Implications of the revised cervical cancer FIGO staging system.

The 2018 revised International Federation of Gynaecology and Obstetrics (FIGO) staging of cervical cancer has brought about a paradigm shift by offering the option of adding imaging and pathology to clinical staging. This makes it applicable to all types of resource situations across geographies with implications for all stakeholders, including gynaecologists, gynaecologic oncologists, radiologists, pathologists and radiation and medical oncologists. The new staging classification has more granularity, with three sub-stages of stage IB and a new category of stage IIIC for all cases with lymph node (LN) involvement. The major limitations of clinical staging were inaccurate assessment of tumour size and inability to assess pelvic and para-aortic LNs with the limited investigations permitted by FIGO to change the stage. This resulted in understaging of stages IB-III, and overstaging of stage IIIB, which has been largely overcome by incorporating imaging findings. Although any imaging modality can be used, magnetic resonance imaging appears to be the best imaging modality for early-stage disease owing to its better soft-tissue resolution. However, the use of contrast-enhanced computed tomography or ultrasonography are also feasible options, depending on the availability and resources. But wherever pathological evaluation is possible, it supersedes clinical and radiological findings.

Predictors of chemotherapy resistance & relapse in gestational trophoblastic neoplasia.

BACKGROUND & OBJECTIVES: Gestational trophoblastic neoplasia (GTN) is a chemosensitive malignancy with an excellent cure rate. The primary objective of the present study was to determine the predictors of chemoresistance and disease relapse, and the secondary objective was to appraise the WHO/FIGO risk scoring and course of disease in women with GTN. METHODS: In this retrospective study, case records of women treated for GTN from January 2011 to June 2019 were reviewed. For the purpose of comparison, sub-stratification of FIGO/WHO low risk group (≤6) into low (0-4) and intermediate (5-6) risk was done. Similarly, WHO high risk (≥7) group was sub-stratified into high (7-12) and ultra-high risk (≥13) groups. RESULTS: Case records of 116 patients were included: 51.7 per cent (60/116) were of low risk disease and 48.2 per cent (56/116) were of high risk disease. Chemoresistance developed in 28.4 per cent (33/116) and relapse in 10.3 per cent (12/116) cases. Risk of chemoresistance was higher in low risk (0-6) while risk of relapse was more in high risk (≥7) group. On sub-stratification, chemoresistance was more with intermediate [0-4: 28.5% (10/35), 5-6: 44% (11/25), 7-12: 22.5% (9/40), ≥13: 18.7% (3/16)] and relapse with ultra-high risk score [0-4: 5.7% (2/35), 5-6: 4% (1/25), 7-12:10% (4/40), ≥13: 31.2% (5/16)]. Age, myometrial invasion, serum beta-human chorionic gonadotropin and tumour size were not related to chemoresistance or relapse. INTERPRETATION & CONCLUSIONS: WHO risk score and presence of metastatic disease predict the probability of developing chemotherapy resistance and disease relapse. Risk of chemotherapy resistance was higher in women with intermediate-risk score (5-6), and risk of relapse was more in those with ultra-high risk score (≥13).

Screening and management of preinvasive lesions of the cervix: Good clinical practice recommendations from the Federation of Obstetrics and Gynaecologic Societies of India (FOGSI).

In India, there are marked variations in resources for cervical cancer screening. For the first time, resource-stratified screening guidelines have been developed that will be suitable for low middle-income countries with similar diversities. The current article describes the process and outcomes of these resource stratified guidelines for screening and treatment of preinvasive lesions of cervix. Evidence from literature was collated and various guidelines were reviewed by an expert panel. Based on the level of evidence, guidelines were developed for screening by human papillomavirus (HPV) testing, cytology and visual inspection after application of acetic acid (VIA), and management of screen positive lesions in different resource settings. Expert opinion was used for certain country-specific situations. The healthcare system was stratified into two resource settings - good or limited. The mode of screening and treatment for each was described. HPV testing is the preferred method for cervical cancer screening. VIA by trained providers is especially suitable for low resource settings until an affordable HPV test becomes available. Healthcare providers can choose the most appropriate screening and treatment modality. A single visit approach is encouraged and treatment may be offered based on colposcopy diagnosis ('see and treat') or even on the basis of HPV test or VIA results ('screen and treat'), if compliance cannot be ensured. The Federation of Obsterician and Gynaecologists of India Good Clinical Practice Recommendations (FOGSI) GCPR are appropriately designed for countries with varied resource situations to ensure an acceptable cervical cancer prevention strategy.

Facility preparedness for an obstetric unit during the Covid-19 pandemic.

Covid-19 infection has placed health systems under unprecedented strain and foresight for preparedness is the key factor to avert disaster. Every facility that provides obstetric service needs a certain level of preparedness to be able to handle at least Covid-suspect pregnant women awaiting test reports, who need to be managed as Covid-positive patients till reports are available. Thus, these facilities need to have triage areas and Covid-suspect labour rooms. Healthcare facilities can have designated areas for Covid-positive patients or have referral linkages with designated Covid-positive hospitals. Preparation includes structural reorganization with setting up a Covid-suspect and Covid-positive facility in adequate space, as well as extensive training of staff about infection control practices and rational use of personal protective equipment (PPE). A systematic approach involving five essential steps of making standard operating procedures, infrastructural reorganization for a triage area and a Covid-suspect labour ward, procurement of PPE, managing the personnel and instituting appropriate infection control practices can ensure uninterrupted services to patients without compromising the safety of healthcare providers.

NCCN Guidelines Insights: Multiple Myeloma, Version 1.2020.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

Pregnancy with massive splenomegaly: A case series.

Background: Pregnancy with massive splenomegaly is a rare entity and is associated with increased risk to both mother and foetus. There is paucity of studies in the literature to guide clinicians for the management of this condition. Methods: We reviewed the course of pregnancy, maternal and foetal outcomes of 5 pregnant women with massive splenomegaly who were managed in our unit during 2015-16. Results: All 5 women had anaemia and thrombocytopenia, and had different causes for splenomegaly. One patient had chronic malaria, 2 had portal hypertension with cirrhosis and the remaining 2 had non-cirrhotic portal hypertension. Life-threatening complications were present in 2 patients; one of them had severe pre-eclampsia complicated by pulmonary oedema, cardiac arrest and the other patient developed spontaneous bacterial peritonitis. Intrauterine growth restriction and meconium-stained liquor were the most common perinatal complications. Two patients had vaginal delivery and 3 required emergency caesarean section. Postpartum haemorrhage was present in 2, and the hospital stay was prolonged in all the patients. All mothers and babies were discharged in a satisfactory condition. Conclusion: Pregnancy with massive splenomegaly poses a challenge because of diverse aetiology and potentially adverse outcomes. Multidisciplinary care in a tertiary centre can help optimize the outcome.

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.

BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development.

Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology.

Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016.

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.

Multiple Myeloma, Version 2.2016: Clinical Practice Guidelines in Oncology.

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM.

Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis.

Epigenetic changes play important roles in carcinogenesis and influence initial steps in neoplastic transformation by altering genome stability and regulating gene expression. To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we modified the HpaII tiny fragment enrichment by ligation-mediated PCR assay to work with small numbers of purified primary marrow plasma cells. The nano-HpaII tiny fragment enrichment by ligation-mediated PCR assay was used to analyze the methylome of CD138(+) cells from 56 subjects representing premalignant (monoclonal gammopathy of uncertain significance), early, and advanced stages of myeloma, as well as healthy controls. Plasma cells from premalignant and early stages of myeloma were characterized by striking, widespread hypomethylation. Gene-specific hypermethylation was seen to occur in the advanced stages, and cell lines representative of relapsed cases were found to be sensitive to decitabine. Aberrant demethylation in monoclonal gammopathy of uncertain significance occurred primarily in CpG islands, whereas differentially methylated loci in cases of myeloma occurred predominantly outside of CpG islands and affected distinct sets of gene pathways, demonstrating qualitative epigenetic differences between premalignant and malignant stages. Examination of the methylation machinery revealed that the methyltransferase, DNMT3A, was aberrantly hypermethylated and underexpressed, but not mutated in myeloma. DNMT3A underexpression was also associated with adverse overall survival in a large cohort of patients, providing insights into genesis of hypomethylation in myeloma. These results demonstrate widespread, stage-specific epigenetic changes during myelomagenesis and suggest that early demethylation can be a potential contributor to genome instability seen in myeloma. We also identify DNMT3A expression as a novel prognostic biomarker and suggest that relapsed cases can be therapeutically targeted by hypomethylating agents.

F-18 FDG-PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma.

Total lymphoid irradiation (TLI) followed by high-dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high-dose chemotherapy and aHSCT. Pre-transplant fludeoxyglucose positron emission tomography (FDG-PET) studies were scored on the 5-point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10-year progression-free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5-year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0·09 and P = 0·007, respectively). TLI and aHSCT yields excellent disease control and long-term survival rates for patients with relapsed/refractory HL, including those with high-risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome.

Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy.

Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, we include evidence of the antimyeloma effects elicited against both cell lines and primary cells by the FDA-approved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer.

A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma.

This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

Clinical profile & outcome of H1N1 infected pregnant women in a tertiary care teaching hospital of northern India.

BACKGROUND & OBJECTIVES: H1N1 influenza is a recognized cause of febrile respiratory infection worldwide. There are not many studies to show its impact on pregnancy. In the present study we aimed to assess clinical characteristics, obstetric and perinatal outcome of pregnant women with H1N1 infection. METHODS: A retrospective observational study was conducted at a tertiary care teaching hospital in New Delhi, India. A total of 24 pregnant women microbiologically positive for H1N1 were included. Maternal characteristics and outcome were recorded. Perinatal outcome which was defined as presence of any of the indicators such as abortion, preterm delivery, intrauterine death and neo natal death was noted. RESULTS: The mean age of the study group was 25.2 ± 3 yr with a mean gestational age of 34.9 ± 4.6 wk. Six patients (25%) had associated co-morbidities. Nine patients (37.5%) presented within 48 h of onset of symptoms and 15 (62.5%) reported after 48 h. In 17 (70.83%) patients treatment was delayed by >48 h. ICU admission was needed in 20.8 per cent patients and mortality rates was 8.3 per cent. There were seven cases of adverse perinatal outcome. INTERPRETATION & CONCLUSIONS: The presenting symptoms of pregnant women with H1N1 were similar to that of general population. Acquiring infection in late trimester, late initiation of antiviral treatment and presence of co-morbid illness were high risk factors for developing critical illness. Pregnant women with suspected H1N1 influenza should be started on antiviral therapy at the earliest. This is likely to help reduce the ICU admission rates and mortalities in this group of women.

Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3.

A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum ß(2)-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.

Multiple myeloma, version 1.2013.

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

Low-grade extrauterine endometrial stromal sarcoma arising from vaginal endometriosis: a case report and literature review.

Extrauterine endometrial stromal sarcoma arising from malignant transformation of the vagina is an extremely rare condition. The diagnosis is often difficult as the symptomatology and pathological features overlap with that of pelvic endometriosis. A 38 years old female presented with complaints of dyspareunia, dysmenorrhea, and painful defecation along with blood-stained vaginal discharge for a year. Examination revealed the presence of multiple brownish irregular nodules in posterior vaginal fornix and fixed tender nodules which on biopsy revealed florid vaginal endometriosis. She improved symptomatically on medical therapy. After 18 months of diagnosis, she presented again with a necrotic growth in posterior fornix, which on repeat biopsy revealed a low-grade endometrial stromal sarcoma. Laparotomy revealed a 7×5 cm mass in the pouch of Douglas, infiltrating the posterior vaginal wall and rectum. A complete cytoreductive surgery with retrograde hysterectomy, excision of posterior vaginal wall and rectosigmoid resection was done. The patient is disease-free at a follow-up of 65 months.