Secondary Lymphedema: Clinical Interdisciplinary Tricks to Overcome an Intriguing Disease.

Secondary lymphedema is a complex pathology which is very impairing to the patient, consisting of fluid accumulation in the tissue, accompanied by alteration of the interstitial fibrous tissue matrix, deposition of cellular debris and local inflammation. It develops mostly in limbs and/or external genitals because of demolishing oncological surgery with excision of local lymph nodes, or it may depend upon inflammatory or infective diseases, trauma, or congenital vascular malformation. Its treatment foresees various approaches, from simple postural attitude to physical therapy, to minimally invasive lymphatic microsurgery.

Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema.

Background: Milroy-like disease is the diagnostic definition used for patients with phenotypes that resemble classic Milroy disease (MD) but are negative to genetic testing for FLT4. In this study, we aimed at performing a genetic characterization and biochemical analysis of VEGF-C variations found in a female proband born with congenital edema consistent with Milroy-like disease.

Methods: The proband underwent next-generation sequencing-based genetic testing for a panel of genes associated with known forms of hereditary lymphedema.

Therapeutic Regeneration of Lymphatic and Immune Cell Functions upon Lympho-organoid Transplantation.

Lymph nodes (LNs) are secondary lymphoid tissues that play a critical role in filtering the lymph and promoting adaptive immune responses. Surgical resection of LNs, radiation therapy, or infections may damage lymphatic vasculature and compromise immune functions. Here, we describe the generation of functional synthetic lympho-organoids (LOs) using LN stromal progenitors and decellularized extracellular matrix-based scaffolds, two basic constituents of secondary lymphoid tissues.

Development of functionally patent lymphatic meshes in postsurgical long-term resolution of peripheral secondary lymphedema.

Objective: In oncologic surgery, secondary lymphedema of male external genital organs and upper or lower limbs frequently develops as a result of excision or mechanical obstruction of collecting lymphatic trunks. We evaluated whether the short-term and long-term outcomes of microsurgical treatment of limb and genital organs improves tissue drainage in patients with secondary lymphedema by restoring the pre-existing lymphatic networks or through new lymphangiogenesis.

Methods: Of 110 secondary lymphedema patients, microsurgery was performed in 45 hospitalized patients.

Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed.

Assessment and follow-up of patency after lymphovenous microsurgery for treatment of secondary lymphedema in external male genital organs.

Secondary lymphedema of external male genital organs is a frequent complication of pelvic radical surgery following pelvic lymphadenectomy. Microsurgical lymphovenous anastomoses are usually performed using only the superficial scrotal lymphatics, excluding testicular lymphatic drainage. We have experimented using a new microsurgical technique based on lymphovenous anastomosis between the collectors of the spermatic funiculus and the veins of the pampiniform plexus, allowing testicular lymphatic drainage.

Peripheral blood lymphocytes genetically modified to express the self/tumor antigen MAGE-A3 induce antitumor immune responses in cancer patients.

Dendritic cell (DC) targeting in vivo has recently been shown to confer strong and protective cytotoxic T lymphocyte (CTL)-based immunity in tumor murine models. Our group has recently demonstrated in preclinical models that the infusion of genetically modified lymphocytes (GMLs) expressing the self/tumor antigen TRP-2 is able to elicit functional TRP-2-specific effectors with antitumor activity by targeting DCs in vivo. Here we have analyzed vaccine- and tumor-specific immune responses of 10 melanoma patients treated with autologous GMLs expressing the cancer germline gene MAGE-A3.

Secondary scrotal lymphedema: a novel microsurgical approach.

Secondary scrotal lymphedema is an infrequent complication of radical cystectomy assiociated with pelvic lymphadenectomy. We report a case of secondary lymphedema of male genitalia presenting more than 4 years after a radical cystectomy with extended pelvic lymphadenectomy for adenocarcinoma of the bladder. Microsurgical lymphovenous anastomoses are usually performed using only the scrotal lymphatics excluding the testicular lymphatics drainage.

Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity.

The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of tyrosinase-related protein 2-transduced (TRP-2-transduced) lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice.

Tolerance to cannabinoid response on the myenteric plexus of guinea-pig ileum and human small intestinal strips.

1. We studied tolerance to cannabinoid agonist action by comparing the in vitro inhibition of electrically evoked contractions of longitudinal muscle from small intestine of human and guinea-pig (myenteric plexus preparations) after 48-h incubation with the synthetic agonist (+) WIN 55,212-2. We also investigated the intrinsic response to the selective cannabinoid CB(1) receptor antagonist rimonabant in control and tolerant strips.

Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P.

Background And Aims: Diverticulosis is a common disease of not completely defined pathogenesis. Motor abnormalities of the intestinal wall have been frequently described but very little is known about their mechanisms. We investigated in vitro the neural response of colonic longitudinal muscle strips from patients undergoing surgery for complicated diverticular disease (diverticulitis).

Transmural pressure in rat initial subpleural lymphatics during spontaneous or mechanical ventilation.

The role played by the mechanical tissue stress in supporting lymph formation and propulsion in thoracic tissues was studied in deeply anesthetized rats (n = 13) during spontaneous breathing or mechanical ventilation. After arterial and venous catheterization and insertion of an intratracheal cannula, fluorescent dextrans were injected intrapleurally to serve as lymphatic markers. After 2 h, the fluorescent intercostal lymphatics were identified, and the hydraulic pressure in lymphatic vessels (P lymph) and adjacent interstitial space (P int) was measured using micropuncture.

Transmural pressure during cardiogenic oscillations in rodent diaphragmatic lymphatic vessels.

Background: The mechanism of initial lymphatic filling and the role of cardiogenic tissue motion in promoting lymph formation and propulsion are at present still controversial issues, in particular when considering interstitial tissues whose fluid pressure is well below atmospheric. To elucidate these aspects, the micropuncture technique was used to record interstitial (P(int)) and intralymphatic pressure (P(lymph)) simultaneously in the diaphragmatic lymphatic plexus draining the pleural cavity.

Methods And Results: The diaphragmatic lymphatic network was identified in anesthetized rabbits and rats through fluorescent dextrans injected intrapleurally.

Functional assessment of neuronal cannabinoid receptors in the muscular layers of human ileum and colon.

Background & Aims: The notion that specific receptors account for the ability of natural and synthetic cannabinoids to alter physiological functions, prompted this study aimed at assessing their functional presence in the human gut.

Methods: The effects have been studied of cannabinoids and selective antagonists of their receptors on chemically or electrically evoked contractions in preparations of human intestinal smooth muscle in vitro.

Results: Atropine prevented the contractions of longitudinal and circular muscle strips of ileum and colon induced by carbachol or electrical field stimulation; tetrodotoxin abolished only the latter which suggests they do involve activation of cholinergic neurons.

[Advanced age as risk factor in liver resection surgery].

To evaluate the influence of age on the outcome of liver resections, 105 consecutive patients undergoing hepatic resection were divided into two groups: age > or = 65 years [Old Group (O-Group)] and age < 65 years [Young Group (Y-Group)]. O-Group and Y-Group patients were analyzed comparatively in terms of primary diagnosis, concomitant diseases, previous surgery, type of operation (major or minor resection), associated procedures, presence and length of portal clamping, intraoperative blood losses and transfusions, and length of operation. The end points of the study were postoperative mortality, morbidity, transfusions, and length of post-operative hospitalization.

Role of hepatic resection in the treatment of hepatolithiasis.

Background: The aim of the present study was to evaluate the safety and the efficacy of hepatic resection in the treatment of hepatolithiasis with intrahepatic biliary strictures.

Experimental Design: retrospective study.

Setting: University hospital, Italy.

Right hepatic artery indwelling catheter for adjuvant chemotherapy after right hepatectomy.

Intraarterial hepatic adjuvant chemotherapy after radical hepatic resection for liver metastases from colorectal carcinoma lowers the rate of liver disease relapse. The technique for catheter implantation in the right hepatic artery for subsequent intraarterial hepatic adjuvant chemotherapy after right hepatectomy is herein described and recommended as an effective alternative approach to the standard catheter implantation in the gastroduodenal artery in cases of hepatectomies for liver metastases from colorectal cancer.

Functional assessment of beta adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle.

Background And Aims: The subtype and species related heterogeneity of beta adrenoceptors prompted a functional reappraisal of these molecular targets of motility inhibition in the human colon.

Methods: Relaxation of muscle strips was measured in vitro.

Results: The following agonists had decreasing relaxing potency (effective concentration range 10(-8)-10(-4) mol/l): (-)isoprenaline (non-selective), terbutaline (beta(2) selective), CGP 12177 (beta(3) selective, also beta(1), beta(2) antagonist), and SR 58611A (beta(3) selective).

In vitro functional evidence of different neurotensin-receptors modulating the motor response of human colonic muscle strips.

1. The newly developed non-peptide neurotensin (NT)-receptor antagonists SR 48692 and SR 142948 were used to challenge NT responses of human colonic circular smooth muscle strips in vitro. The presence of NT1 and NT2 receptor transcripts in this tissue was tested by reverse transcriptase polymerase chain reaction (RT - PCR) analysis.

In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum.

We investigated the effect of the cannabinoid agonist (+)WIN-55212-2 on human ileum longitudinal smooth muscle preparations, either electrically stimulated or contracted by carbachol. Electrical field stimulation mostly activated cholinergic neurons, since atropine and tetrodotoxin (TTX), alone or coincubated, reduced twitch responses to a similar degree (85%). (+)WIN-55212-2 concentration-dependently inhibited twitch responses (IC50 73 nM), but had no additive effect with atropine or TTX.

In vitro characterization of tachykinin NK2-receptors modulating motor responses of human colonic muscle strips.

1. Human in vitro preparations of transverse or distal colonic circular smooth muscle were potently and dose-dependently contracted by neurokinin A (EC50, 4.9 nM), the tachykinin NK2-receptor selective agonist [beta-Ala8]neurokinin A (4-10) ([beta-Ala8]NKA (4-10)) (EC50, 5.

Distribution of diaphragmatic lymphatic lacunae.

The morphology of the submesothelial lymphatic lacunae on the pleural and peritoneal surface over the tendinous and muscular portion of the diaphragm was studied in 10 anesthetized rabbits. The lymphatic network was evidenced by injecting 1 ml of colloidal carbon solution in the pleural (n = 5) or the peritoneal (n = 5) space. After 1 h of spontaneous breathing, the animal was killed and the diaphragm was fixed in situ by injection of approximately 5 ml of fixative in pleural and peritoneal spaces.

[Pyeloureteral junction syndrome caused by "anomalous vessel"].

In presenting and describing the pathogenesis of the pyeloureteral junction syndrome, the Authors report their recent experience with four cases due to an "abnormal vessel". Symptoms, diagnosis, and surgical techniques are discussed.