Cancer therapy-related vaginal toxicity: its prevalence and assessment methods-a systematic review.

PURPOSE: In 2020, almost 9 million women were diagnosed with cancer worldwide. Despite advancements in cancer treatment strategies, patients still suffer from acute and long-term side effects. This systematic review aims to evaluate the most frequently reported adverse effects in the genitourinary system and compare them across cancer types, treatment modalities, and evaluation methods. METHODS: Pubmed Central, SCOPUS, and Cochrane Library were searched following the PRISMA guidelines to identify all prospective and retrospective observational cohort studies and randomized controlled trials assessing vaginal side effects of adult female cancer patients. The study quality was evaluated using The Newcastle-Ottawa Scale or the Risk of Bias 2 tool, as appropriate. RESULTS: The most prevalent population was breast cancer patients, followed by gynaecological cancer patients. Overall, the focus was on vaginal dryness, while vaginal stenosis was the primary outcome in gynaecological cancer patients. Significant discrepancies were found in the frequency and severity of the reported adverse events. Most studies in this review evaluated side effects using patient-reported outcome measures (PROMs). CONCLUSIONS: Genitourinary syndrome of menopause following cancer treatment is most frequently documented in breast and gynaecological cancer patients, often focussing on vaginal dryness and vaginal stenosis based on PROMs. This review provides a complete overview of the literature, but more high-quality clinical trials are necessary to draw firm conclusions on acute and chronic vaginal toxicity following cancer treatment. IMPLICATIONS FOR CANCER SURVIVORS: This review could help improve the current preventive and curative management options for genitourinary complications, thereby increasing the patient's QoL and sexual functioning.

Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study.

BACKGROUND: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR). PATIENTS AND METHODS: This open-label, multi-cohort, phase II study examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and disease progression on standard of care. Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included. Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation. RESULTS: The overall objective response rate across different tumor types was 11% in the BRCA1-mutated (n = 27) and 21% in the BRCA2-mutated (n = 27) cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline-mutated colon cancer has an ongoing complete response with 19+ months on treatment. Median progression-free survival in responding patients was 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1-mutated and 46% in the BRCA2-mutated cohorts. No clinical activity was observed in the ATM (n = 13) and CHEK2 (n = 14) cohorts. CONCLUSION: Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib.

Changes in anticancer treatment plans in patients with solid cancer hospitalized with COVID-19: analysis of the nationwide BSMO-COVID registry providing lessons for the future.

BACKGROUND: Solid cancer is an independent prognostic factor for poor outcome with COVID-19. As guidelines for patient management in that setting depend on retrospective efforts, we here present the first analyses of a nationwide database of patients with cancer hospitalized with COVID-19 in Belgium, with a focus on changes in anticancer treatment plans at the time of SARS-CoV-2 infection. METHODS: Nineteen Belgian hospitals identified all patients with a history of solid cancer hospitalized with COVID-19 between March 2020 and February 2021. Demographic, cancer-specific and COVID-specific data were pseudonymously entered into a central Belgian Society of Medical Oncology (BSMO)-COVID database. The association between survival and primary cancer type was analyzed through multivariate multinomial logistic regression. Group comparisons for categorical variables were carried out through a Chi-square test. RESULTS: A total of 928 patients were registered in the database; most of them were aged ≥70 years (61.0%) and with poor performance scores [57.2% Eastern Cooperative Oncology Group (ECOG) ≥2]. Thirty-day COVID-related mortality was 19.8%. In multivariate analysis, a trend was seen for higher mortality in patients with lung cancer (27.6% versus 20.8%, P = 0.062) and lower mortality for patients with breast cancer (13.0% versus 23.3%, P = 0.052) compared with other tumour types. Non-curative treatment was associated with higher 30-day COVID-related mortality rates compared with curative or no active treatment (25.8% versus 14.3% versus 21.9%, respectively, P < 0.001). In 33% of patients under active treatment, the therapeutic plan was changed due to COVID-19 diagnosis, most frequently involving delays/interruptions in systemic treatments (18.6%). Thirty-day COVID-related mortality was not significantly different between patients with and without treatment modifications (21.4% versus 20.5%). CONCLUSION: Interruption in anticancer treatments at the time of SARS-CoV-2 infection was not associated with a reduction in COVID-related mortality in our cohort of patients with solid cancer, highlighting that treatment continuation should be strived for, especially in the curative setting.

PRECISION: the Belgian molecular profiling program of metastatic cancer for clinical decision and treatment assignment.

PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium.

A phase II randomized trial of cobimetinib plus chemotherapy, with or without atezolizumab, as first-line treatment for patients with locally advanced or metastatic triple-negative breast cancer (COLET): primary analysis.

BACKGROUND: Resistance to standard chemotherapy in metastatic triple-negative breast cancer (mTNBC) is associated with upregulation of the mitogen-activated protein kinase (MAPK) pathway. Cobimetinib, an MAPK/extracellular signal-regulated kinase (MEK) inhibitor, may increase sensitivity to taxanes and programmed death-ligand 1 inhibitors. COLET is a three-cohort phase II study evaluating first-line cobimetinib plus chemotherapy, with or without atezolizumab, in patients with locally advanced or mTNBC. PATIENTS AND METHODS: Patients were ≥18 years with locally advanced or mTNBC. Following a safety run-in, patients in cohort I were randomized 1:1 to cobimetinib (60 mg, D3-D23 of each 28-day cycle) or placebo, plus paclitaxel (80 mg/m2, D1, 8, and 15). Additional patients were randomized (1:1) to cohort II or III to receive cobimetinib plus atezolizumab (840 mg, D1 and D15) and either paclitaxel (cohort II) or nab-paclitaxel [cohort III (100 mg/m2, D1, D8, and D15)]. Primary endpoints were investigator-assessed progression-free survival (PFS) (cohort I) and confirmed objective response rate (ORR) (cohorts II/III). Safety and tolerability were also assessed. RESULTS: In the expansion stages, median PFS was 5.5 months for cobimetinib/paclitaxel versus 3.8 months for placebo/paclitaxel in cohort I [hazard ratio 0.73; 95% confidence interval (CI) 0.43-1.24; P = 0.25]. In cohort I, ORR was 38.3% (95% CI 24.40-52.20) for cobimetinib/paclitaxel and 20.9% (95% CI 8.77-33.09) for placebo/paclitaxel; ORRs in cohorts II and III were 34.4% (95% CI 18.57-53.19) and 29.0% (95% CI 14.22-48.04), respectively. Diarrhea was the most common grade ≥3 adverse events across all cohorts. CONCLUSIONS: Cobimetinib added to paclitaxel did not lead to a statistically significant increase in PFS or ORR, although a nonsignificant trend toward a numerical increase was observed. Cobimetinib plus atezolizumab and a taxane did not appear to increase ORR. This demonstrates the potential activity of a combinatorial MEK inhibitor, chemotherapy, and immunotherapy in this difficult-to-treat population.

Secondary non-Hodgkin lymphoma of the ethmoid sinus after temozolomide.

The paranasal sinuses are rarely the site of malignancy, especially non-Hodgkin lymphoma. In such cases, the ethmoid sinus is the second most frequently involved paranasal sinus. Diagnosis of these malignancies is difficult because the early symptoms often mimic benign sinus pathology. Thus, most cases are diagnosed at an advanced stage, and their prognosis is poor. Here we describe the case of a 58-year-old man with a secondary high-grade B-cell non-Hodgkin lymphoma of the ethmoid sinus. This malignancy was diagnosed two years after the patient had received treatment with temozolomide for a glioblastoma multiforme. This case highlights that malignant tumours of the paranasal sinuses should always be included in the differential diagnosis of sinus disease. Additionally, patients treated with temozolomide should receive regular follow-up care including vigilant evaluation for secondary tumours, such as non-Hodgkin lymphoma.

Prospective non-interventional multicentre observational trial of first-line anti-cancer treatment in patients with metastatic renal cell cancer in Belgium.

OBJECTIVES: Renal cell carcinoma (RCC) accounts for 2·4% of all new cancers in Belgium. Over the past decade, the armamentarium for systemic therapy of metastatic RCC (mRCC) has undergone important changes with implementation of targeted therapies directed against pathways involved in the pathogenesis of RCC. We describe first-line treatment choice of a group of patients in 9 Belgian oncology centres between October 2009 and November 2012. METHODS: A clinical report form was established to assess patient characteristics, Karnofsky performance score, Memorial Sloan-Kettering Cancer Center risk criteria (MSKCC) and first-line therapy of mRCC patients. Choice of therapy and starting dose was analyzed before and after reimbursement of pazopanib in Belgium. RESULTS: Ninety-six patients were eligible for the study. Non-smokers accounted for 53% of the patients. Seventy-three per cent of the patients had 0 or 1 MSKCC criteria in the group of patients that started treatment more than 1 year after initial diagnosis. In the group of patients that started therapy less than 1 year after diagnosis, 85% had 2 or more MSKCC criteria. This difference was statistically significant (P<0·0001). Overall distribution of the first-line therapies consisted of 43% sunitinib, 33% pazopanib, 14% temsirolimus, 7% everolimus and 3% sorafenib. Seventeen (18%) out of 96 patients started at a reduced dose level. CONCLUSION: This report shows that the guidelines for the start of first-line treatment in mRCC in 9 centres in Belgium were applied most of the time: a tyrosine kinase inhibitor was the first treatment choice for most patients while temsirolimus was an option for poor prognosis patients. In the majority of patients standard dose levels were initiated, although in some patients adaptation of dosage/treatment schedule was recorded.

Antibiotic management of febrile neutropenia: current developments and future directions.

Mortality due to febrile neutropenia has decreased since the concept of empiric therapy became standard care. However, infectious complications remain the most common adverse events of chemotherapy. bacterial epidemiology has changed during the past decades. There is currently an increasing trend in infections due to Gramnegative bacteria which have higher rates of resistance for a variety of reasons.The use of biomarkers for diagnosis remains a domain of further investigation. Since the patient population with febrile neutropenia is very heterogeneous, models of risk assessment have been developed with the most commonly used today being the mASCC score.Oral antibiotic treatment seems to be appropriate in low-risk patients. In moderate or high-risk patients monotherapy is the most common option. However, due to emerging resistance this could change by next year. Some new antibiotics have been developed, but experience in the treatment of neutropenic fever is limited. The use of antibiotics for prophylaxis remains controversial, although recent studies suggest a reduction in death from all causes.

Long-term epidemiology of bacterial susceptibility profiles in adults suffering from febrile neutropenia with hematologic malignancy after antibiotic change.

OBJECTIVE: The aim of this study was to investigate the epidemiology and antibiotic susceptibility profiles of isolated bacterial organisms in relation to empiric treatment of neutropenic fever over a 15-year period. METHODS: All patients with or at risk for febrile neutropenia and treated in the hematology ward of the Antwerp University Hospital during 1994-2008 were prospectively included. Skin, blood, and urine cultures were taken. Oral quinolone prophylaxis was started in patients with neutropenia without fever. Empiric starting therapy consisted of amikacin in combination with cefepime. RESULTS: A total of 3624 bacteria were isolated. The most common pathogens were coagulase-negative Staphylococci (46%), followed by Escherichia coli (25%), Enterobacteriaceae (15.6%), Staphylococcus aureus (7.2%), and Pseudomonas aeruginosa (3.8%). The balance between Gram-positive and Gram-negative bacteria remained stable, with a majority of Gram-positive bacteria. A shift from oxacillin-sensitive to oxacillin-resistant coagulase-negative Staphylococci was observed. Regarding susceptibility patterns, no vancomycin resistance was detected in coagulase-negative Staphylococci or in S. aureus. The E. coli susceptibility rates remained stable. However, 66% of bloodstream infections were ciprofloxacin-resistant. A reduced susceptibility of P. aeruginosa strains to meropenem was noticed. CONCLUSIONS: Improvement in antibiotic susceptibility of inducible Enterobacteriaceae following a switch of empiric antibiotic therapy was maintained 15 years after starting the latter treatment. Further improvement in antibiotic susceptibility of these bacteria to ceftazidime was observed, but continuous vigilance is warranted.

Cefepime and amikacin as empirical therapy in patients with febrile neutropaenia: a single-centre phase II prospective survey.

The aim of the survey was to prospectively evaluate the effectiveness of the combination therapy cefepime and amikacin in the initial treatment of haematology patients with febrile neutropaenia. Two hundred twenty (220) episodes of febrile neutropaenia were analysed in 54 males and 82 females (median age 58 years), most patients had a severe neutropaenia with in 72% of all periods a neutrophil count of less than 100. Microbiological infection was confirmed in 72 cases (32.8%). Sixty-one (61) bacteria were isolated from blood cultures of which 22 were identified as Gram-negative bacteria and 38 as Gram-positive bacteria. Sixty-three (63) episodes (28.6%) were clinically documented, 85 episodes (38.6%) were fever of unknown origin. Clinical cure was achieved in 123 febrile episodes (56%) after initiation of the current antibiotic protocol; another 22 patients (10%) became afebrile after modifying the initial antibiotic regimen 48 hours or longer after treatment initiation. In 61 cases (27.7%) there was persistent fever or re-occurrence of fever, these cases were considered as treatment failure. Eight patients (3.6%) died during the study. This survey has demonstrated that the combination therapy with cefepime and amikacin can be considered as an effective treatment for febrile neutropaenia in high-risk haematological patients in our centre with a high incidence of resistance to Gram-negative bacteria.

Sclerosing peritonitis: an unusual cause of ascites in a patient with systemic lupus erythematosus.

Sclerosing peritonitis is a rare condition characterised by fibrosis and adhesion of the peritoneum to loops of the small intestine. It is generally associated with continuous peritoneal dialysis, peritoneo-venous shunts or &beta-adrenergic blocking agents. In this case we report a female patient with idiopathic sclerosing peritonitis and systemic lupus erythematosus.

Primary ovarian small cell carcinoma of the pulmonary type: a case report and review of the literature.

Small cell carcinoma of the ovary is a rare type of ovarian carcinoma with a poor prognosis. Two types should be distinguished: the hypercalcemic type and the pulmonary type. We report the case history of a 54-year-old woman with both a Stage IIIC small cell carcinoma, pulmonary type and a well-differentiated endometrioid adenocarcinoma of the left ovary in combination with a Brenner tumor in the right ovary. A review of the literature on small cell carcinoma of the ovary is given and the findings of our patient are brought into perspective in terms of both histopathogenesis and treatment outcome.

Prevention of anastomotic tumour take by on-table colon washout with povidone-iodine. an experimental study in rats.

The presence of organic material in the intestinal lumen is reported to interfere with the efficacy of cancericidals when used in low concentrations to prevent anastomotic recurrence in colorectal cancer surgery. We aimed at investigating the efficacy of intra-operative whole-colon washout using povidone-iodine in an experimental model of anastomotic tumour growth. A large inoculum of highly 'tumorigenic' carcinoma cells was instilled in the colonic lumen of Fischer rats. The whole-colon water washout was intended to remove the luminal organic material. This was followed by irrigation of increasing concentrations of povidone-iodine up to 5% with or without additional incubation for 10-20 min. Five animals died after 30 min incubation with povidone-iodine 5%. Tumour take was observed in all control animals including after irrigation with physiological saline. Increasing the povidone-iodine concentration from 1 to 5% reduced the rate of tumour take, but not significantly. The anastomotic tumour growth was significantly reduced after tumour cell inoculation followed by whole-colon lavage and luminal incubation for 20 min with povidone-iodine 5%. Application of intra-operative whole-colon washout to remove the luminal 'organic material' followed by luminal application of povidone-iodine 5% for a sufficient incubation time could reduce the risk of anastomotic recurrence in colorectal cancer surgery.

Local and systemic effects of intraoperative whole-colon washout with 5 per cent povidone-iodine.

BACKGROUND: Segmental intraluminal instillation of several tumoricidal agents including povidone-iodine has been advocated to prevent anastomotic recurrence after colonic resection for colorectal cancer. The local and systemic effects of on-table whole-colon washout using 5 per cent povidone-iodine were assessed in patients undergoing elective surgery for colorectal cancer. METHODS: The local effect of 5 per cent povidone-iodine on the colonic mucosa and the effect of colonic mucosal damage by povidone-iodine on tumour take was first investigated in Fischer 344 rats. In 12 euthyroid non-allergic patients, on-table whole-colon lavage via the appendix was performed. Systemic (thyroid function) and local (mucosal damage assessed by repeat biopsies) effects were studied, as well as the in vitro tumoricidal effect of the final anal effluent on tumour cell suspensions. RESULTS: After 30 min of contact with povidone-iodine the rat colonic mucosa was severely injured, with detachment of the epithelial cell layer. Povidone-iodine-induced 'colitis' did not result in tumour development after inoculation of 10(6) Mtln3 carcinoma cells in ten rats. Epithelial desquamation was also observed, in all but one patient, 1 and 4 h after colonic lavage. However, epithelial restitution started within 1 day and no abnormality was revealed after 3-7 days. Urinary iodine excretion increased markedly and was not within normal values after 1 week. Levels of thyroid hormones decreased significantly but became normal within 1 week. The anal effluent containing povidone-iodine was found to be tumoricidal in vitro on a human colonic carcinoma cell line and on a tumour cell suspension produced from the patient's tumour. CONCLUSION: On-table whole-colon washout using 5 per cent povidone-iodine seems clinically feasible. This technique deserves further study as a substitute for preoperative bowel preparation and may help to prevent recurrent cancer due to implantation of viable exfoliated tumour cells.

Decreasing antibiotic resistance of Enterobacteriaceae by introducing a new antibiotic combination therapy for neutropenic fever patients.

Prompt empiric antibiotic therapy is of critical importance for patients with neutropenic fever. However, a major concern with important clinical consequences is the emergence of bacterial resistance to antibiotics. After using ceftazidime with a glycopeptide as initial empiric therapy for neutropenic fever, we were confronted with a 75% reduced susceptibility rate to ceftazidime of inducible Enterobacteriaceae collected in 1994. The initial empiric therapy was therefore replaced in May 1995 by a combination of cefepime with amikacin, with addition of a glycopeptide after 48 h if necessary. After this change, we observed a significant decrease in reduced susceptibility of inducible Enterobacteriaceae, not only to ceftazidime, but also to amikacin, cotrimoxazole and ciprofloxacin. There was also a decrease in reduced susceptibility of non-inducible Enterobacteriaceae, such as Klebsiella spp, to ceftazidime. The reduction of resistance may be related at least in part to the combined use of cefepime together with an aminoglycoside. This study shows that it is possible to reverse bacterial resistance by modifying the antibiotic regimen used.

Experimental transferable vascular bed for laryngotracheal reconstruction: further observations.

Free fascia flaps have proven most reliable in providing a vascular bed for an epithelial free graft without adding bulk. They may be a useful tool for laryngotracheal reconstruction. A free flap consisting of a vascular network running in connective tissue can be developed on the rabbit external ear. The vascular characteristics of this flap were examined to test the reliability of the transferable vascular bed in laryngotracheal repair. The perichondrial free flap is useful for bringing an internal lining inside the lumen and for circumferential protection of supporting tissue. However, the natural tendency for surface contraction of perichondrium is a major disadvantage.

Major histocompatibility class II expression on the small intestinal nervous system in Crohn's disease.

Widespread alterations of the gut autonomic nervous system have been described in Crohn's disease. Immunohistochemistry shows that these alterations are associated with the expression of major histocompatibility (MHC) class II antigens (HLA-DR) on enteroglial cells in the ganglia of the submucous and myenteric plexuses and on the enteroglial sheaths of the nerve extensions. Neuronal cell bodies and extensions do not express MHC class II antigens. The class II expression is associated with the presence of UCHL1-positive T lymphocytes. MHC class II expression can also be found on endothelial cells and vascular smooth muscle cells but not on smooth muscle cells of the muscularis mucosae or propria. The intensity of MHC class II expression on the glial cells of the enteric nervous plexus and on endothelial cells correlates well with the intensity of class II expression on epithelial cells.