At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

[Rhabdomyolysis in a worker exposed to paraffinic mineral oils. Unusual association with bronchiolitis obliterans and organizing pneumonia (BOOP)]. / Rabdomiolisi in operaio esposto ad olii minerali paraffinici. Insolita associazione con bronchiolite obliterante e polmonite organizzativa (BOOP).

We describe a 29-year-old worker; exposed to metal dust, sawdust and paraffinic mineral oils in a factory producing accessories for leather articles and clothing, who came to observation with fever (39 degrees C), chest pain and marked increase of muscular enzymes. Chest computed tomography showed two areas of lung consolidation, that subsequently appeared enlarged with central escavation. Lung biopsy lead to the diagnosis of BOOP. The case has been reported to the judicial and workers' compensation authorities as probable occupational toxic myopathy. Indeed, exposure to paraffinic mineral oils is a known, though unusual, cause of rhabdomyolysis. The association with BOOP has never been previously described.

Complete nodal staging in male breast cancer. (Biopsy of axillary and internal mammary sentinel node).

Carcinoma of the male breast is an uncommon phenomenon, accounting for < 1% of all malignancies in men. Searching for a more conservative treatment we introduced in our clinical practice axillary sentinel node biopsy and, if present, sentinel node biopsy of the internal mammary chain. The potential clinical implications of complete nodal staging are far-reaching, and give us a major new opportunity to stratify male patients with breast cancer for appropriate surgery as well as giving valuable prognostic information.

Granular cell traumatic neuroma: a lesion occurring in mastectomy scars.

BACKGROUND: Granular cell changes can be observed in a variety of benign and malignant tumors, and are seen more commonly in granular cell tumors, which in about 5% of cases develop in the breast. Granular cells also have been observed in sites of previous trauma, such as surgery, and are found to be inflammatory reactions of histiocytic origin. METHODS AND RESULTS: We investigated, morphologically and immunohistochemically, 2 granular cell lesions occurring in mastectomy scars after surgery for carcinoma. Both lesions were composed of strands and nests of large granular cells, haphazardly set in a background of fibrous tissue, with sparse inflammatory infiltrates. Several tortuous hypertrophic nerve bundles were also embedded in the fibrous tissue. A few of these nerve bundles showed degenerative changes and contained granular cells. Immunohistochemically, granular cells were positive for S100 protein, neuron-specific enolase, vimentin, and CD68 antigen. CONCLUSIONS: We consider these proliferative lesions of peripheral nerves to have the features of both granular cell tumor and traumatic neuroma. These cases indicate that traumatic neuroma can undergo extensive granular cell changes and constitute a previously unrecognized entity, which we provisionally label granular cell traumatic neuroma. Granular cell traumatic neuroma has to be taken into consideration when evaluating lesions occurring at mastectomy scars and should be differentiated from malignant tumors with granular cells, such as apocrine carcinoma and alveolar soft part sarcoma.

Malignant mesothelioma of the pleura. The reproducibility of the immunohistological diagnosis.

The reproducibility of the histopathological diagnosis of pleural malignant mesothelioma (MM), after supplementing routine H&E stain by immunohistochemistry (IH) in 77 cases of original diagnoses of MM, was assessed by examining interobserver variation between five pathologists. A battery of commercial antibodies (cytokeratins, vimentin, HMFG-2, anti Leu-M1 [CD15], BerEP4, B72.3 [TAG-72], carcinoembyonic antigen), considered to be useful in enhancing diagnostic accuracy, was used. The number of definitively classified tumors (accepted MM plus rejected MM) increased from 57 on H&E stain to 60 after IH, with 59 (76.6%) cases being accepted as true MM. Based on IH, the chance-adjusted interobserver agreement was poor (kappa w = 0.29) and lower than that observed on previous H&E alone. The intraobserver agreement for four of the five pathologists was rather good (kappa w = 0.54-0.56). The inter- and intraobserver concordance was higher in accepting than excluding the cases as MM. A larger number of cases were classified by all reviewers as mixed or sarcomatous variants after IH. In the interpretation of each immunostain, kappa values ranged from 0.19 for B72.3 to 0.62 for HMFG-2, which were respectively the least and the most consistently interpreted immunostains. The information additionally contributed by IH did not seem to change the pathologists' diagnoses very much in comparison with those made by routine H&E stain. Until highly specific and sensitive probes for the positive identification of MM become available, a careful scrutiny of routinely stained preparations still remains the most rewarding component of the diagnostic pathway.

Malignant mesothelioma of the pleura: interobserver variability.

AIMS: To assess the consistency of histopathological diagnosis of pleural malignant mesothelioma by estimating interobserver agreement between five pathologists. METHODS: Eighty eight histological sets pertaining to original diagnoses of pleural malignant mesothelioma were reviewed separately by each pathologist. Diagnostic likelihood was graded as definite (A), probable (B), possible (C), improbable (D), and definitely not (E) malignant mesothelioma. The following indexes were estimated: observed proportion of agreement (Po), kappa statistics and proportion of agreement for "positive" (Ppos) and "negative" (Pneg) diagnoses. RESULTS: Sixty cases (68.2%) were rated by at least three reviewers as A or B and by none of the others as D or E. Five (5.7%) were rated by at least two reviewers as D or E and by none of the others as A or B. Nine (10.2%) showed a serious disagreement, rated A or B and D or E. Agreement for sets obtained at necropsy/surgery (median kappa w = 0.57) was similar to that for endoscopic material (median kappa w = 0.54). Agreement was poor on material obtained by needle biopsy (median kappa w = 0.21). The median value of Ppos varied between 0.94 (necropsy/surgery) and 0.67 (needle biopsy) and that of Pneg between 0.78 (necropsy/surgery) and 0.34 (unspecified biopsy). Interobserver agreement on histological typing was good overall (median kappa = 0.59). CONCLUSIONS: Of the original histological diagnoses, 70% were consistently reproduced through panel review. Most indexes of agreement between pathologists ranged from poor (needle biopsy) to moderate (necropsy/surgery). Agreement in confirming malignant mesothelioma was greater than that regarding exclusion of this diagnosis. Of the cases finally considered to have malignant mesothelioma, the reproducibility of histological typing was relatively satisfactory.

[Cytodiagnosis by fine needle aspiration biopsy in laryngeal diseases]. / Cytodiagnostic par ponction a l'aiguille fine dans la pathologie laryngienne.

Aspiration cytodiagnosis is widely employed in head and neck tumors since it is atraumatic, it avoids neoplastic seeding and is highly reliable from a diagnostic standpoint. We used such method to support diagnosis in deep intramural laryngeal tumors, and in the post-radiotherapy evaluation of laryngeal areas coated with hard oedema and fibrosis. Needle aspiration was performed during direct laryngoscopy according to Kleinsasser. The method proved to be highly reliable for a diagnostic standpoint, with an agreement of 93% with the final histologic examination, higher than the one provided by traditional bioptic techniques.

Neurofibroma of vocal cord: case report.

A case of neurofibroma of the vocal cord is presented. Such an occurrence is quite rare, because of the unusual involvement site and because the lesion was not related to Von Recklinghausen disease. The pertinent literature is reviewed.

[Secretory carcinoma of the breast: clinicotherapeutic considerations and a review of the literature]. / Carcinoma secretorio della mammella: considerazioni clinico terapeutiche e revisione della letteratura.

Prompted by the observation of a case of secretory (juvenile) secretory carcinoma of the breast, the Authors review the literature on this extremely rare disease. In view of the biological characteristics of this type of tumour, the Authors maintain that to ensure radical surgery and correct staging a quadrantectomy operation combined with emptying of the axillary cavity should be performed in those cases complying with the tumour size indication (2 cm). In larger tumours they regard the Helsted operation as the only form of surgery guaranteeing an adequate degree of radicality.

Prognostic parameters in metastatic spread of laryngeal cancer: clinico-histopathological correlations.

The authors present a series of 130 patients with laryngeal tumours submitted to total or horizontal laryngectomy and to neck dissection. The possible correlations between the staging and histology of the primary lesion, tumour marker (LASA) and the incidence of lymph node metastases are examined. The information provided by clinical and histopathological parameters is no doubt useful, but the margin of clinical error is high. On the contrary, the tumour marker concentration (LASA) was significantly higher in the patients whose lymph nodes were found to be histologically invaded, than in those without metastatic spread. Consequently, the LASA test may assume clinical importance before surgical therapy and in the follow-up of treated patients.

Role of alveolar phospholipids in bleomycin-induced pulmonary fibrosis in the rat.

The events leading to the onset of the experimental bleomycin-induced pulmonary fibrosis are so far unknown, though recent observations emphasize the crucial role played by lung phospholipids and by alveolar macrophages. In an attempt to verify this point, a series of studies were undertaken by treating rats (CD-COBS) with intratracheal instillation of a single dose of bleomycin (1.5 U). At the same time a group of animals was pretreated with ambroxol (which is known to be a powerful inducer of surfactant production both in fetal and adult type II pneumocytes), 4 mg/kg body weight/day per os, 5 days before the treatment with bleomycin and up to the sacrifice of the animals at the 1st, 3rd, 7th, 14th or 28th day from the instillation. In our experimental model, the 14th day from the treatment with bleomycin seems to be a crucial time since it histologically corresponds to the proliferation of type II pneumocytes; furthermore, an increase of total lecithins in the alveolar spaces was observed, together with an increase of macrophage membrane fluidity. In the ambroxol-pretreated group a partial reduction of the rate of interstitial fibrosis was observed. At the 14th day from treatment the alteration of phospholipid levels was much less pronounced and the microviscosity of alveolar macrophages was similar to that of control animals. These data suggest that the onset of bleomycin-induced pulmonary fibrosis in the rat is characterized by an increase of alveolar lecithins and that this fact could modify the physico-chemical peculiarities of alveolar macrophages. Ambroxol shows a partially protective effect, perhaps by modulating the activity of type II pneumocytes.

Interstitial pneumopathy and low-dosage amiodarone.

In a 61-year-old man receiving chronic low-dosage amiodarone an interstitial pneumopathy was observed. In the absence of other causes, we suspected an adverse reaction to amiodarone, not least because of the similarity with histologic findings of cases previously reported. Drug withdrawal and cortisone administration led to resolution of the disease.

Extradural spinal lipomas. Report of two cases and review of the literature.

The authors present two cases of extradural spinal lipomas causing spinal cord compression, not associated with spinal dysraphism. Sixty-nine cases of such tumours have been reported in the literature. It is important to distinguish between two histological types of these neoplasms: angiolipoma and true lipoma. They have a different distribution in relation to age and site of occurrence. The outcome can be quite variable considering the greater surgical problems that true lipomas can cause.

Association of a malignant glioma and an aneurysm of the middle cerebral artery. Report of a case.

A case of association of a malignant glioma of the left frontal lobe and an aneurysm of the middle cerebral artery is reported and the available literature reviewed. The operative mortality of patients with the association of a brain tumor and a cerebral aneurysm is very high (40%). This is the third case reported in the literature in which it was possible to remove the tumor and clip the aneurysm with immediate good surgical results and it is the first case in which the technique of late surgery for malignant glioma was adopted.

Chronic treatment with phenytoin in rats: effects of peripheral nervous system.

60 albino Sprague-Dawley female rats, 250 g of body weight, were treated for 6 months with phenytoin 30 mg/100 g/die per os (mean plasma levels: 10-20 gamma/ml). Between 75 and 90 days of treatment motor and sensory nerve conduction velocities were examined along the tail (Miyoshi and Goto, 1973; Fiaschi et al., 1977) in 15 treated animals and in 10 untreated control animals. A slowing of sensory conduction velocity was shown in 6 treated animals (40%); in 2 of them (13%) the motor conduction velocity was also showed. 25 treated rats were controlled with the same neurophysiologic methods after 165-180 days of PHT treatment in comparison with 10 controls; a slowing of sensory conduction velocity was observed in 14 treated rats (56%) and a slowing of motor conduction in 5 of them (20%). The hystological and ultrastructural study carried out on the sciatic nerves of all animals revealed changes of myelinated fibres only in the animals with slowed motor conduction velocity. The non-myelinated fibres were apparently normal.

Bacillus of Calmette and Guérin and 7, 12-dimethylbenz(a)-anthracene carcinogenesis in mice.

The effects of single or repeated Bacillus of Calmette and Guérin (BCG) treatment on the onset of tumors induced by the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) injected at birth into Swiss mice were studied. Multiple doses of BCG, given at regular intervals significantly lowered the incidence of carcinogen-induced tumors. The DMBA-induced lung adenomas did not differ morphologically from the ones that appeared in mice simultaneously treated with both DMBA and BCG.