El Nobel Watson revoluciona el debate sobre el futuro del cáncer

Un día después de la publicación de los prometedores datos de la evolución del cáncer en EE UU (baja la incidencia de todos los tipos menos el del papiloma), el Nobel James Watson, codescubridor de la doble hélice de ADN en que se basa toda la genética actual, ha puesto patas arriba el debate sobre el futuro de este conjunto de enfermedades, la segunda, tras las cardiovasculares, en mortalidad en los países ricos.
Watson, de 84 años (nació el 6 de abril de 1928 en Chicago) ha utilizado una revista nueva, Open Biology, creada en 2011. La publicación tiene solo edición digital y es de acceso libre (con acreditación). Es tan joven que todavía no tiene un factor de impacto (el índice que mide su importancia en función de las veces que sus artículos son citados por otros autores). En el artículo, el polémico científico afirma que las nuevas terapias basadas en la genética no serán la solución para el cáncer, y critica la moda de los antioxidantes, indicando que pueden hacer más daño que bien a los enfermos.
En una entrevista a Reuters, Watson, que lleva años preparando su artículo, afirma que las nuevas terapias, basadas en la caracterización genética de cada tipo de tumor, “funcionan solo durante unos meses”, y que “no hay nada para las metástasis de pulmón, colon y mama”.

El papel de los antioxidantes es más complejo. Por un lado, reducen los radicales libres que deterioran el ADN. Pero, precisamente, su creación es uno de los medios por los que actúan tratamientos como la quimioterapia, ya que al actuar sobre el ADN matan las células. “Todo el mundo pensaba que los antioxidantes eran buenos, pero pueden impedir que curemos el cáncer”, dice Watson.
Por último, el científico, que hizo su gran descubrimiento con 25 años (junto a Francis Crick y una científica cuyo papel se ha reivindicado después, Rosalind Franklin) y recibió el Nobel en 1962, a los 34, fiel a su fama de iconoclasta de la ciencia concluye que “el principal obstáculo para la curación del cáncer es el carácter conservador inherente a los estamentos que lo investigan”, y que “mientras esto siga así, la curación estará siempre a 10 o 20 años vista”.
Las polémicas declaraciones del investigador han tenido unas medidas reacciones: no es fácil contradecir a un Nobel con su carisma. María Blasco, directora del Centro Nacional de Investigaciones Oncológicas (CNIO), defiende, en líneas generales, el artículo: “Watson ha sido y es un líder de opinión y un visionario en temas claves de la biología y biomedicina moderna”, afirma. “Hace una revisión del estado actual y las perspectivas de futuro de varias de las rutas moleculares que se han propuesto como claves en el desarrollo y tratamiento del cáncer. Es una revisión bastante extensa, completa, y critica. Tras 40 años de investigación en los mecanismos moleculares del cáncer, los éxitos no han sido los previstos y esto es debido a que el problema del cáncer es mucho más complejo de lo que se preveía”, afirma. “Lo que hace es pedir que seamos creativos”. Por eso, “en definitiva, creo que cualquiera que investigamos en el cáncer podemos encontrar de interés esta revisión y artículo de opinión de Watson”, dice Blasco.

La investigadora también descarta que haya cierto oportunismo en el autor. “Watson ha estado interesado en el problema del cáncer desde que se inicio el estudio molecular”, y prueba de ello es que "a sus más de 80 años se inscribió —como lo haría cualquier estudiante— en una de las conferencias del cáncer del CNIO sobre el tema de Cáncer y metabolismo, ya que considera que esta es una de las vías de ataque prometedoras contra el cáncer".
Pero frente a esta visión tan positiva, otros colegas de Blasco tienen más dudas.
“No se trata de un trabajo demasiado novedoso si no fuera porque lo escribe Watson”, opina Rogelio González Sarmiento, investigador en el Centro de Investigación del Cáncer (CIC) de Salamanca en declaraciones a la web SINC.

El presidente de la Sociedad Española de Oncología Médica, Juan Jesús Cruz, cree que las acusaciones del artículo —“en una revista poco importante”— “no tienen mucho sentido”. “El esfuerzo que se está haciendo es muy grande. En 2015 probablemente tengamos un mapa de los tumores, que no sé lo que habrá costado. A su desesperanza yo opongo la de que tengamos en unos años 20 o 30 vías comunes de las metástasis”, ha dicho. Sobre los antioxidantes cree que Watson exagera: “El efecto de las terapias es tan destructivo que por muchos antioxidantes que se tomen dudo que se anule”.

En EE UU también hay dudas. Por ejemplo, Robert Weinberg, del prestigioso MIT, ha defendido la aproximación genética, y ha explicado que lo que ocurre es que cuando se bloquea una vía de proliferación del cáncer, este muta y encuentra otra.
En cambio, sobre el tema de los antioxidantes, le dan la razón: lo que es bueno como medida preventiva, puede no serlo cuando ya ha aparecido el tumor. “Todo lo que mantenga el cáncer lleno de radicales libres es un componente efectivo del tratamiento”, ha dicho Robert Benezra, del Sloan-Kettering Cancer Center de Nueva York.

FUENTE: EL PAÍS.

Trichoscopy of Non-Cicatricial Alopecia.

MAIN FINDINGS

Alopecia areata
Micro-eclamation mark hairs, tapered hairs, black dots, yellow dots, upright regrowing hairs, pigtail regrowing hairs, vellus hairs and broken hairs.

Androgenetic alopecia
Increased proportion of thin and vellus hairs, hair shaft thickness heterogeneity, perifollicular discoloration (hiperpigmentation), and presence of variable number of yellow dots

Telogen effluvium
Upright regrowing hairs and predominance of hair follicle openings with only one emerging hair shaft.

Psoriasis 
Silver-white scales, red dots and globules, twisted red loops, and glomerular vessels.

Seborrheic dermatitis
Yellowish scales, arborizing vessels and atypical red vessels.

Tinea capitis
Comma hairs, corckscrew hairs, broken hairs, damaged hairs, black dots, zigzag hairs and interrupted hairs.


ALGORITHM

- Yellow dots: Numerous: Alopecia areata (AA)
                      A few:  Other alopecia: hypotrichosis congenita, Kerion celsie..
                                  Hair diameter diversity (≥20%), perifollicular pigmentation ⁄peripilar sign: AGA

- Black dots and/or broken hairs:  Tapering hairs (exclamation mark hairs): AA
                                                      Short vellus hairs: AA
                                                      Curled hairs: Trichotillomania                                               
                                                      No findings: AA and/or trichotillomania

                                                      Others: Tinea capitis, chemotherapy - induced alopecia, after laser depilation or trichogram.
- Others:  Perifollicular scale/sebum: Seborrheic alopecia
                Short vellus hairs, many: AA remitting
                Comma hairs: tinea capitis
                No findings: Telogen effluvium
              

UpToDate: Management of SJS/TEN.

• Early recognition and immediate withdrawal of any potentially causative agents are critical first steps in the management of SJS/TEN.
• Multiple specialists should be involved in the care of patients with SJS/TEN when possible, including experts in critical care, plastic surgery, dermatology, infectious disease, ophthalmology, and nutrition.
• For patients with extensive desquamation, we suggest transfer to a burn unit if possible (Grade 2C).
• The optimal approach to wound care has not been determined. Success has been reported with both repeated debridement of exfoliating skin, and "anti-shear" wound care, in which the necrotic skin is left in place to act as a biologic dressing.
• Sepsis is the major cause of death. Sterile handling, infection control measures, topical antibiotic agents, and surveillance cultures of possible sites of superinfection are important components of prevention. Prophylactic systemic antibiotics are not utilized by the majority of burn centers, although antimicrobials should be administered at the first sign of infection, and choice of agent should be guided by specific culture data.
• Supportive care should be the primary focus of management of SJS/TEN. Beyond this, there is insufficient evidence to establish the benefit of any adjunctive therapies (table 1). Systemic glucocorticoids and intravenous gammaglobulin (IVIG) are commonly used at many centers, although not all. Our approach is described below.
• For children (aged 16 years and younger) with SJS, we suggest NOT administering glucocorticoids (Grade 2C).
• For adult patients with mild to moderate SJS, in whom the diagnosis has been made within a few days of symptom onset, we suggest high dose, short-term systemic glucocorticoids (Grade 2C). We typically use prednisone, 2 mg per kg daily or an equivalent amount of prednisolone or methylprednisolone, initiated as soon as possible after diagnosis. Glucocorticoids are discontinued after four to seven days or at the first sign of infection.
• For pediatric and adult patients with severe SJS and TEN, we suggest IVIG (Grade 2C). We administer a dose of 1 gram/kg daily for three consecutive days. We do not administer glucocorticoids, due to concern about increasing the risk of sepsis, or employ plasmapheresis in the treatment of TEN.
• The mortality of SJS is 1 to 3 percent, while the mortality of TEN ranges from 25 to 35 percent. Predictors of mortality include older age at onset and greater extent of skin involvement. Long-term sequelae of the skin and eyes are common among survivors.

For more information:

Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae
Whitney A High, MD Milton H Nirken, MD	UpToDate

Hair Transplantation and Cicatricial Alopecia.

Unger W, Unger R & Wesley C. The surgical treatment of cicatricial alopecia. Dermatologic Therapy 2008: 21: 295–311.

Do not miss this book: Unger WP, Shapiro R. Hair Transplantation, 4th edn. New York: Marcel Dekker, 2004.


Availability of donor hair 
The long-term donor-recipient area ratio – that is, the ratio of “permanent” donor hair relative to the ultimate size of present, as well as future areas of alopecia that might develop – is perhaps the most important factor to consider. In many patients, however, the ratio is inadequate to satisfactorily treat both the current and possibly future areas of cicatricial alopecia, in addition to addressing surrounding areas that are likely to develop male pattern baldness (MPB) or female pattern hair loss (FPHL). Furthermore, if donor hair is taken from an area that is eventually destined to lose its hair secondary to MPB/FPHL or some of the diseases that cause unstable cicatricial alopecias (UCAs), it will also be lost in the recipient area.
Given the difficulty in accurately estimating this ratio, excision is generally preferable to hair transplanting. This is especially true with respect to larger alopecic regions in younger individuals, while older patients with small areas of scarring may often be appropriately treated with hair transplantation.

Scalp laxity
The less scalp laxity, the more preferable hair transplantation is to excision.

Patient’s healing characteristics 
Hypertrophic or keloid scars, less or greater than average scalp laxity (especially those with Elhers–Danlos syndrome), and individuals who have experienced inexplicable excessive postoperative bleeding in the past favor a decision to utilize hair transplantation as opposed to excision.

Vascular circulation
Grafts in the center of a large scar are most distant from a good blood supply. To test the blood supply of a large area, it is recommended that one first anesthetize a portion of the area with a 2% lidocaine solution without epinephrine. Then a 19-G needle can be used to make several incisions. There should be evidence of bleeding when this is done. If not, the area would be best treated with surgical excision.

Area of involvement
Hair transplantation is preferable in sites such as the hairline and eyebrow. If excision is employed, ideally the surgeon should use a “trichophytic” closure in which a narrow zone of the epidermis of one flap of the wound is removed and the wound is closed in such a way as to result in hair which grows through the scar itself.

Melanoma, Vemurafenib and Ipilimumab.

Vemurafenib 

It has been approved in Europe for use in the treatment of patients with unresectable or metastatic melanoma whose tumors have a BRAF mutation. About 50% of patients with melanoma have this BRAF mutation. A companion diagnostic test, the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), is already commercially available.A post hoc analysis showed that vemurafenib significantly improved median survival, compared with dacarbazine (13.2 vs 9.6 months): N Engl J Med 2011; 364: 2507-16.       

Potential adverse events include severe allergic reactions, severe skin reactions, cardiac events such as QT prolongation (which can be potentially life-threatening), abnormal liver function tests, eye problems, and new melanoma lesions. Common adverse effects include joint pain, rash, hair loss, tiredness, sunburn or sun sensitivity, nausea, itching, and warts.

Patients with advanced melanoma who are treated with vemurafenib should be tested for RAS mutations!! The testing is important because there is "potential for secondary tumor development" that arises from treatment with vemurafenib. Thus, patients with RAS mutations could also develop secondary cancers in organs beyond the skin, namely cutaneous squamous cell carcinoma and keratoacanthomas.

 Ipilimumab 

 

Ipilimumab is a fully human monoclonal antibody (IgG1) that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an immune checkpoint molecule that downregulates pathways of T-cell activation. By inhibiting CTLA-4, ipilimumab acts to "release the brake" on the immune system. The role of CTLA-4 is to guard against unwanted and harmful self-directed activities (ie, autoimmunity). 

Treatment Arm	12 months (%)	18 months (%)	24 months (%)
Ipilimumab + gp100	43.6	30.0	21.6
Ipilimumab alone	45.6	33.2	23.5
gp100 alone	25.3	16.3	13.7

Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711–723 (2010).
•• First Phase III study to demonstrate the efficacy of ipilimumab in patients with advanced melanoma. 

 

A more recent Phase III trial comparing treatment with ipilimumab with dacarbazine versus dacarbazine alone has also provided evidence for efficacy of ipilimumab in melanoma patients with improved overall survival in the ipilimumab plus dacarbazine group (11.2 months vs 9.1 months) and durable responses in a small number of patients. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364(26), 2517–2526 (2011).

The current dosing of ipilimumab is 3 mg/kg of body weight, administered by intravenous infusion over 90 minutes once every 3 weeks, for a total of 4 treatments. Disease regression has been reported 3-6 months following treatment initiation. In addition, a partial response followed by stable disease has been noted. Complete responses have been recorded approximately 1 year after receiving therapy.

The most common severe immune-mediated adverse reactions are: enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. These reactions often can be mitigated by withholding or permanently discontinuing ipilimumab, as well as by the administration of corticosteroids.  

Vismodegib for Advanced Basal Cell Carcinoma

Vismodegib is an oral drug that is designed to selectively inhibit abnormal signaling in the Hedgehog pathway, which is an underlying molecular driver of BCC. It binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

Vismodegib was reviewed under the US Food and Drug Administration (FDA) priority review program offering an expedited 6-month review. It was approved for use in advanced basal cell carcinoma (BCC) ahead of the prescription user fee goal date, which was March 8, 2012.

 

Clinical Implications

• The FDA has approved vismodegib for treatment of BCC that has metastasized or relapsed after treatment with surgery, or for treatment of BCC in patients who are not candidates for surgery or radiation.

• The recommended dose of vismodegib is one 150-mg capsule orally once daily, with or without food. If a dose is missed, it should not be made up but should be resumed with the next scheduled dose.

• Vismodegib is pregnancy category D and can cause fetal harm. Men as well as women should be advised concerning pregnancy prevention and planning. Breast-feeding mothers should discontinue either vismodegib or breast-feeding, depending on how important the drug is to the mother. The safety and efficacy of vismodegib have not been established in pediatric patients or in patients with hepatic or renal impairment. 

The most common adverse reactions (incidence of 10% or more) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia.

Therapy for Infantile Hemangiomas.

Propranolol vs Corticosteroids for Infantile Hemangiomas: A Multicenter Retrospective Analysis

Price CJ, Lattouf C, Baum B, et al. Arch Dermatol 2011;147:1371-6.

The patients were subdivided into 2 treatment groups: those receiving propranolol (n = 68; mean treatment duration, 7.9 months; target dose, 2 mg/kg/d) and those receiving oral corticosteroids (n = 42; mean treatment duration, 5.2 months; target dose, 4 mg/kg/d). To insure comparability, investigators matched these groups for patient age and lesion size, location, and type.
Outcome measures included percentage of IH clearance (< 75% or ≥ 75%), adverse effects, percentage of patients needing subsequent surgical referral, and average treatment cost per IH. Propranolol proved superior in all of these criteria:

1. 82% of patients treated with propranolol achieved ≥ 75% clearance vs 29% of patients treated with oral corticosteroids (P < .01).
2. 1 of 68 patients treated with propanolol had transient hypoglycemia, 2 patients (3%) had nonspecific skin eruptions, all patients completed treatment, and no patients suffered serious adverse events, whereas all patients treated with oral corticosteroids had adverse effects, including cushingoid features (100%), gastroesophageal reflux (n = 4), and hypertension (n = 2). One patient had a life-threatening bleed due to IH ulceration eroding into the external carotid artery.
3. 12% of patients treated with propranolol required surgery after therapy vs 29% of patients treated with oral corticosteroids.
4. The average cost per IH treated (excluding monitoring costs and prophylaxis/treatment of adverse effects) was $205.32 for propranolol vs $416.00 for oral corticosteroids

 Although "propranolol blows away corticosteroids" is the headline here, the investigators of this study also made several other important observations. For example, they found that:

1. Propranolol induced IH regression even when treatment was initiated after the first year of IH growth, confirming previous reports that the drug works to debulk more mature lesions beyond the proliferative phase.
2. Initial treatment with oral corticosteroids followed by oral propranolol showed a trend toward slightly improved efficacy over propranolol alone, although this benefit was not statistically significant.
3. IHs were less likely to relapse if propranolol therapy continued until at least 1 year of age.
4. The risk for propranolol-related side effects can be minimized with proper monitoring (eg, cardiac preclearance and checking for signs or symptoms of bradycardia, hypotension, and hypoglycemia).

Finally, Price and colleagues acknowledged that at least one more critical question remains: We still do not know how propranolol works to slow IH and induce regression. Does it trigger endothelial cell apoptosis, inhibit proangiogenic cytokines, or cause vasoconstriction by reducing nitric oxide levels? As researchers try to solve this complex puzzle, powerful new IH treatments will surely follow.