Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma.

PURPOSE: Promising new therapeutic options for follicular lymphoma (FL) include fludarabine plus mitoxantrone (FM) and the mouse/human anti-CD20 antibody, rituximab. We performed a randomized comparative trial of FM with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) front-line chemotherapy with and without sequential rituximab. PATIENTS AND METHODS: All previously untreated CD20(+) FL patients presenting in 15 Italian cooperative institutions from October 1999 were randomly allocated to FM or CHOP. Following clinical or molecular restaging, patients in complete remission (CR) with bcl-2/IgH negativity (CR(-)) received no further treatment; those in CR with bcl-2/IgH positivity (CR(+)) received rituximab, as did those in partial remission (PR) with bcl-2/IgH negativity (PR(-)) or positivity (PR(+)); nonresponders (NR subgroup) were off study. RESULTS: After chemotherapy, the FM arm achieved higher rates of CR (68% [49 of 72 patients] v 42% [29 of 68 patients]; P =.003) and CR(-) (39% [28 of 72 patients] v 13 of 68 patients [19%]; P =.001). Rituximab elicited CR(-) in 55 of 95 treated patients (58%). The final CR(-) rate was higher in the FM arm (71% [51 of 72 patients] v 51% [35 of 68 patients]; P =.01). However, with a median follow-up of 19 months (range, 9 to 37 months), no statistically significant difference was found among the various study arms in terms of both progression-free (PFS) and overall survival (OS). CONCLUSION: These results indicate that FM is superior to CHOP for front-line treatment of FL and that rituximab is an effective sequential treatment option. However, they also confirm that this superiority is unlikely to translate into either better PFS or OS.     

Oestrogen and progesterone receptors in melanoma and nevi: an immunohistochemical study

Background

The effect of hormonal stimulation and fertility treatments, on the development of malignant melanoma (MM) remains to be determined.

Objectives

The aim of this study was to investigate the presence of oestrogen receptor alpha (ERα) and progesterone receptor (PR) inMM and nevi after hormonal stimulation.

Materials & Methods

Immunohistochemical analyses were performed utilizing antibodies specifically directed against ERα and PR in MM and atypical nevi specimens from patients: (1) diagnosed during pregnancy, (2) diagnosed in the six months following delivery, or (3) who had undergone repetitive cycles of hormonal stimulation for in vitro fertilization (IVF) in the year that preceded MM diagnosis. Controls were atypical nevi and MM specimens of female patients of the same age group who had received no hormonal therapies and reported no pregnancies in the five years before diagnosis.

Results

Twenty-eight female patients at childbearing age were selected for this study. Strong cytoplasmic positivity of ERα and PRwas detected in atypical melanocytes of two MM specimens of patients who had undergone repetitive cycles of hormonal stimulation during IVF procedures. All other specimens showed no expression ofERαor PR.

Conclusion

Since our results represent preliminary findings, conclusions regarding a possible correlation between IVF therapy and melanoma occurrence cannot be ascertained. Larger laboratory studies should be performed to investigate reproductive hormone receptor expression in MM in women following IVF, pregnancy, prolonged contraceptive use, or hormone replacement therapy.

     

Adrenomedullin binding protein in the plasma of multiple species: characterization by radioligand blotting.

Frequently, peptide hormones circulate in plasma associated with specific binding proteins that modify the clearance and biochemical activities of the peptide. Our experimental approach was to use 125I-ligand blotting procedures to probe for the presence of specific adrenomedullin (AM) binding proteins (AMBPs). Plasma proteins from chick, calf, dog, goat, guinea pig, human, mouse, pig, rabbit and sheep blood were separated electrophoretically in 10% nonreducing SDS-polyacrylamide gels and transferred to nitrocellulose. Nonspecific binding of tracer was blocked on the nitrocellulose with a hydrolyzed casein matrix. Blots were probed with synthetic human 125I-AM. Autoradiogram scanning of blots revealed a mixture of 140- and/or 120- kD protein complexes that bound 125I-AM in all species tested. Binding of the ligand was specific as judged by a linear competitive displacement of the tracer binding from human, bovine and pig plasma AMBP bands with increasing concentrations of nonlabelled AM in the binding buffer. A series of peptide fragments of AM representing amino- and carboxyterminal regions of the hormone, or amylin, calcitonin gene-related peptide (CGRP), or insulin failed to displace intact 125I-AM from ligand blot bands. Bovine plasma proteins from healthy and parasitized calves with an infection-related stunting syndrome were separated electrophoretically, transferred to nitrocellulose and probed with 125I-AM; phosphoimage densitometry analysis revealed a 67% decrease in AMBP band intensity in the 120 and 140 kD proteins from infected calves. We conclude that a specific binding protein(s) for AM exists in mammalian and avian blood that might impact on the bioactivity and function of AM in health and disease.     

Impact of booster vaccination on the control of COVID-19 Delta wave in the context of waning immunity: application to France in the winter 2021/22

Europe has experienced a large COVID-19 wave caused by the Delta variant in winter 2021/22. Using mathematical models applied to Metropolitan France, we find that boosters administered to ≥ 65, ≥ 50 or ≥ 18 year-olds may reduce the hospitalisation peak by 25%, 36% and 43% respectively, with a delay of 5 months between second and third dose. A 10% reduction in transmission rates might further reduce it by 41%, indicating that even small increases in protective behaviours may be critical to mitigate the wave.     

CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab

KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)-specific monoclonal antibodies cetuximab and panitumumab-based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS-mutated cancer cell growth in vitro by natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), KRAS-mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS-mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fcγ-CR constructs including CD16^158F-CR, CD16^158V-CR, CD32^131H-CR, and CD32^131R-CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32^131H-CR (83.5 ± 9.5) and CD32^131R-CR (77.7 ± 13.2) were significantly higher than those expressing with CD16^158F-CR (30.3 ± 10.2) and CD16^158V-CR (51.7 ± 13.7) (p < 0.003). CD32^131R-CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16^158V-CR T cells released high levels of interferon gamma (IFNγ = 1,145.5 pg/ml ±16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNFα = 614 pg/ml ± 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16^158V-CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16^158V-CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16^158V-CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies.     

Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions

In our study, we investigated the role of CD39 on tumor-infiltrating CD8⁺ T lymphocytes (CD8⁺ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T-cell exhaustion, we demonstrated a divergent functional activity in CD39⁺CD8⁺ TILs. On the one hand, CD39⁺CD8⁺ TILs (as compared to their CD39⁻ counterparts) produced significantly lower IFN-γ and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39⁺CD8⁺ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8⁺ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39⁺CD8⁺ T-cell effector function ex vivo, and that CD39⁺CD8⁺ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39⁺CD8⁺ T-cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8⁺ TILs.     

Ovarian torsion: developing a machine-learned algorithm for diagnosis

Background

Ovarian torsion is a common concern in girls presenting to emergency care with pelvic or abdominal pain. The diagnosis is challenging to make accurately and quickly, relying on a combination of physical exam, history and radiologic evaluation. Failure to establish the diagnosis in a timely fashion can result in irreversible ovarian ischemia with implications for future fertility. Ultrasound is the mainstay of evaluation for ovarian torsion in the pediatric population. However, even with a high index of suspicion, imaging features are not pathognomonic.

Objective

We sought to develop an algorithm to aid radiologists in diagnosing ovarian torsion using machine learning from sonographic features and to evaluate the frequency of each sonographic element.

Materials and methods

All pediatric patients treated for ovarian torsion at a quaternary pediatric hospital over an 11-year period were identified by both an internal radiology database and hospital-based International Statistical Classification of Diseases and Related Health Problems (ICD) code review. Inclusion criteria were surgical confirmation of ovarian torsion and available imaging. Patients were excluded if the diagnosis could not be confirmed, no imaging was available for review, the ovary was not identified by imaging, or torsion involved other adnexal structures but spared the ovary. Data collection included: patient age; laterality of torsion; bilateral ovarian volumes; torsed ovarian position, i.e. whether medialized with respect to the mid-uterine line; presence or absence of Doppler signal within the torsed ovary; visualization of peripheral follicles; and presence of a mass or cyst, and free peritoneal fluid. Subsequently, we evaluated a non-torsed control cohort from April 2015 to May 2016. This cohort consisted of sequential girls and young adults presenting to the emergency department with abdominopelvic symptoms concerning for ovarian torsion but who were ultimately diagnosed otherwise. These features were then fed into supervised machine learning systems to identify and develop viable decision algorithms. We divided data into training and validation sets and assessed algorithm performance using sub-sets of the validation set.

Results

We identified 119 torsion-confirmed cases and 331 torsion-absent cases. Of the torsion-confirmed cases, significant imaging differences were evident for girls younger than 1 year; these girls were then excluded from analysis, and 99 pediatric patients older than 1 year were included in our study. Among these 99, all variables demonstrated statistically significant differences between the torsion-confirmed and torsion-absent groups with P-values <0.005. Using any single variable to identify torsion provided only modest detection performance, with areas under the curve (AUC) for medialization, peripheral follicles, and absence of Doppler flow of 0.76±0.16, 0.66±0.14 and 0.82±0.14, respectively. The best decision tree using a combination of variables yielded an AUC of 0.96±0.07 and required knowledge of the presence of intra-ovarian flow, peripheral follicles, the volume of both ovaries, and the presence of cysts or masses.

Conclusion

Based on the largest series of pediatric ovarian torsion in the literature to date, we quantified sonographic features and used machine learning to create an algorithm to identify the presence of ovarian torsion — an algorithm that performs better than simple approaches relying on single features. Although complex combinations using multiple-interaction models provide slightly better performance, a clinically pragmatic decision tree can be employed to detect torsion, providing sensitivity levels of 95±14% and specificity of 92±2%.