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.

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.

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.

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.

Histochemistry of gamma-glutamyl transpeptidase in human liver biopsies.

The histochemical activity of gamma-glutamyl transpeptidase is examined in human liver biopsy specimens in normal and pathological conditions. Different histochemical patterns can be recognized. In histologically normal liver a faint sinusoidal membrane staining is observed. In pathological liver tissue invariably a pronounced canalicular gamma-GT activity is detected in addition to the faint sinusoidal membrane activity. The canalicular staining pattern is variable in extent and staining intensity, without clear correlation with specific disease entities. Cases with severe degrees of cholestasis, however, show a "washed-out" appearance of the tissue, apparently parallel to the degree of cholestasis. This phenomenon may be explained by the detergent action of bile salts accumulating in cholestatic tissue.

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.

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.

The histopathology of reflux esophagitis.

The histological features of the esophageal mucosa in patients with gastroesophageal reflux are basal zone hyperplasia of the squamous epithelium, elongation of the papillae towards the epithelial surface, an increase in the transverse diameter of the papillae and the blood vessels, and an ingrowth of capillaries into the epithelial layers. The presence of polymorphonuclear leucocytes in the epithelium and the lamina propria clearly represents esophagitis. In the advanced stages, erosions and ulcerations can be seen. Intra-epithelial lymphocytes are present in the normal esophageal mucosa. They are mainly T-cytotoxic lymphocytes.

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.

Myofibroblasts in focal nodular hyperplasia of the liver.

Myofibroblasts have been identified by electron microscopy in a case of Focal Nodular Hyperplasia (FNH) of the liver associated with oral contraceptives. The contractile fibroblasts were observed in the immediate vicinity of, or in close contact with, the proliferating bile ductules and in the recesses between parenchymal cells. Transitional forms between fat-storing cells (Ito cells), fibroblasts and myofribroblasts were observed. Transition of fat-storing cells to myofibroblasts, possibly under the influence of oestrogens, may be responsible for the fibrosis and retraction in FNH.

PIP: The purpose of this discussion is to document the finding of contractile fibroblasts and to examine their possible origin in a further pathological process: focal nodular hyperplasia (FNH) of the liver. A 31-year old female patient underwent laparotomy for a hypochondrial mass. The patient had been taking OCs for 1 year. The mass was located in the right lobe of the liver and excision of the tumor was performed. Some distance from it a subcapsular hemangioma was discovered and resected. After 16 months of follow-up the patient is well. The tumor mass (10 cm diameter) grey in color, was very well demarcated, although not encapsulated. A central scar was present. Radiating septa divided the periphery of the mass into multiple, variable sized modules, simulating a pattern of focal cirrhosis. No areas of hemmorhage or infraction were observed. The hemangioma specimens showed multiple cyst-like cavities filled with blood. The bosselated and lobulated appearance was because of areas of fibrosis, which was most marked centrally. Vascular changes similar to those described by Mays et al. and bile ductular proliferation analogous to that described by others were seen. Single small bile ductules were frequently observed within parenchymal nodules, without any relation to the intranodular scars. Cells with elongated, cross banded nuclei were in close vicinity of the newly formed ductules. Inflammatory and fibroblast-like cells were seen in the fibrous connective tissue septa. The 2nd lesion showed the typical features of a cavernous hemangioma. Typical fibroblasts were identified by their elongated or star-like shape, the slender fusiform shape and relatively smooth outline of the nucleus, the well developed RER and Golgi apparatus, the scattered mitochondria, and the absence or scanty presence of cytofilaments. A large number of elongated cells exhibited the characteristic morphology of modified contractile fibroblasts (MF). They showed a variable amount of intracytoplasmic microfilaments, arranged in longitudinal bundles, usually parallel to the long axis of the cell predominantly located beneath the plasma membrane. Intracellular connections between modified fibroblasts were frequently observed; they were mostly of the macula-adherens type. The finding of contractile fibroblasts raises questions concerning the origin and the significance of such cells in FNH. Since MFs are similar to both fibroblasts and smooth muscle cells, it seemed reasonable to conclude that both cells, under appropriate conditions, may become MF. Fat storing cells of Ito may also be a progenitor of contractile fibroblasts.