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Human papillomavirus (HPV) infection is linked with several cancers such as cancer cervix, vagina, vulva, head and neck, anal, and penile carcinomas. Although there is a proven association of HPV with these cancers, questions regarding HPV testing, vaccination, and treatment of HPV-related cancers continue to remain unanswered. The present article provides an overview of the HPV-associated cancers. [ABSTRACT FROM AUTHOR]

Lymphomas are diverse group of neoplasm affecting the lymphoreticular system. Diffuse large B cell lymphoma is the most frequently diagnosed type of non-Hodgkin lymphoma and is the fifth most frequent malignancy, accounting for about 40% of cases reported. In the present case report a 40 year old female patient complains of swelling on right side of face since 45 days and gradually increased to present size. Intra-orally an ulcero-proliferative growth was present on the right side of hard palate. Incisional biopsy was suggestive of Lymphoproliferative disorder. Panel of immunohistochemical antibodies were used; which showed positivity for CD45, PAX5, Bcl2, Ki67, CD138 and negativity for CD3, CD10, CD20 and CD30. Therefore through routine standard hematoxylin and eosin staining a clear cut diagnosis of specific lymphoma was difficult to obtain and thus immunohistochemistry plays an important role in confirming the pinpoint diagnosis. [ABSTRACT FROM AUTHOR]

Background & objectives: Chemoradiation is the standard therapy for locally advanced invasive cervical cancer and response to treatment determines the outcome. Cancer stem cells (CSCs) and epithelial– mesenchymal transition (EMT) play a role in response to treatment and hence the aim of this study was to evaluate if their levels in pre-treatment biopsies by immunohistochemistry (IHC) could predict response to treatment and outcome. Methods: The study comprised 60 patients with FIGO Stage IIB/III invasive cervical carcinoma treated by chemoradiation. They were divided into two groups based on their clinical outcome: group 1, 30 patients who had no evidence of disease at 48 month follow up and group 2, 30 patients who had disease relapse within 6-12 months of treatment completion. IHC was performed for CSC markers (ALDH1, CD133, Nanog and Oct-4), EMT markers (E-cadherin and vimentin) and squamocolumnar junction (KRT7) markers and H-scores determined. Intergroup comparison was performed. The expression of these markers was also evaluated in histological sections of cervical pre-cancer (CIN1 and CIN3) in comparison to normal cervix. Results: Cervical Intraepithelial Neoplasia grade 3 (CIN3) showed high expression of ALDH1 and KRT7 as compared to normal cervical epithelium. Aldehyde dehydrogenase 1 (ALDH1) and CD133 were overexpressed in 70 and 24 per cent cervical carcinoma cases whereas E-cadherin showed reduced expression in invasive carcinoma as compared to normal controls. ALDH1 overexpression was significantly associated with disease relapse in invasive cervical carcinoma treated by chemoradiation (P<0.01). Interpretation & conclusions: Determination of ALDH1 levels in pre-treatment cervical biopsies of invasive cervical carcinoma may be useful for prediction of response to chemoradiation, with high levels predicting for a poor response. [ABSTRACT FROM AUTHOR]

To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas. [ABSTRACT FROM AUTHOR]

Six teaching courses with focus on 3D IGABT for cervical cancer were conducted in India between 2017 & 2023, as collaborative effort of AROI and ESTRO. The purpose is to report impact of teaching courses, as observed from pre-course surveys and a recent master survey of all course participants. Pre-course surveys were conducted before each of the six courses, where in information related to pre-course BT practice of each participating team (physician and physicist) was collected. Recently, a detailed online master survey was conducted to understand impact of courses on BT approach and practice. A total of 456 participants (344 physicians and 112 physicists) who were responsible for treating cervical cancer patients attended the courses. As per pre-course surveys, BT planning was frequently done using X rays, CT and MRI by 25%, 75% and 10% of participants respectively. Hybrid IC+IS and 3D dose prescription (to high-risk CTV) were commonly used by 31% and 35% participants. Among 456 participants, 104 teams (one team per institute was allowed to respond) from 104 centres responded (83 physicians and 21 physicists). Of these, 101 (97.1%) continued to practice cervical cancer brachytherapy at the time of the survey. Percentage-wise implementation/utilisation of various critical processes/resources in cervical cancer brachytherapy workflow at the time of master survey are presented in Figure 1 (upper panel).Teaching course empowered participants in implementing/ improvising critical processes, like examination under anaesthesia (14%), clinical drawings (55%), ultrasound guidance (23%), IC+IS (32%), target volume delineation (46%) & volume-based prescription (39%); however, these processes could be sustained in 8%, 32%, 17%, 25%, 41% and 33% centres, respectively,. (FIgure1 lower panel). Frequent reasons cited for inability to implement and sustain these critical processes include heavy patient load, lack of availability of infrastructure (dedicated ultrasonography, compatible applicators, access to MRI etc), suboptimal human resources (Anesthesiologists, Radiologists, Radiation Oncologists) etc.Among the participants, 94% and 87% felt that their knowledge and practice of BT improved substantially after the course, respectively. About 94% of the participants expressed interest in collaborative prospective research related to IGABT for cervical cancer. Survey results suggest that the teaching courses substantially improved clinical workflow, use of ultrasonography for guidance, utilisation of pre-BT MR/MR/CT-TRUS based BT, advanced BT applications (IC + IS), target volume delineation and volumetric dose prescription. Majority of centres appear to be interested in exploring prospective research related to IGABT. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to estimate and incorporate rotational error to translational error for clinical target volume (CTV) to planning target volume (PTV) margin calculations for non-6D couch. Materials and Methods: The study involved cone-beam computed tomography (CBCT) images of the patients who already had treatment in Varian Trilogy Clinac. The different sites studied were brain (70 patients, 406 CBCT images), head and neck (72 patients, 356 CBCT images), pelvis (83 patients, 606 CBCT images), and breast (45 patients, 163 CBCT images). Rotational and translational patient shifts were measured with the help of Varian eclipse offline review. The rotational shift introduces translational shift as it resolved along craniocaudal and mediolateral directions. Both rotational and translational error follow normal distribution and their respective errors were used to calculate CTV-PTV margin using van Herk model. Results: Rotational effect on CTV-PTV margin contribution increases with increase in size of CTV. It also increases with increase in distance between center of mass of CTV and isocenter. These margins were more pronounce in single isocenter supraclavicular fossa-Tangential Breast plans. Conclusions: There is always rotational error in all sites and it causes shift and rotation of the target. Rotational contribution to the CTV-PTV margin depends upon geometric center of CTV and isocenter distance and also on size of CTV. CTV-PTV margins should incorporate rotational error along with transitional error. [ABSTRACT FROM AUTHOR]

Purpose: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation.Methods and Materials: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TSD) and at BT (TSBT) by the sum of points obtained from the 8 locations at the 2 occasions.Results: Median TSD and TSBT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTVHR), CTVHR D90 (minimal dose to 90% of the target volume), D2cm3 bladder (minimal dose to the most exposed 2 cm3 of the bladder), and D2cm3 rectum. TS regression (TSBT≤5) was associated with improved local control and survival and with less morbidity compared with patients with TSBT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment.Conclusions: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate patient- and treatment-related risk factors for late persistent fatigue within the prospective, multicenter EMBRACE-I study.Methods and Materials: Fatigue was prospectively assessed (Common Terminology Criteria for Adverse Events, version 3) at baseline and during regular follow up in 993 patients with locally advanced cervical cancer after treatment with chemoradiotherapy and magnetic resonance imaging-guided brachytherapy. Risk factors for baseline and late persistent fatigue were evaluated with multivariable logistic regression. Late persistent fatigue was defined when either grade ≥1 or ≥2 was scored in at least half of the follow ups.Results: The median follow-up time was 57 months. Baseline fatigue grade ≥1/≥2 (35.8%/6.3%, respectively) was associated with preexisting comorbidities, World Health Organization performance status, being underweight, severe pain, and tumor volume. Late persistent grade ≥1/≥2 fatigue (36.3%/5.8%, respectively) was associated with patient-related factors (baseline fatigue, younger age, obesity) along with the size of irradiated volumes and the level of radiation doses from external beam radiation therapy (EBRT) and brachytherapy (EBRT: V43Gy, V57Gy; EBRT + brachytherapy: V60Gy equivalent dose in 2-Gy fractions). Large-volume lymph node (LN) boost increased the risk for late persistent fatigue grade ≥2 by 18% and 5% in patients with and without baseline fatigue, respectively, compared with no LN boost. The risk for late persistent fatigue grade ≥1 increased by 7% and 4% with V43Gy <2000 cm³ versus >3000 cm³ in patients with and without baseline fatigue, respectively. Late persistent grade ≥1 fatigue occurred in 13% of patients without late persistent organ-related symptoms (gastrointestinal, genitourinary, and vaginal) versus 34% to 43%, 50% to 58%, and 73% in patients suffering from persistent symptoms involving 1, 2, or 3 organs, respectively.Conclusions: Late persistent fatigue occurs in a considerable number of patients after chemoradiotherapy, and is associated with patient-related factors, the size of volumes irradiated to intermediate and high EBRT and brachytherapy doses, and other persistent organ-related morbidity. These findings support the importance of ongoing efforts to better tailor the target dose and reduce irradiation of healthy tissue without compromising target coverage, using highly conformal EBRT and brachytherapy techniques. [ABSTRACT FROM AUTHOR]

Purpose: The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer.Methods and Materials: Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups.Results: The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms to varying degrees. Among treatment-related factors, rectum D2cm3 and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D2cm3 correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps.Conclusions: The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D2cm3, ICRU RV-RP , and bowel D2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate patient-reported sexual outcomes after chemoradiation therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer in the observational, prospective, multicenter EMBRACE-I study.Methods and Materials: Sexual outcomes were assessed prospectively with the European Organization for Research and Treatment of Cancer Qualify of Life Questionnaire (EORTC-QLQ-CX24) at baseline and follow-up. Crude incidence and prevalence rates of sexual activity, vaginal functioning problems (dryness, shortening, tightening, pain during intercourse), and sexual enjoyment were evaluated. Associations between pain during intercourse and vaginal functioning problems or sexual enjoyment were calculated, pooling observations over all follow-ups (Spearman correlation coefficient). In patients who were frequently sexually active (≥50% of follow-ups), the effects of regular hormonal replacement therapy (HRT) on vaginal functioning problems were evaluated (Pearson χ2).Results: The analysis involved 1045 patients with a median follow-up of 50 months. Sexual activity was reported by 22% of patients at baseline and by 40% to 47% of patients during follow-up (prevalence rates). Vaginal functioning problems in follow-up were dryness (18%-21%), shortening (15%-22%), tightening (16%-22%), pain during intercourse (9%-21%), and compromised enjoyment (37%-47%). Pain during intercourse was significantly associated with vaginal tightening (r = 0.544), shortening (r = 0.532), and dryness (r = 0.408) and negatively correlated with sexual enjoyment (r = -0.407). Regular HRT was associated with significantly less vaginal dryness (P = .015), shortening (P = .024), pain during intercourse (P = .003), and borderline higher sexual enjoyment (P = .062).Conclusions: Vaginal functioning problems are associated with pain and compromised sexual enjoyment. Further effort is required for the primary prevention of vaginal morbidity with dose optimization and adaptation. Secondary prevention strategies, including HRT for vaginal and sexual health after radiation therapy in locally advanced cervical cancer, should be considered and sexual rehabilitation programs should be developed further. [ABSTRACT FROM AUTHOR]

• Nodal disease, tumour width and local failure are risk factors for NF post-treatment for LACC. • Any CI nodes without PAO nodes' and 'any PAO nodes' are stronger risk factors than 'small pelvis' nodes. • Elective PAO-irradiation was associated with significantly less NF PAO. To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. Data for pelvic NF and para-aortic (PAO) NF (NF PAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). 1338 patients with 152 NF and 104 NF PAO events were analysed with a median follow-up of 34.2 months (IQR 16.4–52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NF PAO (HR 0.53, 95%-CI 0.28–1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NF PAO (HR 0.38, 95%-CI 0.17–0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF. In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NF PAO , particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis. [ABSTRACT FROM AUTHOR]

• CT Based Contouring recommendations in IGABT for cervical cancer is a collaborative effort of 13 experts from Indian Brachytherapy Society (IBS), GEC-ESTRO and American Brachytherapy Society (ABS). • The recommendations are comprehensive, providing a pragmatic solution to contour target on CT Imaging at BT in different prevailing clinic-radiological environments which have not been comprehensively addressed. • We expect each institution with no access to MRI at BT to review their working environment and utilize appropriate definitions for defining the target to implement CT based IGABT for cervical cancers. MR Imaging is regarded as the gold standard for Image Gudied Adaptive Brachytherapy (IGABT) for cervical cancer. However, its wide applicability is limited by its availability, logistics and financial implications. Use of alternative imaging like CTand Ultrasound (US) for IGABT has been attempted. In order to arrive at a systematic, uniform and international approach for CT based definition and contouring of target structures, GEC ESTRO, IBS and ABS agreed to jointly develop such recommendations based on the concepts and terms as published in the ICRU Report 89. The minimum requirements are clinical examination & documentation, CT or MR imaging at diagnosis and at a minimum, CT imaging with the applicator in place. The recommendations are based on (i) assessment of the GTV at diagnosis and at brachytherapy, (ii) categorizing the response to external radiation into different clinical remission patterns, (iii) defining various clinico-radiological environments and (iv) definition & delineation of a target on CT imaging at the time of brachytherapy with the applicator in situ. CT based target contouring recommendations based on 4 remission categories within 8 defined environments, aim at improving the contouring accuracy for IGABT using CT, US and MRI as available. For each clinico-radiological environment, there is an attempt to minimize the specific uncertainties in order to arrive at the best possible contouring accuracy. Evaluating feasibility & reproducibility, to achieve a benchmark towards a gold standard MR IGABT and further clinical research including outcomes with CT Based IGABT will become the next steps. [ABSTRACT FROM AUTHOR]

• Urinary morbidity after treatment of locally advanced cervical cancer is prevalent. • Bladder dose constraints based on a high level clinical evidence are not available. • EMBRACE I provides prospective morbidity data for analysis in a large cohort. • Individual physician and patient reported urinary endpoints were analysed in EMBRACE I. • Bladder fistula, bleeding and cystitis showed dose–effect with bladder D 2cm3. To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse. Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3–120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D 2cm3 correlated with G ≥ 2 fistula, bleeding and cystitis, while ICRU bladder point dose correlated with EORTC pain "quite a bit" or worse. An increase from 75 Gy to 80 Gy in bladder D 2cm3 resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis. Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose–effect was established with bladder D 2cm3 , reinforcing the importance of continued optimization during individualized IGABT planning. [ABSTRACT FROM AUTHOR]

• Urinary side effects after radiotherapy can rely on different bladder substructures. • EMBRACE I provides prospective morbidity data to study individual urinary symptoms. • Frequency and incontinence are frequent side effects in cervix cancer radiotherapy. • Limited clinical evidence supports the predictive value of ICRU Bladder point dose. • This analysis showed correlation of ICRU Bladder point dose with incontinence. To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups. Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D 2cm3. The 5-year actuarial estimate of G ≥ 2 incontinence increased from 11% to 20% with ICRU-BP doses > 75 Gy compared to ≤ 65 Gy. Frequency showed weaker associations with dose. ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose–effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes. [ABSTRACT FROM AUTHOR]

Highlights • Nodal failure rate after chemo-radiation and MRI guided BT is 11%. • Nodal failure rates for the N− and N+ group were 7 and 16% • Complete remission after treatment was seen in 95% of N+ patients. • Nodes at diagnosis were mainly located in the pelvis, nodal failures more often in PAO. • Forty-one percent of nodal failure patients had failure outside the treated volume. Abstract Purpose/Objective(s) To investigate the patterns of nodal failure in patients enrolled in the international multicentre EMBRACE study. Materials/Methods Nodal disease at diagnosis (N−, N+) and nodal failure were analysed per region (NF) (pelvic (parametrial, common iliac, internal/external iliac), inguinal and para-aortic (PAO)) in 1338 patients. Treatment consisted of chemo-radiation and MRI guided brachytherapy. PAO radiotherapy and/or nodal boost was left to the treating centre. At time of diagnosis 52% of patients had pathologic nodes. Frequency analyses were performed in relation to patient, primary tumour and nodal disease characteristics, and treatment related factors. Results Median follow up was 34 months and 83% of NF occurred within 24 months. At diagnosis 99% of the N+ patients had pathologic nodes in the pelvis and 14% in the PAO. NF pelvic and NF PAO were reported in 55% and 68% of patients with NF, respectively. Overall NF was reported in 152 patients (11%); 7 and 16% for N- and N+ patients. Of the patients with NF, 41% were located outside the elective target (39% PAO), 40% inside and 35% inside the nodal boost target. Twelve percent of N+ patients that received a nodal boost had a NF inside the nodal boost target. Conclusion Within the EMBRACE study cohort the overall number of patients developing nodal failure is low, significantly lower for N− compared to N+ patients. Pathological nodes at diagnosis are mainly located in the pelvis, whereas nodal failures are more often reported in the PAO region. About 40% of all nodal failures were reported outside the treatment targets. [ABSTRACT FROM AUTHOR]

• Impact of morbidity on quality of life (QOL) of cancer survivors depends on severity and persistence. • Prospective data from EMBRACE-I allowed to assess the association for cervical cancer survivors. • All persistent symptoms were significantly associated with QOL aspects, but with different magnitude. • Role functioning and global health/general QOL were the most impaired aspects reported by patients. • Persistent pain and fatigue were more detrimental compared to other organ-related symptoms. To quantify the association of persistent morbidity with different aspects of quality of life (QOL) in locally advanced cervical cancer (LACC) survivors. Longitudinal outcome from the EMBRACE-I study was evaluated. Patient-reported symptoms and QOL were prospectively scored (EORTC-C30/CX24) at baseline and regular follow-ups. Physician-assessed symptoms were also reported (CTCAEv.3). Persistent symptoms were defined if present in at least half of the follow-ups. QOL items were linearly transformed into a continuous scale. Linear mixed-effects models (LMM) were applied to evaluate and quantify the association of persistent symptoms with QOL. Overall QOL deterioration was evaluated by calculating the integral difference in QOL over time obtained with LMM for patients without and with persistent symptoms. Out of 1416 patients enrolled, 741 with baseline and ≥ 3 late follow-ups were analyzed (median 59 months). Proportions of persistent EORTC symptoms ranged from 21.8 % to 64.9 % (bowel control and tiredness). For CTCAE the range was 11.3–28.6 % (limb edema and fatigue). Presence of any persistent symptom was associated with QOL, although with varying magnitude. Role functioning and Global health/QOL were the most impaired aspects. Fatigue and pain showed large differences, with reductions of around 20 % for most of the QOL aspects. Among organ-related symptoms, abdominal cramps showed the largest effect. Persistent symptoms are associated with QOL reductions in LACC survivors. Organ-related symptoms showed smaller differences than general symptoms such as fatigue and pain. In addition to optimizing treatment to minimize organ-related morbidity, effort should be directed towards a more comprehensive and targeted morbidity management. [ABSTRACT FROM AUTHOR]

Purpose To quantify the gross tumor volume at diagnosis (GTV D ) and high-risk clinical target volume (CTV HR ) at brachytherapy (BT) and describe subgroups of patients with different patterns of response to chemoradiotherapy (CRT) in patients with FIGO stage IIB and IIIB cervical cancer treated with image-guided adaptive brachytherapy (IGABT). Additionally, to evaluate the feasibility of IGABT achieving adequate target coverage in these groups. Materials and methods Patients with FIGO stage IIB and IIIB cervical cancer enrolled in the EMBRACE study were analyzed. T2-weighted MRI scans were obtained at diagnosis and at BT. GTV D and CTV HR were defined as per the GEC ESTRO recommendations. Patients were classified taking into account that initial tumor volume and response to CRT represented by the volume of residual disease (CTV HR ) and extent of residual parametrial disease are all major factors determining local dose delivery by BT, local control, and overall disease outcome. These factors were quantified applying the following criteria: (1) volume of the GTV D relative to the median volume of the GTV D ; (2) the ratio (R) of CTV HR to GTV D for each patient; (3) the extent of residual parametrial disease at the time of BT. Accordingly, patients were classified into six groups (G1–G6): stage IB 1 -like tumors (G1), tumors with good response and any size (G2), small tumors with moderate response (G3), large tumors with moderate response (G4), tumors with poor response (G5) and those with progressive disease (G6). Tumor and treatment characteristics were then compared among the first five groups (only 3 patients were allocated to G6). Results A total of 481 patients were evaluated. The number of patients in the 6 groups were 55, 78, 123, 147, 75 and 3, respectively. The mean (SD) GTV D was 43.6 (32.8) cm 3 and the mean (SD) CTV HR was 31.6 (16.1) cm 3 . The mean GTV D and CTV HR were 12.6 cm 3 and 23.7 cm 3 in G1 ( R > 1.1), 47.5 cm 3 and 25.3 cm 3 in G2 ( R < 0.9), 23.9 cm 3 and 29.9 cm 3 in G3 (R 0.9–1.1), 73.4 cm 3 and 38.5 cm 3 in G4 (R 0.9–1.1), 79.4 cm 3 and 59.5 cm 3 in G5 ( R > 1.1), respectively. Parametrial disease extent at BT was as follows: no involvement in G1 and G2, proximal at most in G3 and G4, distal or to the pelvic wall in G5, progressive in G6. The use of interstitial needles was progressively higher among the groups (mean 0, 0, 2, 3, 6 in G1–5, P < 0.001). The mean GTV BT D 100 in G1-5 was 103.1 Gy, 91.8 Gy, 93.5 Gy, 88.3 Gy and 87.1 Gy. The mean CTV HR D 90 in G1-5 was 95.1 Gy, 92.1 Gy, 92.6 Gy, 87.6 Gy and 88.4 Gy. Conclusions In patients with FIGO stage IIB and IIIB disease, intra-FIGO stage heterogeneity and overlap between the two stages exist with respect to tumor volume, treatment response and extent of parametrial disease at BT. Taking into account GTV D , parametrial disease at BT and the ratio of CTV HR /GTV D , five major groups exist. These enable prediction of GTV BT and CTV HR dose coverage through BT. IGABT, as performed in EMBRACE, accommodates to a considerable degree for the different variants of tumor regression in these groups through adaptation of the treatment technique including the use of needles. However, major variations remain at present with regard to dose to GTV BT and to CTV HR , which are most pronounced in G4 and G5. This new classification will be validated in future in regard to clinical outcome in EMBRACE. [ABSTRACT FROM AUTHOR]

Background/purpose To identify risk factors for vaginal stenosis and to establish a dose–effect relationship for image-guided brachytherapy in locally advanced cervical cancer. Materials/Methods Patients from the ongoing EMBRACE study with prospectively assessed morbidity (CTCAEv3.0) at baseline and at least one follow-up were selected. Patient-, disease- and treatment characteristics were tested as risk factors for vaginal stenosis G ⩾ 2 in univariate and multivariable analyses (Cox proportional hazards model) and a dose–effect curve was deduced from the estimates. The ICRU rectum point was used to derive the recto-vaginal reference point dose. Results In 630 patients included (median follow-up 24 months), 2-year actuarial estimate for vaginal stenosis G ⩾ 2 was 21%. Recto-vaginal reference point dose (HR = 1.025, p = 0.029), external beam radiotherapy (EBRT) dose >45 Gy/25 fractions (HR = 1.770, p = 0.056) and tumor extension in the vagina (HR = 2.259, p ⩽ 0.001) were risk factors for vaginal stenosis, adjusted for center reporting effects. Based on the model curve, the risk was 20% at 65 Gy, 27% at 75 Gy and 34% at 85 Gy (recto-vaginal reference point dose). Conclusion Keeping the EBRT dose at 45 Gy/25 fractions and decreasing the dose contribution of brachytherapy to the vagina decrease the risk of stenosis. A planning aim of ⩽65 Gy EQD2 (EBRT + brachytherapy dose) to the recto-vaginal reference point is therefore proposed. [ABSTRACT FROM AUTHOR]

Purpose/Introduction To assess the variation in the doses received by the organs at risk (OARs) that can occur during treatment planning of cervical cancer by image-based brachytherapy. Methods and Materials After intracavitary application, two sets of images—CT and MRI—were obtained. The two sets of images were fused together with respect to the applicator. Contouring was done separately on CT and MR images. Dose received by the OARs on CT images with respect to the plans made on the MR images was estimated and compared with those on the MR images. Results Although there was always a difference between the dose received by the OARs based on the CT and MRI contours, it was not significant for the bladder and rectum; 2 cc doses differed by 0.49 Gy (±0.44) p = 0.28 for the bladder and 0.30 Gy (±0.29) p = 0.16 for the rectum. The 1 cc and 0.1 cc differences were also not significant. However for the sigmoid colon, there was significant intrafraction variation in the 2 cc doses 0.61 (±0.6) p = 0.001, 1 cc doses 0.73 (±0.67) Gy p = 0.00, and 0.1 cc dose 0.97 (±0.93) Gy p = 0.009. Conclusions The variation in the doses to the OARs must be considered while weighing target coverage against overdose to the OARs. Although not significant for the bladder and rectum, it was significant for the sigmoid colon. Estimated doses to OARs on the planning system may not be the same dose delivered at the time of treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of accelerated fractionation with concomitant boost for organ preservation as compared to concurrent chemoradiation in patients with locally advanced carcinoma of larynx and hypopharynx. Materials and methods: Forty newly diagnosed patients of locally advanced carcinoma of larynx and hypopharynx were selected following a pre-decided inclusion and exclusion criteria. They were randomized to receive either concurrent chemoradiation using Injection Cisplatin 100mg/m2 every 3weeks and external radiation 66Gy/6.5weeks/33# (Arm A) or accelerated radiotherapy with concomitant boost (Arm B) delivering 45Gy/5weeks/25# to entire tumour bearing region and a boost of 22.5Gy/3weeks/15# to the gross tumour. The boost was given as a second daily dose during the last 3weeks of treatment and the BED of radiation given to both arms were comparable. The primary endpoint was to assess the functional organ preservation at one year. The acute toxicities of treatment and change in quality of life were also compared between the two arms. The statistical significance was calculated using SPSS v18. Results: All the patients completed treatment as planned. Only one patient in Arm B had residual disease requiring laryngectomy. Functional organ preservation with good voice and swallowing functions were seen in 90% in Arm A and 95% in Arm B. Statistically significant difference was seen in Grade 3 dysphagia scoring, Arm A 60%, Arm B 30% (p =0.024). All other acute toxicities and quality of life scores were comparable. Conclusion: This preliminary analysis suggests that accelerated radiation with concomitant boost is as effective as chemoradiation for functional organ preservation in locally advanced cancers of larynx and hypopharynx. A bigger study is underway to see if concomitant boost can be offered as an alternative to chemoradiation in these patients. [Copyright &y& Elsevier]

Purpose: BIOEMBRACE was designed to study the impact of biomarkers in addition to clinicopathological factors on disease outcomes in patients treated with chemoradiation and magnetic resonance imaging (MRI)-guided brachytherapy (BT) for locally advanced cervical cancer in the EMBRACE study., Methods and Materials: Between 2018 and 2021, 8 EMBRACE-I sites contributed tumor tissue for the immunohistochemistry of p16, PD-L1, and L1CAM. These biomarkers and clinicopathological factors (International Federation of Gynecology and Obstetrics 2009 stage, nodal status, histology, and necrosis on MRI) were analyzed to predict poor response at BT (high-risk clinical target volume [HR-CTV] ≥ 40 cc) at BT) and 5-year local control, pelvic control, and disease-free survival. Interaction between p16, PD-L1, radiation therapy dose (HR-CTV D90), and disease outcomes was investigated. Univariable and multivariable analyses were performed., Results: Two hundred sixty-four patients were included. The median HR-CTV D90 was 89 Gy (86-95). P-16 positive status, PD-L1 > 1%, and L1CAM ≥ 10% was noted in 86.6%, 20.1%, and 17.8% of patients, respectively. P16 negative status (odds ratio, 2.0; 95% CI, 1.0-5.7; P = .04) and necrosis on MRI (odds ratio, 2.1; 95% CI, 1.1-4.3; P < .02) independently predicted for HR-CTV ≥ 40 cc, as did the International Federation of Gynecology and Obstetrics stage and tumor width >5 cm. PD-L1 > 1% was associated with reduced local (82% vs 94%; P = .02) and pelvic control (79% vs 89%; P = .02). HR-CTV D90 < 85 Gy was associated with inferior 5-year local control in p16-positive patients, especially if PD-L1 was coexpressed. On multivariable analysis, PD-L1 > 1% was the only independent factor for 5-year local control (hazard ratio, 3.3; P = .04) and L1CAM ≥ 50% for pelvic control (hazard ratio, 5.5; 95% CI, 1.3-23.3; P = .02)., Conclusions: P16 negative status and tumor necrosis on MRI are independently associated with poor response to chemoradiation, whereas PD-L1 > 1% and L1CAM ≥ 50% have an independent impact on local and pelvic control, suggesting an impact of biomarker expression on outcomes. Further validation is needed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to provide risk estimations for vaginal morbidity with regard to vaginal dilation (summarizing the use of dilators and/or sexual activity) in patients with locally advanced cervical cancer treated with definitive radiochemotherapy and image guided adaptive brachytherapy within the prospective, multi-institutional EMBRACE-I study., Methods and Materials: Physician-assessed vaginal morbidity (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0), use of vaginal dilators, and patient-reported sexual activity (EORTC-CX24) were prospectively assessed at baseline and during regular follow-ups. Frequency analysis for vaginal dilation was performed in a subcohort of patients with ≥3 follow-ups. Regular dilation was defined if reported in ≥50% of follow-ups, and no/infrequent dilation if reported in <50%. Actuarial estimates were calculated with Kaplan-Meier method; comparisons were evaluated with the log-rank test. Univariate and multivariable Cox proportional hazard regressions were used to evaluate risk factors for vaginal stenosis G≥2., Results: The EMBRACE-I study included a total of 1416 patients (2008-2015); 882 were evaluated in the present report with a median follow-up of 60 months. Of those, 565 (64%) reported regular dilation. This was associated with a significantly lower 5-year risk of vaginal stenosis G≥2 compared with no/infrequent dilation (23% vs 37%, P ≤ .001). This univariate finding was confirmed by multivariable analysis, after adjusting for other risk factors (hazard ratio, 0.630; P = .001). Regular vaginal dilation was also associated with a significantly higher risk for vaginal dryness G≥1 (72% vs 67%, P = .028) and bleeding G≥1 (61% vs 34%, P ≤ .001)., Conclusions: Vaginal stenosis represents irreversible fibrotic changes that can cause pain during gynecologic examination and dyspareunia in locally advanced cervical cancer patients survivors. Regular vaginal dilation (defined as the use of dilators and/or sexual activity) is associated with a significantly lower risk for G≥2 vaginal stenosis, suggesting a potential improvement of vaginal patency. It is also associated with a significantly higher risk for mild G≥1 dryness and bleeding (no higher risk for G≥2), which can be clinically managed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Turner syndrome (TS) and Noonan syndrome (NS) are distinct genetic conditions with highly similar physical and neurodevelopmental phenotypes. TS is caused by X chromosome absence, whereas NS results from genetic mutations activating the Ras-mitogen-activated protein kinase signaling pathway. Previous neuroimaging studies in individuals with TS and NS have shown neuroanatomical variations relative to typically developing individuals, a standard comparison group when initially examining a clinical group of interest. However, none of these studies included a second clinical comparison group, limiting their ability to identify syndrome-specific neuroanatomical phenotypes., Methods: In this study, we compared the behavioral and brain phenotypes of 37 girls with TS, 26 girls with NS, and 37 typically developing girls, all ages 5 to 12 years, using univariate and multivariate data-driven analyses., Results: We found divergent neuroanatomical phenotypes between groups, despite high behavioral similarities. Relative to the typically developing group, TS was associated with smaller whole-brain cortical surface area (p ≤ .0001), whereas NS was associated with smaller whole-brain cortical thickness (p = .013). TS was associated with larger subcortical volumes (left amygdala, p = .002; right hippocampus, p = .002), whereas NS was associated with smaller subcortical volumes (bilateral caudate, p ≤ .003; putamen, p < .001; pallidum, p < .001; right hippocampus, p = .015). Multivariate analyses also showed diverging brain phenotypes in terms of surface area and cortical thickness, with surface area outperforming cortical thickness at group separation., Conclusions: TS and NS have syndrome-specific brain phenotypes, despite their behavioral similarities. Our observations suggest that neuroanatomical phenotypes better reflect the different genetic etiologies of TS and NS and may be superior biomarkers relative to behavioral phenotypes., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: The global cervical cancer burden is disproportionately high in low- and middle-income countries (LMICs), and outcomes can be governed by the accessibility of appropriate screening and treatment. High-dose-rate (HDR) brachytherapy plays a central role in cervical cancer treatment, improving local control and overall survival. The American Brachytherapy Society (ABS) and Indian Brachytherapy Society (IBS) collaborated to provide this succinct consensus statement guiding the establishment of brachytherapy programs for gynecological malignancies in resource-limited settings., Methods and Materials: ABS and IBS members with expertise in brachytherapy formulated this consensus statement based on their collective clinical experience in LMICs with varying levels of resources., Results: The ABS and IBS strongly encourage the establishment of HDR brachytherapy programs for the treatment of gynecological malignancies. With the consideration of resource variability in LMICs, we present 15 minimum component requirements for the establishment of such programs. Guidance on these components, including discussion of what is considered to be essential and what is considered to be optimal, is provided., Conclusions: This ABS/IBS consensus statement can guide the successful and safe establishment of HDR brachytherapy programs for gynecological malignancies in LMICs with varying levels of resources., (Copyright © 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Extramammary Paget's disease (EMPD) is a rare intraepithelial adenocarcinoma. To increase awareness and knowledge regarding this rare dermatosis, we hereby reported a case of ulcerated plaque on genitalia.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function., (© 2023. The Author(s).)

Purpose: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study., Materials and Methods: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis., Results: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTV HR ), maximum tumor dimension, CTV HR > 45 cm 3 , overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTV HR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology., Conclusion: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer., Competing Interests: Maximilian P. SchmidHonoraria: ElektaResearch Funding: Elekta (Inst), Varian Medical Systems (Inst)Patents, Royalties, Other Intellectual Property: Patent: US20170120072 Umesh MahantshettyConsulting or Advisory Role: AstraZenecaResearch Funding: Varian Medical Systems (Inst) Kari TanderupResearch Funding: Varian Medical Systems (Inst), Elekta (Inst) Peter HoskinResearch Funding: Varian Medical Systems (Inst), Astellas Pharma (Inst), Bayer (Inst), Roche (Inst), Pfizer (Inst), Elekta (Inst), Bristol Meyers (Inst) Bradley R. PietersConsulting or Advisory Role: BD Bard (Inst)Research Funding: ElektaTravel, Accommodations, Expenses: BD BardOther Relationship: Elekta (Inst) Remi NoutConsulting or Advisory Role: Merck KGaA (Inst)Research Funding: Varian Medical Systems (Inst), Elekta (Inst), Accuray (Inst) Nicole NesvacilHonoraria: ElektaConsulting or Advisory Role: ElektaTravel, Accommodations, Expenses: Elekta Richard PötterResearch Funding: Elekta (Inst), Varian Medical Systems (Inst) Christian KirisitsHonoraria: ElektaResearch Funding: Elekta (Inst), Varian Medical (Inst)Patents, Royalties, Other Intellectual Property: Patent WO2015181632A1 on Methods and Systems for Brachytherapy Planning Based on Imaging DataNo other potential conflicts of interest were reported.

Background: Successful pregnancy outcome in women with synchronous ovarian and endometrial cancers is very rare. We report successful pregnancy outcome in a young woman managed conservatively for synchronous endometrial and ovarian cancer., Case Presentation: Thirty years old nulliparous lady presented following exploratory laparotomy, left salpingo-oophorectomy and hysteroscopic polypectomy for left adnexal mass. Histology revealed endometrioid carcinoma of left ovary and moderately differentiated adenocarcinoma in the resected polyp. She underwent staging laparotomy along with hysteroscopy which confirmed above findings without any evidence of further tumor spread. She was treated conservatively with high dose oral progestin (megestrol acetate, 160 mg) and leuprolide acetate 3.75 mg monthly injections for three months along with four cycles of carboplatin and paclitaxel based chemotherapy followed by monthly injection of leuprolide for further three months. After failure of spontaneous conception, she underwent ovulation induction for six cycles along with intrauterine insemination which failed. She underwent in vitro fertilization with donor egg followed by elective cesarean section at 37 weeks of gestation. She delivered a healthy baby of weight 2.7 kg. Intraoperatively 5 × 6 cm right ovarian cyst was found which drained chocolate coloured fluid on puncture and cystectomy was carried out. Histological examination revealed endometrioid cyst of right ovary. Uterus was spared as she wanted to preserve her fertility. She is being followed periodically and is normal nine months following delivery. She is on injection Depot medroxy progesterone acetate once every three months., (© 2023. The Author(s).)

Competing Interests: Conflict of interestNo potential conflict of interest was reported by the author.

Introduction: Palliative care (PC) has been classically synonymous with end-of-life care offered to patients with advanced incurable cancers with an aim to improve their quality-of-life (QoL). However, there is growing evidence to suggest that early integration of PC (EIPC) along with cancer-directed management improves patient-reported outcomes. In this study, we aim to evaluate the impact of EIPC on QoL of cervical cancer patients treated with curative intent., Material and Methods: Patients with locally advanced cervical cancer (stage IB2 to IIIB) having eastern cooperative oncology group (ECOG) performance score 0-2 were randomized into EIPC arm and standard of care arm of concurrent chemoradiation by a computer-generated table of random numbers. QoL was assessed by functional assessment of cancer therapy - general (FACT-G) questionnaire twice in both arms. The first assessment was done prior to starting treatment and second assessment at three months after treatment completion. The mean scores on physical, mental, emotional, social, and functional well-being subscales of FACT-G scale were calculated in both arms, and Wilcoxon test was used to evaluate differences in QoL scores within and in between the arms. This trial was registered with Clinical Trials Registry of India (CTRI) vide CTRI/2017/05/008704., Results: Fifty patients were enrolled in each arm. However, only 42 and 45 patients in EPIC and standard oncological care arm were evaluated in the final analysis. Comparing QoL scores between the two time points in each arm, the mean pre-treatment scores in EIPC arm was significantly higher than post-treatment scores in the domains of physical and emotional well-being, whereas social and functional well-being scores improved significantly after treatment as compared with that as baseline. However, when compared between two arms, the difference of mean scores pre- and post-treatment were almost similar for physical and functional well-being but statistically significant differences were found only in social and emotional well-being scales., Conclusions: Our study is a feasibility study done in an attempt to test the validity of EIPC in cervical cancers. The results are inspiring to conduct robust studies in the future to explore this new domain of integration of palliative services in curable cancers., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Family Medicine and Primary Care.)

Objective: Adult granulosa cell tumors (AGCTs) are rare ovarian malignant neoplasms; their etiopathogenetic mechanisms remain largely unelucidated. Lately, defects in mismatch repair (MMR) have been implicated in the pathogenesis of AGCTs. Demonstration of MMR deficiency in these tumors can help identify patients potentially eligible for immune checkpoint inhibition therapy. The present study was done to explore the role of MMR deficiency in the etiopathogenesis of AGCTs., Methods: This was a retrospective study conducted on histopathologically confirmed AGCT cases. MMR protein expression was evaluated by immunohistochemistry (IHC) on tissue microarrays using an antibody panel of MSH2, MSH6, MLH1, and PMS2., Results: Of a total of 40 ovarian AGCTs evaluated for MMR deficiency, none demonstrated loss of expression of any of the 4 MMR proteins., Conclusions: The results of our preliminary study show that there is no association between MMR deficiency with AGCT. Nevertheless, larger multicenter studies are needed to confirm or refute this observation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Primary ovarian large cell neuroendocrine carcinoma (POLNEC) is an extremely rare and highly aggressive malignancy. Establishing a definite diagnosis requires histopathologic examination with immunohistochemical demonstration of neuroendocrine differentiation in the tumor cells. The histopathology may overlap with a variety of other ovarian malignancies; however, rendering an accurate diagnosis is essential, owing to the therapeutic and prognostic implications., Case: A 62-year-old, post-menopausal woman presented with complaints of abdominal fullness and dull-aching abdominal pain for the last three months. A pelvic ultrasound revealed the presence of a complex adnexal mass. Serum levels of tumor markers, CA125, carcinoembryonic antigen, alpha-fetoprotein, and beta-human chorionic gonadotropin, were within normal limits. Pelvic magnetic resonance imaging showed a heterogeneous lobulated right adnexal mass measuring 6.7×5.8×5.6 cm, which was T2-hyperintense and T1-hypointense. A provisional diagnosis of ovarian carcinoma was made, and a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed., Results: Histopathology showed an organoid and nesting pattern with a focal perivascular arrangement of the tumor cells with large, moderately pleomorphic, round to oval nuclei, granular chromatin, conspicuous nucleoli, and a moderate amount of pale-eosinophilic cytoplasm. Brisk mitosis and lymphovascular space involvement were noted. On immunohistochemistry, the tumor cells showed positivity for chromogranin, synaptophysin, and neuron-specific enolase and were negative for PAX8, WT1, vimentin, and epithelial membrane antigen. p53 showed wild-type, and SMARCB1/INI-1 showed retained nuclear expression. Based on the histopathologic and immunohistochemical features, a final diagnosis of POLNEC was rendered. The patient received 4 cycles of adjuvant chemotherapy and is disease-free, 28 months post-treatment., Conclusions: The present report highlights the characteristic histopathologic and immunohistochemical features of POLCNEC to distinguish it from other clinicopathologic mimics and present a comprehensive review of the published literature of all such cases., Competing Interests: None., (IJCEP Copyright © 2021.)

Purpose: To evaluate the clinical outcomes in patients with cervical cancer with limited residual disease at brachytherapy (BT) treated with point-based dose prescription., Methods: Patients with locally advanced squamous cell carcinoma of the cervix treated with computed tomography (CT)-based intracavitary BT were considered for analysis. Patients with good response to external beam radiotherapy and limited residual disease suitable for intracavitary BT alone were included. Postapplication CT scans were performed before each fraction and individual plans were made for each session. The dose per fraction was 9Gy high dose rate, prescribed to point-A. Two sessions were planned, 1 week apart. The organs at risk were contoured, and cumulative dose-volume histograms were computed. Local control, pelvic control, disease-free survival, and overall survival were evaluated and late toxicities were documented., Results: Four hundred ninety patients were included. Overall, 79.8% had International Federation of Gynecology and Obstetrics (FIGO) stage IB2 to IIB disease and 20.2% had stage III to IVA disease. Median dose at point A (EQD2 10Gy ) was 74.4 Gy (interquartile range [IQR] 72.3-74.5 Gy) and median D 2cc (EQD2 3Gy ) for bladder, rectum, and sigmoid were 82.5 Gy (IQR, 65.5-90.8 Gy), 66.5 Gy (IQR, 60.7-75.7 Gy), and 54.1 Gy (IQR, 50.5-77.3 Gy), respectively. At a median follow-up of 62 (IQR, 33-87) months, the 5-year local and pelvic control rates were 90.1% and 88.3%, respectively. The 5-year disease-free survival was 80% and overall survival was 88%. Rates of grade 3-4 bladder and rectosigmoid toxicities were 6.93% and 4.08%, respectively., Conclusion: In patients with limited residual disease at BT, point-based dose prescription with CT planning results in good local control and acceptable toxicity. In a resource-constrained setting, patients may be triaged to receive point-based BT or magnetic resonance imaging-guided adaptive BT depending on the extent of residual disease.

Objective: To prospectively analyze the effect of three-dimensional chemoradiation on the bone mineral density of pelvic bones and its association with low back pain and disability in patients with locally advanced cervical cancer., Methods: In biopsy proven locally advanced cervical cancer patients, bone mineral density and T scores for lumbar vertebrae 5, dorsal thoracic vertebrae 12, and T scores for the femoral neck were analyzed. Low back pain was scored using the visual analog scale while disability scoring was done using the Oswestry low back pain disability scale. Furthermore, a subgroup analysis for patients (classified according to menopausal status) was performed., Results: In total, 106 patients were analyzed. A statistically significant decline in mean bone mineral density was observed at all three sites (vertebrae 5 and 12, and the femoral neck) post-chemoradiation therapy compared with pretreatment bone mineral density (0.671 vs 0.828, -2.083 vs -1.531, -2.503 vs -1.626; all p<0.001). Similarly, in subgroup analyses, at all three sites, pre-menopausal patients showed a statistically significant association (0.876 vs 0.697, -1.203 vs -0.2.761, -1.403 vs -2.232; all p<0.001) while a non-significant association was observed for post-menopausal patients at vertebrae 12 (-1.707 vs -1.719; p=0.09) with a statistically significant association at vertebrae 5 and the femoral neck (0.803 vs 0.656, -1.746 vs -2.648; p<0.01). Although statistically significant low back pain and disability scores were observed overall and irrespective of menopausal status, no correlation between bone mineral density and low back pain and disability was observed., Conclusion: Pelvic bone mineral density decreases significantly after chemoradiation, irrespective of menopausal status. However, no correlation with low back pain and disability was observed. Pelvic bone mineral density analysis should be considered before chemoradiation in cervical cancer., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Estimation of health-related quality of life of cervical cancer patients in India is important in assessing the well-being of patients, monitor treatment outcomes, and conduct health technology assessments. However, health-related quality of life estimates for different stages of cervical cancer are not available for the Indian population. This study aims to generate stage-specific quality of life scores for cervical cancer patients in India., Methods: A cross-sectional study using the EQ-5D (EuroQol 5-dimensions) instrument, that consists of the EQ-5D-5L descriptive system and the EuroQol Visual Analog Scale (EQ-VAS) was conducted. A total of 159 cervical cancer patients were interviewed. Mean EQ-5D-5L quality of life scores (utility scores) were calculated using the EQ-5D-5L index value calculator across different stages of cervical cancer. The proportion of patients reporting problems in different attributes of EQ-5D-5L was assessed. The impact of socio-economic determinants on health-related quality of life was evaluated using multiple linear regression., Results: The mean EQ-5D-5L and EQ-VAS utility scores among patients of cervical cancer were 0.64 [95% CI=0.61-0.67] and 67.6 [95% CI=65.17-70.03], respectively. The most frequently reported problem among cervical cancer patients was pain/discomfort (61.88%), followed by difficulty in performing usual activities (53.81%), and anxiety/depression (41.26%)., Conclusion: Cervical cancer significantly impacts the health-related quality of life of the patients in India. Clinical interventions should focus on the control of pain and relief of anxiety. The measurement of health-related quality of life should be an integral component of the effectiveness of interventions as well as health technology assessment., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The categorization of endometrial carcinomas into endometrioid and serous categories has prognostic implications but many-a-times, it is difficult to categorize based solely on morphology. The present study was conducted to determine an appropriate immunohistochemical panel to distinguish grade 3 endometrioid carcinoma from serous carcinoma., Experimental Design: This study was a retrospective and a prospective study including 63 cases of endometrial carcinoma diagnosed on morphology as either grade 3 endometrioid (n=29) or serous endometrial carcinomas (n=34). Immunohistochemistry (IHC) was performed using tissue microarrays for 8 immunomarkers on 60 cases., Results: The mean age of presentation was not significantly different for both types of carcinomas and the most common presentation was postmenopausal bleeding (93% of the total cases, P=0.66). Obesity (P=0.038), lymph nodal involvement (P=0.044), and stage at presentation (P=0.042) were found to be significantly different among the 2 types of carcinomas. Estrogen and progesterone receptor (ER, PR) positivity was more common (47.6% and 28.2%, respectively) in endometrioid carcinomas as compared with serous. Mutation type (diffuse or null) p53 staining was a powerful predictor of serous carcinomas. IMP3 and p16 were found to be positive in most cases of serous carcinoma (64.1% and 79.5%, respectively). Vimentin and β-catenin were found to be of limited utility. On the basis of IHC, 21 cases could be categorized as grade 3 endometrioid carcinomas and 39 as type 2 carcinomas (serous and clear cell carcinoma)., Conclusions: The most appropriate IHC panel to differentiate endometrioid and serous endometrial carcinomas includes ER, PR, IMP3, p53, and p16.

Purpose: The entire world is currently facing a devastating crisis due to growing coronavirus pandemic, which was declared as a public health emergency by the World Health Organization on March 11, 2020. Management of cancer patients at this time is an overwhelming task. This study highlights our experience in the management of patients of gynecological malignancies over a period of 2 months during the COVID-19 pandemic., Methods: Patients of confirmed gynecological malignancies who visited our outpatient clinic and those who received radiotherapy/chemotherapy in March and April 2020 were included for analysis. Guidelines issued by the National Institute of Health and Care Excellence, National Health Service, MD Anderson Cancer Centre and those by young oncologists in Italy were followed with minor modifications while managing the logistics and health worker safety., Results: A total of 160 patients were treated in our department during this time period. In total, 44.4% of patients on treatment had associated comorbidities that imposed an additional risk. One hundred twenty-three patients continued treatment with their initial plan of radiotherapy or chemotherapy. New patients were prioritized based on the severity of clinical symptoms and whether the expected outcome would significantly affect their survival and quality of life. Patients were monitored for the development of treatment-related toxicities and COVID-19-related symptoms., Conclusions: All oncology personnel need to identify the correct balance between risks and benefit and then proceed with further management. Thus, it is essential to cautiously select patients for treatment, minimizing the risk of exposure but adequately addressing the underlying disease., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interests., (© Association of Gynecologic Oncologists of India 2020.)

Background: Carcinoma cervix is amongst the leading causes of mortality and morbidity in women population worldwide. High-dose-rate intracavitary brachytherapy (HDR-ICBT) post external beam radiation therapy (EBRT) is the standard of care in managing locally advanced stage cervical cancer patients. HDR-ICBT is generally performed under general anaesthesia (GA) in operation theatre (OT), but due to logistic reasons, sometimes, it becomes difficult to accommodate all patients under GA. Since prolonged overall treatment time (OTT) makes the results inferior, taking patients in day care setup under procedural sedation (PS) can be an effective alternative. In this audit, we tried to retrospectively analyse the dosimetric difference, if any, in patients who underwent ICBT at our centre, under either GA in OT or PS in day care., Results: Thirty five patients were analysed 16/35 (45.71%) patients underwent HDR-ICBT under GA while 19/35 (54.28%) patients under PS. In both groups, a statistically significant difference was observed between the dose received by 0.1 cc as well as 2 cc of rectum (p < 0.05), while the bladder and sigmoid colon had comparable dosages., Conclusion: Though our dosimetric analysis highlighted better rectal sparing in patients undergoing HDR-ICBT under GA when compared to patients under PS, PS can still be considered an effective alternative, especially in centres dealing with significant patient load. Further studies are required for firm conclusion.