Quality of Life After Extended Pelvic Surgery with Neurovascular or Bony Resections in Gynecological Oncology: A Systematic Review.

BACKGROUND: Extended pelvic surgery with neurovascular or bony resections in gynecological oncology has significant impact on quality of life (QoL) and high morbidity. The objective of this systematic review was to provide an overview of QoL, morbidity and mortality following these procedures. METHODS: The registered PROSPERO protocol included database-specific search strategies. Studies from 1966 onwards reporting on QoL after extended pelvic surgery with neurovascular or bony resections for gynecological cancer were considered eligible. All others were excluded. Study selection (Rayyan), data extraction, rating of evidence (GRADE) and risk of bias (ROBINS-I) were performed independently by two reviewers. RESULTS: Of 349 identified records, 121 patients from 11 studies were included-one prospective study, seven retrospective studies, and three case reports. All studies were of very low quality and with an overall serious risk of bias. Primary tumor location was the cervix (n = 78, 48.9%), vulva (n = 30, 18.4%), uterus (n = 21, 12.9%), endometrium (n = 15, 9.2%), ovary (n = 8, 4.9%), (neo)vagina (n = 3, 1.8%), Gartner duct/paracolpium (n = 1, 0.6%), or synchronous tumors (n = 3, 1.8%), or were not reported (n = 4, 2.5%). Bony resections included the pelvic bone (n = 36), sacrum (n = 2), and transverse process of L5 (n = 1). Margins were negative in 70 patients and positive in 13 patients. Thirty-day mortality was 1.7% (2/121). Three studies used validated QoL questionnaires and seven used non-validated measurements; all reported acceptable QoL postoperatively. CONCLUSIONS: In this highly selected patient group, mortality and QoL seem to be acceptable, with a high morbidity rate. This comprehensive study will help to inform eligible patients about the outcomes of extended pelvic surgery with neurovascular or bony resections. Future collaborative studies can enable the collection of QoL data in a validated, uniform manner.

Performance of MRI for Detection of ≥pT1b Disease in Local Staging of Endometrial Cancer.

Magnetic resonance imaging (MRI) can be used for the preoperative local staging of endometrial cancer (EC). The presence of ≥pT1b disease (i.e., tumor invasion in ≥50% of the myometrium, into the cervical stroma or spread outside the uterus) has important prognostic value and implications for the decision to perform lymphadenectomy. The purpose of this study was to assess the performance of MRI for the detection of ≥pT1b disease and to evaluate whether tumor size measured via MRI was predictive for ≥pT1b disease, independent of imaging signs of deep invasion. MRI T-staging and tumor diameter and volume were correlated with histopathology of the hysterectomy specimen in 126 patients. MRI had a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 70.0%, 83.3%, 79.2%, 75.3% and 77.0%, respectively, for the detection of ≥pT1b disease. A tumor diameter of ≥40 mm and volume of ≥20 mL measured via MRI were predictive for ≥pT1b disease at rates of 78.3% and 87.1%, respectively. An EC size of at least 5 mm upon MRI was predictive for ≥pT1b disease in more than 50% of cases. Our results support the use of MRI in the preoperative staging of EC and suggest including size criteria in EC staging guidelines.

Identification of potentially actionable genetic variants in epithelial ovarian cancer: a retrospective cohort study.

Ovarian cancer is the most lethal gynecologic malignancy, mainly due to late-stage diagnosis, frequent recurrences, and eventually therapy resistance. To identify potentially actionable genetic variants, sequencing data of 351 Belgian ovarian cancer patients were retrospectively captured from electronic health records. The cohort included 286 (81%) patients with high-grade serous ovarian cancer, 17 (5%) with low-grade serous ovarian cancer, and 48 (14%) with other histotypes. Firstly, an overview of the prevalence and spectrum of the BRCA1/2 variants highlighted germline variants in 4% (11/250) and somatic variants in 11% (37/348) of patients. Secondly, application of a multi-gene panel in 168 tumors revealed a total of 214 variants in 28 genes beyond BRCA1/2 with a median of 1 (IQR, 1-2) genetic variant per patient. The ten most often altered genes were (in descending order): TP53, BRCA1, PIK3CA, BRCA2, KRAS, ERBB2 (HER2), TERT promotor, RB1, PIK3R1 and PTEN. Of note, the genetic landscape vastly differed between the studied histotypes. Finally, using ESCAT the clinical evidence of utility for every genetic variant was scored. Only BRCA1/2 pathogenic variants were classified as tier-I. Nearly all patients (151/168; 90%) had an ESCAT tier-II variant, most frequently in TP53 (74%), PIK3CA (9%) and KRAS (7%). In conclusion, our findings imply that although only a small proportion of genetic variants currently have direct impact on ovarian cancer treatment decisions, other variants could help to identify novel (personalized) treatment options to address the poor prognosis of ovarian cancer, particularly in rare histotypes.

Sexual health in Belgian cervical cancer survivors: an exploratory qualitative study.

PURPOSE: To assess experiences of sexuality and of receiving sexual healthcare in cervical cancer (CC) survivors. METHODS: A qualitative phenomenological study using semistructured one-on-one interviews was conducted with 15 Belgian CC survivors recruited in 5 hospitals from August 2021 to February 2022. The interviews were audiotaped and transcribed verbatim. Data were analyzed using inductive thematic analysis. COREQ and SRQR reporting guidelines were applied. RESULTS: Most participants experienced an altered sexuality after CC treatment with often long-term loss/lack of sex drive, little/no spontaneity, limitation of positions to avoid dyspareunia, less intense orgasms, or no sexual activity at all. In some cases, emotional intimacy became more prominent. Physical (vaginal bleeding, vaginal dryness, dyspareunia, menopausal symptoms) and psychological consequences (guilt, changed self-image) were at the root of the altered sexuality. Treatment-induced menopause reduced sex drive. In premenopausal patients, treatment and/or treatment-induced menopause resulted in the sudden elimination of family planning. Most participants highlighted the need to discuss their altered sexual experience with their partner to grow together toward a new interpretation of sexuality. To facilitate this discussion, most of the participants emphasized the need for greater partner involvement by healthcare providers (HPs). The oncology nurse or sexologist was the preferred HP with whom to discuss sexual health. The preferred timing for information about the sexual consequences of treatment was at treatment completion or during early follow-up. CONCLUSION: Both treatment-induced physical and psychological experiences were prominent and altered sexuality. Overall, there was a need for HPs to adopt proactive patient-tailored approaches to discuss sexual health.

Towards the Clinical Implementation of Extracellular Vesicle-Based Biomarker Assays for Cancer.

BACKGROUND: Substantial research has been devoted to elucidating the role of extracellular vesicles (EVs) in the different hallmarks of cancer. Consequently, EVs are increasingly explored as a source of cancer biomarkers in body fluids. However, the heterogeneity in EVs, the complexity of body fluids, and the diversity in methods available for EV analysis, challenge the development and translation of EV-based biomarker assays. CONTENT: Essential steps in EV-associated biomarker development are emphasized covering biobanking, biomarker discovery, verification and validation, and clinical implementation. A meticulous study design is essential and ideally results from close interactions between clinicians and EV researchers. A plethora of different EV preparation protocols exists which warrants quality control and transparency to ensure reproducibility and thus enable verification of EV-associated biomarker candidates identified in the discovery phase in subsequent independent cohorts. The development of an EV-associated biomarker assay requires thorough analytical and clinical validation. Finally, regulatory affairs must be considered for clinical implementation of EV-based biomarker assays. SUMMARY: In this review, the current challenges that prevent us from exploiting the full potential of EV-based biomarker assays are identified. Guidelines and tools to overcome these hurdles are highlighted and are crucial to advance EV-based biomarker assays into clinical use.

Vaginal morbidity, sexual functioning, and health-related quality of life in cervical cancer survivors: a cross-sectional multicenter study (VAMOS).

PURPOSE: To compare sexual/vaginal functioning between early cervical cancer (ECC) and locally advanced cervical cancer (LACC) survivors. METHODS: VAMOS was a multicenter, cross-sectional, questionnaire, noninferiority study including ECC patients treated with surgery and, if clinically indicated, adjuvant (chemo)radiotherapy and LACC patients treated with neoadjuvant (chemo)radiotherapy followed by surgery. Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-CX24, and Female Sexual Functioning Index (FSFI) questionnaires. Clinical reported outcomes (ClinROs) consisted of vaginal morbidity scored according to the CTCAE v4.0 scoring system. RESULTS: One hundred forty-three patients were included. Compared to ECC patients (n = 97), LACC patients (n = 46) were significantly less sexually active in the 4 weeks prior to completion of the questionnaires (65% vs. 41%; p = .005). The primary endpoint was not met: LACC patients reported a higher mean score (more problems) for sexual/vaginal functioning than ECC patients, with a non-clinically relevant mean difference of 6.38 ([95% CI: - 6.41, 19.17]; p = .570 for noninferiority). Regarding the secondary endpoints, the prevalence of sexual dysfunction between the two groups did not differ significantly (p = 0.124). Compared to ECC patients, LACC patients did not have significantly more vaginal morbidity (adjusted odds ratio [OR] 1.51 [95% CI: 0.22, 10.29]; p = .674). Moreover, there was poor agreement between any vaginal morbidity and sexual dysfunction (Cohen's kappa of 0.17). CONCLUSION: Compared to ECC survivors, LACC survivors were significantly less sexually active and reported equivalent or worse sexual/vaginal functioning, although the proportion of patients with sexual dysfunction was similar. Clinical assessment of vaginal morbidity was poorly correlated with sexual dysfunction.

Integrating human papillomavirus testing as a point-of care service using GeneXpert platforms: Findings and lessons from a Kenyan pilot study (2019-2020).

BACKGROUND: Globally, cervical cancer is a major public health problem, with about 604,000 new cases and over 340,000 deaths in 2020. In Kenya, it is the leading cause of cancer deaths, with over 3,000 women dying in 2020 alone. Both the Kenyan cancer screening guidelines and the World Health Organization's Global Cervical Cancer Elimination Strategy recommend human papillomavirus (HPV) testing as the primary screening test. However, HPV testing is not widely available in the public healthcare system in Kenya. We conducted a pilot study using a point of care (POC) HPV test to inform national roll-out. METHODS: The pilot was implemented from October 2019 to December 2020, in nine health facilities across six counties. We utilized the GeneXpert platform (Cepheid, Sunnyvale, CA, USA), currently used for TB, Viral load testing and early infant diagnosis for HIV, for HPV screening. Visual inspection with acetic acid (VIA) was used for triage of HPV-positive women, as recommended in national guidelines. Quality assurance (QA) was performed by the National Oncology Reference Laboratory (NORL), using the COBAS 4800 platform (Roche Molecular System, Pleasanton, CF, USA). HPV testing was done using either self or clinician-collected samples. We assessed the following screening performance indicators: screening coverage, screen test positivity, triage compliance, triage positivity and treatment compliance. Test agreement between local GeneXpert and central comparator high-risk HPV (hrHPV) testing for a random set of specimens was calculated as overall concordance and kappa value. We conducted a final evaluation and applied the Nominal Group Technique (NGT) to identify implementation challenges and opportunities. KEY FINDINGS: The screening coverage of target population was 27.0% (4500/16,666); 52.8% (2376/4500) were between 30-49 years of age. HPV positivity rate was 22.8% (1027/4500). Only 10% (105/1027) of HPV positive cases were triaged with VIA/VILI; 21% (22/105) tested VIA/VILI positive, and 73% (16/22) received treatment (15 received cryotherapy, 1 was referred for biopsy). The median HPV testing turnaround time (TAT) was 24 hours (IQR 2-48 hours). Invalid sample rate was 2.0% (91/4500). Concordance between the Cepheid and COBAS was 86.2% (kappa value = 0.71). Of 1042 healthcare workers, only 5.6% (58/1042) were trained in cervical cancer screening and treatment, and only 69% (40/58) of those trained were stationed at service provision areas. Testing capacity was identifed as the main challenge, while the community strategy was the main opportunity. CONCLUSION: HPV testing can be performed on GeneXpert as a near point of care platform. However, triage compliance and testing TAT were major concerns. We recommend strengthening of the screening-triage-treatment cascade and expansion of testing capacity, before adoption of a GeneXpert-based HPV screening among other near point of care platforms in Kenya.

Integrating automated liquid handling in the separation workflow of extracellular vesicles enhances specificity and reproducibility.

BACKGROUND: Extracellular vesicles (EV) are extensively studied in human body fluids as potential biomarkers for numerous diseases. Major impediments of EV-based biomarker discovery include the specificity and reproducibility of EV sample preparation as well as intensive manual labor. We present an automated liquid handling workstation for the density-based separation of EV from human body fluids and compare its performance to manual handling by (in)experienced researchers. RESULTS: Automated versus manual density-based separation of trackable recombinant extracellular vesicles (rEV) spiked in PBS significantly reduces variability in rEV recovery as quantified by fluorescent nanoparticle tracking analysis and ELISA. To validate automated density-based EV separation from complex body fluids, including blood plasma and urine, we assess reproducibility, recovery, and specificity by mass spectrometry-based proteomics and transmission electron microscopy. Method reproducibility is the highest in the automated procedure independent of the matrix used. While retaining (in urine) or enhancing (in plasma) EV recovery compared to manual liquid handling, automation significantly reduces the presence of body fluid specific abundant proteins in EV preparations, including apolipoproteins in plasma and Tamm-Horsfall protein in urine. CONCLUSIONS: In conclusion, automated liquid handling ensures cost-effective EV separation from human body fluids with high reproducibility, specificity, and reduced hands-on time with the potential to enable larger-scale biomarker studies.

Completion surgery after intensity-modulated arc therapy for locally advanced cervical cancer: long-term follow-up and update on surgical outcome and oncologic results of a unique tertiary care single-center retrospective cohort.

BACKGROUND: Chemoradiotherapy (CRT) followed by brachytherapy (BT) is the standard treatment for locally advanced cervical cancer (LACC), but replacement of BT by surgery (CRT-S) could be an acceptable alternative. The main concern is the risk of operative morbidity. The aim is to report on therapeutic morbidity, OS, PC, and LC of CRT-S. METHODS: This was a single tertiary center retrospective cohort study in patients treated with CRT-S. A type II Wertheim hysterectomy was performed 6-8 weeks after CRT. Acute and chronic radiotherapy-related and surgical morbidity was classified according to the CTCAE v4.0. OS, and DFS, PC, and LC were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard models were performed to determine variables with a prognostic role. RESULTS: A total of 130 consecutive LACC patients were treated with CRT, and 119 underwent completion surgery. The median follow-up was 53 months. Five-year OS rate, local control, pelvic control, and 5-year DFS rate were 73%, 93%, 90%, and 74%, respectively. The 5-year OS rate was 92%/72%/67%/56% for FIGO (2009) stage I/II/III/IV, respectively. The five-year OS rate was 79% and 71% for adenocarcinoma and squamous cell carcinoma (p > 0.05), respectively. There was no intra- and perioperative mortality. Intraoperative and early postoperative complication rates were 7% and 20% (3% ≥ G3), respectively; they resolved within 3 months. The late postoperative complication rate was 9% (7% ≥ G3). Acute/late radiotherapy-related G3 side effects were 5%/3% for gastrointestinal and 3%/7% for genitourinary side effects. CONCLUSIONS: CRT-S is safe with an acceptable rate of complications for both the CRT and completion surgery and shows encouraging outcome data for stage III/IV and adenocarcinoma patients.

Cervical cancer programme, Kenya, 2011-2020: lessons to guide elimination as a public health problem.

Background: Cervical cancer is the leading cause of cancer mortality in Kenya, with an estimated 3,200 deaths in 2020. Kenya has implemented cervical cancer interventions for more than a decade. We describe the evolution of the cervical cancer programme over the last 20 years and assess its performance. Methods: We searched the Ministry of Health's archives and website (2000-2021) for screening policy documents and assessed them using seven items: situational analysis, objectives, key result areas, implementation framework, resource considerations, monitoring and evaluation and definition of roles/responsibilities. In addition, a trend analysis was performed targeting screening and disease burden indicators in the period 2011-2020, using data from Kenya Health Information System and the Global Burden of Disease database. Findings: Policy guidance improved over time, but the implementation of screening was poor. Before 2016, a clear leadership and accountability structure was lacking; improvement occurred after the establishment of the National Cancer Control Program. The main health system gaps included the lack of a trained healthcare workforce and poor data collection. Annual screening coverage varied between <1% and 36% of the target population for the year for HIV-negative women and between <1% and 7% for HIV-positive women, from 2011 to 2020. Test positivity for visual inspection with acetic acid was below 5% for most of the period. Compliance to treatment of precancerous lesions ranged between 22% and 39%. The detection rate of cervical cancer ranged between 0.5% and 1.0%. The burden of invasive cervical cancer did not change significantly: world age-standardised incidence and mortality rates of 26.3-27.4 and 16.6-18.0/100,000 women-years, respectively; disability-adjusted life years of 579-624/100,000 life years. Conclusion: The Kenyan cervical cancer control programme suffered from inadequate health system strengthening and poor quality implementation. Evidence-based policy implementation and sustained health system strengthening are necessary to move towards cervical cancer elimination as a public health problem.

Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease. IMPLICATIONS: The newly characterized differences between ascitic and solid cancer cells before and after chemotherapy could inform novel treatment strategies for metastatic HGSOC.

Single-Dose Human Papillomavirus Vaccination in Low- and Middle-Income Countries-Time for Implementation?

Although cervical cancer is becoming a rare disease in high income regions, it is still a major health issue in low- and middle-income countries (LMICs). Cervical cancer develops after infection with a high-risk human papilloma virus (hrHPV), an infection against which vaccination has been possible since 2006. Large population immunization programs have been organized in many higher income countries, and yet they have not been implemented in most of the lower and middle-income nations. The cost of the vaccine, as well as the need for two doses impedes coverage in the most vulnerable groups. Studies are suggesting the efficacy of single dose vaccination, but so far only observational data are available while large, randomized, double-blind studies are still ongoing. In order to prevent and combat this disease, it is essential to inform the population of vaccination benefits and offer accessible programs in higher as well as low-and middle-income countries. In this commentary, we wish to focus our attention on the case for implementing single dose vaccination in lower- and middle-income nations.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

BACKGROUND: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age. METHODS: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study. RESULTS: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study. CONCLUSIONS: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220.

Cervical Adenoma Malignum in Third Trimester Pregnancy.

Teaching Point: Adenoma malignum is a rare, non-HPV associated subtype of mucinous adenocarcinoma of the cervix, of which we present an exceptional case that was discovered during the third trimester of pregnancy.

Splenic 18F-FDG uptake on baseline PET/CT is associated with oncological outcomes and tumor immune state in uterine cervical cancer.

OBJECTIVE: The spleen represents an important contributor to tumor immune escape, but the relevance of increased splenic metabolic activity remains to be fully elucidated. METHODS: We retrospectively measured the spleen-to-liver standard uptake value (SLR) on 18F-FDG PET/CT examinations of 92 consecutive patients with FIGO stage IB1 to IVA cervical cancer and integrated the results with survival, response to treatment, tumor immune infiltrate, and baseline characteristics. RESULTS: SLRmax > 0.92 (p = .026) and SLRmean > 0.94 (p = .005) were significantly associated with decreased DFS in univariable analysis. Multivariable models were built using best subset selection; ΔSLRmax and either SLRmax or SLRmean were consistently selected, strongly reinforcing the association between SLR variables and DFS in relation to potential confounders (all models p ≤ .002). Independent associations were found for SLRmax using multivariable Cox regression models for DFS (all p ≤ .003). Further, uni- and multivariable analyses demonstrated the negative impact of higher SLR values on pathological complete response. A statistically significant higher proportion of patients with high SLRmax had a dense infiltrate of CD20+ (p = .036) and CD68+ (p = .015) immune cells, as well as PD-L1+ tumor cells (p = .019) as compared to those with low SLRmax. Finally, high SLRmax status was neither associated with systemic inflammatory markers (except for an increased white blood cell count; p = .038), nor with clinically overt infection. CONCLUSION: This hypothesis-generating study provides the first evidence that increased splenic metabolic activity is a negative prognostic and predictive biomarker in locally advanced cervical cancer. In addition, it might help to discriminate immunologically 'hot' from 'cold' cervical tumors.

PKPD Modeling and Dosing Considerations in Advanced Ovarian Cancer Patients Treated with Cisplatin-Based Intraoperative Intraperitoneal Chemotherapy.

Intraperitoneal chemoperfusion (IPEC) of cisplatin is a popular treatment for advanced ovarian cancer, typically under hyperthermia (HIPEC). The use of cisplatin under (H)IPEC is off-label, and the role of hyperthermia is unknown. The aim of this study was to characterize the pharmacokinetic/pharmacodynamic (PKPD) properties of cisplatin under (H)IPEC and to predict the optimal treatment regimen. Using a randomized design, data on intact cisplatin perfusate and plasma concentrations, leukocyte counts-a hematotoxicity marker-and serum creatinine-a nephrotoxicity marker-were collected from 50 patients treated with a combination of cytoreductive surgery (CRS) and either normothermic or hyperthermic IPEC of cisplatin dosed at 75, 100, and 120 mg/m2. The non-linear mixed effects modeling technique was used to construct the PKPD models. The PK of intact cisplatin was characterized by a two-compartment model. A semi-physiological myelosuppression model for the leukopenia was modified to account for the CRS-induced leukocytosis and the residual myelosuppression effect of neoadjuvant chemotherapy. The incidence and severity of nephrotoxicity were described by a discrete-time Markov model. Hyperthermia increased the absorption rate of cisplatin by 16.3% but did not show a clinically relevant impact on the investigated toxicities compared with normothermia. Leukopenia was not severe, but nephrotoxicity can become severe or life-threatening and was affected by the dose and IPEC duration. The model predicted that nephrotoxicity is minimal at a cisplatin dose of 75 mg/m2 with an IPEC duration of 1-2 h and an 1-h duration is favored for doses between 100 and 120 mg/m2. Graphical abstract.

Immunologic impact of chemoradiation in cervical cancer and how immune cell infiltration could lead toward personalized treatment.

We investigated the potential of tumor-infiltrating immune cells (ICs) as predictive or prognostic biomarkers for cervical cancer patients. In total, 38 patients treated with (chemo)radiotherapy and subsequent surgery were included in the current study. This unique treatment schedule makes it possible to analyze IC markers in pretreatment and posttreatment tissue specimens and their changes during treatment. IC markers for T cells (CD3, CD4, CD8 and FoxP3), macrophages (CD68 and CD163) and B cells (CD20), as well as IL33 and PD-L1, were retrospectively analyzed via immunohistochemistry. Patients were grouped in the low score or high score group based on the amount of positive cells on immunohistochemistry. Correlations to pathological complete response (pCR), cause-specific survival (CSS) and metastasis development during follow-up were evaluated. In analysis of pretreatment biopsies, significantly more pCR was seen for patients with CD8 = CD3, CD8 ≥ CD4, positive IL33 tumor cell (TC) scores, IL33 IC < TC and PD-L1 TC ≥5%. Besides patients with high CD8 scores, also patients with CD8 ≥ CD4, CD163 ≥ CD68 or PD-L1 IC ≥5% had better CSS. In the analysis of posttreatment specimens, less pCR was observed for patients with high CD8 or CD163 scores. Patients with decreasing CD8 or CD163 scores between pretreatment and posttreatment samples showed more pCR, whereas those with increasing CD8 or decreasing IL33 IC scores showed a worse CSS. Meanwhile, patients with an increasing CD3 score or stable/increasing PD-L1 IC score showed more metastasis during follow-up. In this way, the intratumoral IC landscape is a promising tool for prediction of outcome and response to (chemo)radiotherapy.