in age between benign, borderline or malignant phyllodes tumours. Except for benign phyllodes tumours (mean size = 5.8 cm) being significantly smaller at presentation compared with borderline (mean size = 12.5 cm) and malignant (mean size = 15.8 cm) (p<0.05) tumours, history of previous pregnancy, breast feeding, hormonal contraception and tumour laterality did not differ between the three categories. Family history of breast cancer was noted in 2 cases of benign phyllodes. Local excision was performed in 17 benign, 2 borderline and 3 malignant tumours and mastectomy in 4 benign, 2 borderline and 2 malignant tumours. Surgical clearance was not properly recorded in 10 benign phyllodes tumours. Six benign and all 4 borderline and 5 malignant tumours had clearances of <10 mm. Two benign tumours recurred locally at 15 and 49 months after local excision, however information regarding surgical clearance was not available in both cases. One patient with a malignant tumour developed a radiologically-diagnosed lung nodule 26 months after mastectomy, was given a course of radiotherapy and remained well 8-months following identification of the lung nodule.

ERRATUM: Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience.

No abstract available.

Prognostic factors in metaplastic carcinoma of the breast: a multi-institutional study.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare type of breast cancer that has basal-like characteristics and is perceived to have poorer prognosis when compared with conventional no specific type/ductal carcinomas (ductal/NST). However, current data on MBC are largely derived from small case series or population-based reports. This study aimed to assess the clinicopathological features and outcome of MBC identified through an international multicentre collaboration. METHODS: A large international multicentre series of MBC (no=405) with histological confirmation and follow-up information has been included in this study. The prognostic value of different variables and outcome has been assessed and compared with grade, nodal status and ER/HER2 receptor-matched ductal/NST breast carcinoma. RESULTS: The outcome of MBC diagnosed in Asian countries was more favourable than those in Western countries. The outcome of MBC is not different from matched ductal/NST carcinoma but the performance of the established prognostic variables in MBC is different. Lymph node stage, lymphovascular invasion and histologic subtype are associated with outcome but tumour size and grade are not. Chemotherapy was associated with longer survival, although this effect was limited to early-stage disease. In this study no association between radiotherapy and outcome was identified. Multivariate analysis of MBC shows that histologic subtype is an independent prognostic feature. CONCLUSIONS: This study suggests that MBC is a heterogeneous disease. Although the outcome of MBC is not different to matched conventional ductal/NST breast carcinoma, its behaviour is dependent on the particular subtype with spindle cell carcinoma in particular has an aggressive biological behaviour. Management of patients with MBC should be based on validated prognostic variables.

Genetic Interactions Between TRPC6 and NPHS1 Variants Affect Posttransplant Risk of Recurrent Focal Segmental Glomerulosclerosis.

Individuals with TRPC6 mutations have variable phenotypes, ranging from healthy carrier to focal segmental glomerulosclerosis (FSGS) leading to renal failure. Here, we describe a family where six members had a novel TRPC6 p.R68W (c.202C>T) mutation, two of whom had renal failure from FSGS, and one had proteinuria. One healthy carrier donated a kidney to her sister. Both donor and recipient had no proteinuria at 20 years posttransplant. Two synonymous NPHS1 polymorphisms, rs2285450 (c.294C>T) and rs437168 (c.2289C>T) segregated with renal failure in this family. These variants had higher allele frequencies in 97 unrelated patients with nephrotic syndrome or FSGS compared to 224 controls. Using patch-clamp experiments in HEK293 and podocytes, we showed that the p.R68W mutation increased TRPC6 current amplitudes, which may be explained by enhanced TRPC6 surface expression. Additionally, while wild-type nephrin suppressed TRPC6 currents, this ability was lost in the presence of NPHS1 c.294C>T polymorphism. When cells were transfected according to combined TRPC6 and NPHS1 genotypes in the family, those representing the donor had lower TRPC6 currents than cells representing the recipient, suggesting that interactions between TRPC6 and NPHS1 variants could possibly account for the variable penetrance of TRPC6 mutations and the absence of recurrence in the graft.

Carrier and polarization dynamics in monolayer MoS2.

In monolayer MoS2, optical transitions across the direct band gap are governed by chiral selection rules, allowing optical valley initialization. In time-resolved photoluminescence (PL) experiments, we find that both the polarization and emission dynamics do not change from 4 to 300 K within our time resolution. We measure a high polarization and show that under pulsed excitation the emission polarization significantly decreases with increasing laser power. We find a fast exciton emission decay time on the order of 4 ps. The absence of a clear PL polarization decay within our time resolution suggests that the initially injected polarization dominates the steady-state PL polarization. The observed decrease of the initial polarization with increasing pump photon energy hints at a possible ultrafast intervalley relaxation beyond the experimental ps time resolution. By compensating the temperature-induced change in band gap energy with the excitation laser energy, an emission polarization of 40% is recovered at 300 K, close to the maximum emission polarization for this sample at 4 K.

ALDH1 expression is enriched in breast cancers arising in young women but does not predict outcome.

BACKGROUND: Tumours arising in younger women appear to be biologically more aggressive and tend to have a poorer outcome. Being relatively resistant to conventional treatments, breast cancer stem cells (CSCs) have been postulated as a possible cause of disease recurrence after treatment. In this study, we used ALDH1 as a CSC marker and determined whether ALDH1 expression correlated with clinical outcome in young women with breast cancer. METHODS: The expression of ALDH1 was evaluated through immunohistochemistry on microarrayed cores obtained from 141 consecutive patients up to 35 years of age. RESULTS: The expression of ALDH1 was observed in 25% (35 of 141) of tumours, in a median of 5% of cells. Younger women were 14 times more likely to have ALDH1-positive tumours (P<0.01, OR 14.4, 95% CI 4.34-48.09). The ALDH1 correlated independently with ER negativity (P=0.01, OR 0.33, 95% CI 0.15-0.77). There was no correlation with disease recurrence or breast cancer-related deaths. CONCLUSION: In younger women, ALDH1 was more highly expressed, and it correlated with ER negativity. It, however, did not predict survival in this study.

The shear mode of multilayer graphene.

The quest for materials capable of realizing the next generation of electronic and photonic devices continues to fuel research on the electronic, optical and vibrational properties of graphene. Few-layer graphene (FLG) flakes with less than ten layers each show a distinctive band structure. Thus, there is an increasing interest in the physics and applications of FLGs. Raman spectroscopy is one of the most useful and versatile tools to probe graphene samples. Here, we uncover the interlayer shear mode of FLGs, ranging from bilayer graphene (BLG) to bulk graphite, and suggest that the corresponding Raman peak measures the interlayer coupling. This peak scales from ~43 cm(-1) in bulk graphite to ~31 cm(-1) in BLG. Its low energy makes it sensitive to near-Dirac point quasiparticles. Similar shear modes are expected in all layered materials, providing a direct probe of interlayer interactions.

Mesenchymal stem cells differentially mediate regulatory T cells and conventional effector T cells to protect fully allogeneic islet grafts in mice.

AIMS/HYPOTHESIS: Limited information is available on the cellular interactions between regulatory T (T(reg)) cells and mesenchymal stem cells (MSCs). In particular, a direct effect of MSCs on the survival and proliferation of T(reg) cells has not been demonstrated. METHODS: We investigated the effects of MSCs on effector T (T(eff)) cells and T(reg) cells, and the molecular mechanisms involved in the distinct regulation of these two cell populations by MSCs in vivo and in vitro. RESULTS: We show that MSCs are capable of selectively suppressing T(eff) cells and fostering the generation of T(reg) cells. T(eff) cells, but not T(reg) cells, fail to respond to IL-2 and undergo profound apoptosis in the presence of MSCs. The differential regulations of these two T cell subsets by MSCs are associated with their distinct expressions of CD25, with MSCs specifically reducing the expression of CD25 on T(eff) and sparing T(reg) cells intact. In vivo, the administration of MSCs significantly delays the rejection of allogeneic islet grafts in adaptive transferred recipients by favouring the induction of T(reg) cells. In this model, MSCs inhibit the proliferation and development of alloreactive T(eff) but potently enhance the induction of T(reg) cells. CONCLUSIONS/INTERPRETATION: We demonstrate that MSCs are capable of regulating T(eff) and T(reg) cells differentially in vitro. MSCs inhibit T(eff) cells by inducing apoptosis and impairing the proliferative response to IL-2 in T(eff) cells, but favour the survival and expansion of T(reg) cells. This result is further demonstrated in mice that have undergone allogeneic islet transplantation, in which MSCs suppress alloreactive T(eff) cells while favouring the induction of T(reg) cells, thus protecting the islet allografts from rejection.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.

Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population.

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.

Short small-interfering RNAs produce interferon-α-mediated analgesia.

BACKGROUND: There is increasing interest in RNA interference in pain research using the intrathecal route to deliver small-interfering RNA (siRNA). An interferon (IFN) response is a common side-effect of siRNA. However, the IFN response in the spinal cord after intrathecal administration of siRNA remains unknown. We hypothesized that high doses of siRNAs can elicit off-target analgesia via releasing IFN-α. We investigated the IFN response and its role in regulating pain sensitivity in the spinal cords after intrathecal administration of siRNAs. METHODS: Male Sprague-Dawley rats were given intrathecal injections of non-targeting (NT) siRNAs or IFN-α and tested for complete Freund's adjuvant (CFA)-induced mechanical allodynia and heat hyperalgesia. IFN-α in the spinal cord after injection of NT siRNAs was measured by western blotting and immunohistochemical staining. RESULTS: IFN-α was up-regulated in the spinal cord after intrathecal treatment of NT siRNAs. Intrathecal injection of NT siRNAs, at high doses of 10 or 20 µg, reduced CFA-induced inflammatory pain (P<0.05). Intrathecal application of IFN-α inhibited pain hypersensitivity in inflamed rats and produced analgesia in naïve rats (P<0.05). Notably, the anti-nociceptive effects elicited by NT siRNAs and IFN-α were reversed by IFN-α neutralizing antibody and naloxone. CONCLUSIONS: Our data suggest that (i) intrathecal administration of high doses of siRNA (≥ 10 µg) induced up-regulation of IFN-α in the spinal cord and produced analgesic effects through IFN-α, and (ii) IFN-α's analgesic effect is mediated via opioid receptors. Caution must be taken to avoid IFN-α-mediated analgesic effects of siRNAs in pain research.

The pre-emptive analgesic effect of a cyclooxygenase-2 inhibitor in a rat model of acute postoperative pain.

We examined the pre-emptive analgesic effect of a cyclooxygenase (COX)-2 inhibitor in a rat surgical pain model and characterised the changes in cutaneous COX-2 around a surgical site. Thermal hyperalgesia and mechanical allodynia were tested in the rats for three days after incision and skin tissues were collected for analysis of COX-2. There was decreased expression of cutaneous COX-2 one day after surgical incision. Pre-incision injection of the COX-2 inhibitor significantly inhibited expression of COX-2 and also reduced thermal hyperalgesia (but not mechanical allodynia) compared with the post-incision COX-2-inhibitor injection group, one day after incision.

The effect of transoesophageal echocardiography probe insertion on tracheal cuff pressure.

Increased tracheal cuff pressure during mechanical ventilation is associated with reduced mucosal blood flow and ischaemia, as well as postoperative sore throat. We assessed the potential effects of transoesophageal echocardiography probe insertion on the tracheal cuff pressure in patients undergoing cardiac surgery. Using a manometer, the cuff pressure of a high-volume, low-pressure tracheal tube (inner diameter 7.0 mm for women and 7.5 mm for men) was adjusted to 25-30 cm H(2)O before blind insertion of a transoesophageal echocardiography probe. The pressure changes were then recorded for 1 min. After probe insertion, the mean (SD) intra-cuff pressure increased from 27.7 (1.5) to 36.2 (6.4) cm H(2)O (p < 0.001) and was > 35 cm H(2)0 in 17/38 patients (45%). Our results suggest that transoesophageal echocardiography probe insertion may increase the tracheal cuff pressure more than that is generally recommended and therefore the latter should be routinely monitored under such circumstances.

Controlling the cost of breast cancer.

Breast cancer management is an important part of the health-care system. In the current harsh economic climate, these costs have to be controlled, and achieving this without compromising quality of care is a daunting challenge. This article discusses the need to find effective and well-targeted chemotherapeutic regimens, which, when combined with appropriate implementation of novel strategies, will provide the optimum treatment for patients while maintaining economic viability.

Good outcomes with mycophenolate-cyclosporine-based induction protocol in children with severe proliferative lupus nephritis.

The outcomes of children with severe proliferative lupus nephritis (LN) were examined using a new mycophenolate and cyclosporine-based (MMF-CSA) induction protocol. Sixteen children with LN (WHO class III and IV), 31.3% of whom required dialysis at induction, were retrospectively studied. Median MMF dose was 942 mg/m( 2)/day. Thirteen patients (81%) with persistent proteinuria received CSA. Clinical and laboratory parameters were compared at pre-induction, 6 and 12 months. Treatment outcome was defined by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), renal function, haematuria, proteinuria and serological markers (complements C3, C4 and anti-dsDNA). Comparing these parameters at induction, 6 months and 12 months, respectively, SLEDAI (25.4 +/- 8.7 versus 3.2 +/- 2.9 versus 2.9 +/- 2.8), serum C3 (47 +/- 21 versus 107 +/- 27 versus 111 +/- 38 mg/dl), C4 (12 +/- 14 versus 23 +/- 14 versus 22 +/- 11 mg/dl) and urine protein (6.97 +/- 7.09 versus 0.98 +/- 1.56 versus 0.21 +/- 0.13 g/ day/1. 73 m(2)) improved significantly (p < 0.05). Anti-dsDNA titres decreased in 73% by 6 and 12 months (p < 0.05). Complete renal remission was achieved in 7/16 (43.8%) at 6 months and 12/16 (75%) at 12 months, the rest achieving partial remission with no treatment failures. In conclusion, a combination MMF-CSA protocol is an effective therapeutic alternative for induction of children with severe proliferative LN, resulting in significant clinical and serological improvement with minimal adverse effects.

The changing pattern of primary glomerulonephritis in Singapore and other countries over the past 3 decades.

This review of 2,586 renal biopsies over the past 3 decades in Singapore documents the changing pattern of glomerulonephritis (GN) from that of a third world country to that of a developed nation. In the 1st decade, mesangial proliferative glomerulonephritis was the most common form of primary GN, just as it was in the surrounding Asian countries. In the 2nd decade, the prevalence of mesangial proliferative GN decreased with a rise in membranous, GN which is also seen in China and Thailand. In the 3rd decade, there was a dramatic increase in focal sclerosing glomerulosclerosis. This increase reflects aging and obesity in keeping with more developed countries like Australia, India, Thailand and the United States of America. IgA nephritis remains the most common GN. Apart from the geographical influence, other socioeconomic factors play a significant role in the evolution of the renal biopsy pattern. Mesangial proliferative GN remains prevalent in many Asian countries, but in Singapore the prevalence is decreasing just as it is in Japan, Korea and Malaysia. Worldwide, the prevalence of focal sclerosing glomerulosclerosis continues to increase in many countries.

A prospective study to compare the diagnostic performance of breast elastography versus conventional breast ultrasound.

AIM: To compare the diagnostic performance of breast elastography versus conventional ultrasound in the assessment of breast lesions. MATERIALS AND METHODS: The study was approved by the hospital's institutional review board. A prospective study involving 99 consecutive women who gave informed consent were enrolled from September 2007 to March 2008. One hundred and ten breast lesions were evaluated separately by conventional ultrasound, elastography and combined conventional ultrasound with elastography. Ultrasound assessment was based on the BIRADS classification, whereas elastographic assessment was based on strain pattern and the elastographic size ratios. Histological diagnosis was used as the reference standard. The sensitivity, specificity, and accuracy of each technique were compared. RESULTS: The mean age of the patients was 46.7 years. Twenty-six lesions were malignant and 84 were benign. Sensitivity, specificity, and accuracy were 88.5, 42.9 and 53.6%, respectively, for conventional ultrasound, 100, 73.8, and 80%, respectively, for elastography, and 88.5, 78.6, and 80.9%, respectively, for combined imaging. The specificity and accuracy of elastography and combined imaging were significantly better than that of conventional ultrasound (p<0.0001), whereas there was no statistically significant difference in the sensitivity between all three groups. Two-thirds (66.7%) of sonographic false-positive lesions had benign elastogram findings, which might have been spared from biopsy. CONCLUSION: This initial experience with ultrasound breast elastography showed that it was more specific and more accurate than conventional ultrasound. Combining elastography with ultrasound improved specificity and accuracy of ultrasound and can potentially reduce unnecessary breast biopsies.