Update Breast Cancer 2022 Part 4 – Advanced-Stage Breast Cancer

For the treatment of patients with advanced HER2-negative hormone receptor-positive breast cancer, several substances have been introduced into practice in recent years. In addition, other drugs are under development. A number of studies have been published over the past year which have shown either an advantage for progression-free survival or for overall survival. This review summarizes the latest results, which have been published at current congresses or in specialist journals, and classifies them in the clinical treatment context. In particular, the importance of therapy with CDK4/6 inhibitors – trastuzumab deruxtecan, sacituzumab govitecan and capivasertib – is discussed. For trastuzumab deruxtecan, an overall survival benefit in HER2-negative breast cancer with low HER2 expression (HER2-low expression) was reported in the Destiny-Breast-04 study. Similarly, there was an overall survival benefit in the FAKTION study with capivasertib. The lack of overall survival benefit for palbociclib in the first line of therapy raises the question of clinical classification.Key words: advanced breast cancer, chemotherapy, endocrine therapy, antibody drug conjugates     

Update Breast Cancer 2022 Part 5 – Early Stage Breast Cancer

The treatment of patients with early stage breast cancer has changed in recent years due to the introduction of pembrolizumab, olaparib, and abemaciclib. These and other drugs with the same class of active ingredient are currently in trial for various indications. This review article summarizes the latest results that have either been presented at major conferences such as the ESMO 2022 or published recently in international journals. This includes reports on newly discovered breast cancer genes, atezolizumab in neoadjuvant therapy in HER2-positive patients, long-term data from the APHINITY study, and on how preoperative peritumoral application of local anesthetics can influence the prognosis. We also present solid data on dynamic Ki-67 from the ADAPT studies.Key words: breast cancer, surgery, chemotherapy, therapy standard     

Comparative in vitro activity of -ofloxacin and FK037 to other agents against 10,040 fresh clinical isolates

Fresh clinical isolates collected from November 1, 1992 through November 1, 1993, were tested by agar dilution against 26 different antimicrobial agents including FK037 and -ofloxacin. Among the 10 040 organisms tested were Staphylococcus aureus (n = 1222), methicillin-resistant Staphylococcus aureus (MRSA, n = 455), Staphylococcus epidermidis (n = 533), Staphylococcus hominis (n = 90), Staphylococcus hemolyticus (n = 89), Streptococcus pneumoniae (n = 144), Escherichia coli (n = 2326), Klebsiella pneumoniae (n = 745), Enterobacter cloacae (n = 258), Proteus mirabilis (n = 445), Pseudomonas aeruginosa (n = 998), and Stenotrophomonas (Xanthomonas) maltophilia (n = 102). Both -ofloxacin and FK037 inhibited 98% of S. aureus strains at 4 μg/ml. FK037 was at least 4 times more effective than the third generation cephalosporins against MRSA, inhibiting 79% of the strains at 16 μg/ml. While the potency of these agents looks promising, their clinical utility will depend in part upon the maximal dosage that can be safely administered.     

The morphology of the amelanotic Greene melanoma

Pieces of amelanotic Greene melanoma were transplanted onto the iris surface of rabbit eyes, where they started to grow rapidly after a dormant period of four to five days. Light microscopically, the melanoma cells appeared round or polygonal and contained large, lightly staining nuclei and prominent nucleoli. Electron microscopy revealed rather electron translucent nuclei containing only a small rim of heterochromatin immediately subjacent to the nuclear envelope. The very prominent, reticulated nucleoli frequently lay close to the nuclear surface. The cytoplasm of the cells showed a well developed Golgi field which contained myriad vesicles of different shape and density and cross-striated, membrane-bound organelles of early melanin synthesis. The mitochondria were short and the smooth-surfaced endoplasmic reticulum was inconspicuous. The rough-surfaced endoplasmic reticulum was sparse and exhibited predominantly short segments. Like other very active cells, the melanoma cells contained a multitude of ribosomes. Melanoma cells which were not completely surrounded by other cells exhibited numerous processes at the free cell surface and, directly subjacent to these, a layer of very electron dense cytoplasm, indicating that these cells may possess a certain amount of motility. Many light and electron microscopical aspects of the amelanotic Greene melanoma are identical or similar to human uveal melanomas, especially of the epithelioid variety. On morphological grounds it is therefore possible to suspect a close biological relationship of these tumors. Thus, the use of the Greene amelanotic melanoma as a model for study of diagnostic and therapeutic problems in opthalmology may be considered adequate.

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Zusammenfassung Stücke des amelanotischen Greene Melanoms wurden auf die Irisoberfläche von Kaninchenaugen verpflanzt, wo sie nach einer Ruhephase von vier bis fünf Tagen schnell an Größe zunahmen. Lichtmikroskopisch waren die Melanomzellen rund bis polygonal und zeigten außerordentlich große, helle Kerne mit prominenten Nucleoli. Elektronenoptisch erschienen die Zellkerne weitgehend durchlässig. Nur unmittelbar unter ihrer Oberfläche enthielten sie eine dünne Heterochromatinschicht. Die ausgeprägten Nucleoli hatten eine netzförmige Struktur und lagen häufig peripher. Das Cytoplasma der Melanomzellen enthielt einen stark entwickelten Golgi-Komplex mit Vesikeln unterschiedlicher Größe und Dichte und periodisch gestreiften, membranumgebenen Organellen der frühen Melaninsynthese. Die Mitochondrien waren verhältnismäßig klein, das glatte endoplasmatische Retikulum war unauffällig. Das rauhe endoplasmatische Retikulum bestand aus nur wenigen, kurzen Segmenten. Die Melanomzellen enthielten eine große Anzahl Ribosomen, wie viele besonders stoffwechselaktive Zellen. Melanomzellen, die nicht allseitig von anderen Zellen umgeben waren, wiesen eine ausgeprägte elektronendichte periphere Plasmaschicht auf und bildeten an ihrer freien Oberfläche Zellfortsätze. Sie besitzen daher möglicherweise eine gewisse Motilität. Viele licht- und elektronenmikroskopische Eigenschaften des amelanotischen Greene Melanoms entsprechen oder gleichen denen menschlicher Uveamelanome, insbesondere des epitheloidzelligen Typs. Die Morphologie läßt daher auf eine enge biologische Verwandschaft dieser Tumoren schließen. Es erscheint folglich gerechtfertigt, das amelanotische Greene Melanom als Modell zur Untersuchung diagnostischer und therapeutischer Fragestellungen in der Ophthalmologie zu verwenden.

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This investigation was supported by the Wasserman Professorship Fund     

DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress-induced apoptosis

The DHCR24 gene encoding for the 3beta-hydroxysterol delta24-reductase, an oxidoreductase involved in cholesterol biosynthesis, was isolated by subtractive hybridization as highly expressed in a short-term melanoma cell line derived from a cutaneous metastases (S/M2) compared to that obtained from the autologous primary tumor (S/P). DHCR24 (alias seladin-1, diminuto/dwarf1 homolog) has been reported to act as an antiapoptotic factor in neurons. Gene expression analysis by Northern blot confirmed that DHCR24 was 5-fold upregulated in S/M2 compared to S/P cells. High levels of DHCR24 gene expression were detected in 13/25 melanoma metastases and in 1/7 primary melanomas by real-time PCR, indicating that upregulation of this gene may occur in melanoma progression. In S/M2 cells, high DHCR24 gene expression associated with resistance to apoptosis triggered by oxidative stress induced by exposure to hydrogen peroxide. DHCR24 gene transfer was shown to protect melanoma cells from H2O2-induced cytotoxicity. Although higher cholesterol levels were shown in S/M2 cells compared to S/P cells, DHCR24 gene transfer did not increase cholesterol content. To evaluate whether DHCR24 acts as an antiapoptotic factor in melanoma metastases, the cytotoxic effect of chemotherapeutic agents was tested in DHCR24 transfectants and in the presence of a DHCR24 inhibitor, U18666A. High DHCR24 gene expression in transfectants did not result in a higher resistance to cytotoxic agents; treatment with U18666A was cytotoxic in S/P cells with a lower DHCR24 content and showed additive cytotoxic effect only when associated with H2O2 and not with cysplatin or etoposide, indicating that the DHCR24 protective effect is exerted through an oxidative stress-specific mechanism.     

Physiological and pharmacological properties of a modified Brooke ileostomy: justification for retaining the most distal ileum

Purpose

The traditional Brooke ileostomy removed the last 8–15 cm of the ileum due to concern of occurrence of terminal ileal Crohn’s disease, vide infra the ileocolic sphincter was removed. Retaining all the terminal ileum has the potential of retaining the ileocolic sphincter. Our aim was to investigate whether a high-pressure zone existed within the last few centimetres of the ileum and its response to pharmacological stimuli.

Methods

A balloon manometry catheter was introduced into the stoma of 16 patients who had formation of an end ileostomy (ileocolic sphincter retained, ICS). Recordings were made at 1 cm intervals from the meatus in order to identify the maximum intra-luminal resting and intra-abdominal pressure. At the point of maximum resting pressure, the response to phenylephrine (10 % gel) and glyceryl trinitrate (GTN) (0.2 % paste) was recorded. Results were recorded using an Ohmeda Oestiva 5 manometry system (in millimeter of mercury) and data were analysed using ANOVA. Results were compared with 13 historical controls (ileocolic sphincter removed).

Results

There was no significant difference in resting intra-abdominal pressure between the two groups (historical controls 8.5?±?3.0 mmHg; ICS 9.0?±?3.2 mmHg), p?=?NS. The maximum resting intra-luminal pressure in ICS patients exceeded historical controls 16?±?2.9 vs 10.0?±?2.5 mmHg, p?<?0.001. In ICS patients, phenylephrine increased the resting pressure to 26.0?±?3.5 mmHg, p?<?0.001. In historical controls, the pressure remained unchanged, 12?±?4.7 mmHg, p?=?NS. Subsequent addition of GTN to both groups lowered maximum intra-luminal pressure to pre-study values, 10?±?4.2 mmHg (ICS) and 7?±?3.5 mmHg (controls), p?=?NS.

Conclusion

Retention of the ileocolic sphincter in a modified Brooke ileostomy preserves a physiological high-pressure zone, the properties of which can be modified by pharmacological agents.     

Endoscopically controlled sinus floor augmentation. A preliminary report.

Sinus augmentation has been advocated to be a surgical technique with predictable results in peri‐implant surgery. Endoscopic surgery of the maxillary sinus so far has been used as diagnostic procedure. In this paper, the use of endoscopy is described as a low invasive adjunctive technique in sinus floor augmentation. After preparation of the mucoperiosteum, bone grafts can be placed under endoscopic control between sinus floor and mucoperiosteum. A laterobasal approach via a small osteotomy and a transalveolar approach are possible for mucosal elevation and graft placement. First clinical results are reported. Endoscopic sinus lift may contribute to a reduction of perioperative morbidity, reduction of oroantal fistulae and control of graft position. The less invasive technique may allow to extend the indication for sinus augmentation.